CN109678787A - A kind of new HCV virus NS3/4A inhibitor synthetic intermediate and synthetic method - Google Patents
A kind of new HCV virus NS3/4A inhibitor synthetic intermediate and synthetic method Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 27
- 241000700605 Viruses Species 0.000 title claims description 17
- 239000003112 inhibitor Substances 0.000 title claims description 17
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 20
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 13
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 12
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 9
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229910015900 BF3 Inorganic materials 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 229960001866 silicon dioxide Drugs 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- -1 dichloromethane Alkane Chemical class 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical group ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- 238000012544 monitoring process Methods 0.000 claims 1
- 238000005059 solid analysis Methods 0.000 claims 1
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 4
- BJGKVCKGUBYULR-UHFFFAOYSA-N 3-bromo-2-methylbenzoic acid Chemical compound CC1=C(Br)C=CC=C1C(O)=O BJGKVCKGUBYULR-UHFFFAOYSA-N 0.000 abstract description 3
- AMXFGLZWKBYNGE-UHFFFAOYSA-N 4-bromo-2,3-dihydro-1h-isoindole Chemical compound BrC1=CC=CC2=C1CNC2 AMXFGLZWKBYNGE-UHFFFAOYSA-N 0.000 abstract 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- HPAPGONEMPZXMM-CMWVUSIZSA-N vaniprevir Chemical compound O=C([C@H]1C[C@@H]2OC(=O)N3CC=4C=CC=C(C=4C3)CCCCC(C)(C)COC(=O)N[C@@H](C(N1C2)=O)C(C)(C)C)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C HPAPGONEMPZXMM-CMWVUSIZSA-N 0.000 description 4
- 229950000843 vaniprevir Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 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 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 208000020403 chronic hepatitis C virus infection Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物中间体的合成方法，属于药物合成领域。本发明以3‑溴‑2‑甲基‑苯甲酸为原料合成制备4‑溴异吲哚啉(盐酸盐)，不仅原料成本低，而且该制备工艺简单，合成收率高，具有工业化应用推广价值。同时，本发明通过进一步叔丁基氧羰基化，可以提高中间体原料的稳定性，减少合成过程中的原料投入量，进一步降低成本，提高合成收率。The invention relates to a method for synthesizing a pharmaceutical intermediate, and belongs to the field of pharmaceutical synthesis. The present invention uses 3-bromo-2-methyl-benzoic acid as a raw material to synthesize and prepare 4-bromoisoindoline (hydrochloride), not only the cost of raw materials is low, but also the preparation process is simple, the synthesis yield is high, and it has industrial application Promote value. Meanwhile, by further tert-butyloxycarbonylation in the present invention, the stability of the intermediate raw material can be improved, the input amount of the raw material in the synthesis process can be reduced, the cost can be further reduced, and the synthesis yield can be improved.
Description
Technical field
The present invention relates to a kind of new HCV virus NS3/4A inhibitor synthetic intermediates and synthetic method, belong to drug conjunction
At field.
Background technique
Vaniprevir is HCV virus NS3/4A inhibitor, and the big peptide ring of invertibity combination NS3/4A inhibits NS3/4A pairs
The decomposition of HCV precursor protein, thus the suppressing virus replication period.The drug is on September 26th, 2014 by Japanese Ministry of Health, Labour and Welfare
(MHLW) the anti-hepatitis drug of approval listing.The medicine is developed by Mo Shadong (MSD), is produced and sold.The drug is approved for
1 chronic hepatitis C infection of therapeutic gene type and viremia virusemia.
The structural formula of Vaniprevir is as follows:
The synthetic route of Vaniprevir is as follows:
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of new pharmaceutical intermediates, and are provided in this drug simultaneously
The synthetic method of mesosome, so as to solve the problems such as product yield is low, and cost of material is high in current pharmaceutical intermediate synthesis,
Basis is provided for the industrialized production of Vaniprevir.
In order to solve the above-mentioned technical problem, the invention disclosesAs pharmaceutical intermediate in HCV
The application of virus NS/4A inhibitor synthetic intermediate.
And further, invention additionally discloses describedIt is closed in HCV virus NS3/4A inhibitor
It is converted intoParticipate in the synthesis of HCV virus NS3/4A inhibitor.
The present invention further discloses a kind of synthetic method of pharmaceutical intermediate simultaneously, and this method synthetic route is as follows:
The synthetic method specifically: compound II is dissolved in organic solvent, 0 DEG C is cooled to, is gradually added sodium borohydride
After stirring is stablized, boron trifluoride ether 2.0eq is added dropwise, then be warming up to 70 DEG C, back flow reaction 8 hours, TLC was monitored to anti-in 2.5eq
It should be complete.Be cooled to 0 DEG C, methanol quenching reaction be added dropwise, hydrochloric acid is then added dropwise, after adjusting pH to 3-4,70 DEG C back flow reaction 8 hours.
It is cooled to room temperature, filters, mother liquor concentrations obtain the hydrochloride of compound I；
Then, sodium hydrate aqueous solution is added into the HCI solution of compound I, shakes up, and organic solvent extraction is added
It takes, obtains compound I.
Preferably, the compound II is dissolved in tetrahydrofuran solvent.
As a kind of perferred technical scheme, it adopts and is extracted with dichloromethane.
Further, the synthetic method of the compound II is also disclosed in the present invention, and synthetic route is as follows:
The synthetic method specifically: compound III is added in methanolic ammonia solution, is stirred overnight.It is solid to there is no whites
Body is precipitated, and filtering obtains white solid, i.e. compound II.
Preferably, the concentration of the ammonia methanol is 10M.
Further, the synthetic method of the compound III is also disclosed in the present invention, and synthetic route is as follows:
The synthetic method specifically: CCl is first added in reaction flask4, compound IV is then added, compound is added later
The AIBN of IV mass fraction 2%, is gradually added NBS 1.1eq, under nitrogen protection, is warming up to 85 DEG C of back flow reactions 10 hours.TLC
Detect raw material fully reacting.Reaction solution is cooled to room temperature, and is poured into sodium thiosulfate solution, and organic phase is separated, and water phase is used
MTBE extraction, divides and takes MTBE organic phase, after then organic phase is merged, washed 3 times with sodium thiosulfate solution respectively, is saturated
Sodium-chloride water solution washs 2 times, and anhydrous sodium sulfate is dry, concentration.Residue is isolated and purified by the way of column chromatography, is eluted
It is evaporated under reduced pressure to after crude product, then by crude product, 2Torr, 168 DEG C of outer temperature, 120 DEG C of interior temperature.Obtain colourless liquid compound III.
Wherein column purification uses the silica gel of 100-200 mesh for filler, and eluant, eluent PE:EA=40:1-20:1 obtains crude product.
Further, the synthetic method of the compounds Ⅳ is also disclosed in the present invention, and synthetic route is as follows:
The synthetic method specifically: compound V is added in methanol (MeOH) solution first, the concentrated sulfuric acid is then added dropwise,
Back flow reaction is stayed overnight, and TLC is monitored to fully reacting, after reduced pressure, adds water, is extracted with ethyl acrylate (EA), point is taken organic
Phase is washed, dry, and concentration obtains compound IV.
Wherein preferred, washing includes once washing and secondary washing, and wherein once washing uses saturated sodium carbonate solution
Washing, secondary washing are washed using saturated sodium chloride solution.
It is further preferred that each substance adding proportion is in the synthesis, and when the additional amount of compound V is 150g, methanol
The additive amount of solution is 2L, and the additive amount of the corresponding concentrated sulfuric acid is 10mL.
Disclosed in this invention using the bromo- 2- methyl-benzoic acid of 3- as Material synthesis prepare 4- bromine isoindoline hydrochloride
Preparation route it is as follows:
Further preferred, it further comprises the steps of:
Specifically, which includes These steps.
And it is further preferred the following steps are included:
(1) compound V being added in methanol (MeOH) solution first, the concentrated sulfuric acid is then added dropwise, back flow reaction is overnight,
TLC is monitored to fully reacting, after reduced pressure, adds water, is extracted with ethyl acrylate (EA), is divided and is taken organic phase, is washed, dry,
Concentration, obtains compound IV；
(2) CCl is added in reaction flask4, compound IV is added, the AIBN of compound IV mass fraction 2% is added, gradually
NBS 1.1eq is added, under nitrogen protection, is warming up to 85 DEG C of back flow reactions 10 hours.TLC detects raw material fully reacting.Reaction solution
It is cooled to room temperature, pours into sodium thiosulfate solution, separate organic phase, water phase is extracted with MTBE, and organic phase is used thio respectively
Aqueous sodium persulfate solution washs 3 times, and saturated sodium-chloride water solution washs 2 times, and anhydrous sodium sulfate is dry, concentration.Residue uses column
The mode of chromatography isolates and purifies, and wherein chromatographic column is 100-200 mesh silica filler column, and eluant, eluent PE:EA=40:1-20:1 is obtained
Crude product, then crude product is evaporated under reduced pressure, 2Torr, 168 DEG C of outer temperature, 120 DEG C of interior temperature；Obtain colourless liquid compound III.
(3) compound III is added in excessive methanolic ammonia solution, is stirred overnight.To there is no white solid precipitation, mistakes
Filter, obtains white solid, i.e. compound II；
(4) compound II is dissolved in organic solvent, is cooled to 0 DEG C, sodium borohydride 2.5eq is added in four batches, stirring is steady
After fixed, boron trifluoride ether 2.0eq is added dropwise, then be warming up to 70 DEG C, back flow reaction 8 hours, TLC was monitored to fully reacting.Cooling
To 0 DEG C, methanol quenching reaction is added dropwise, is then added dropwise hydrochloric acid, after adjusting pH to 3-4,70 DEG C back flow reaction 8 hours.It is cooled to room temperature,
Filtering, mother liquor concentrations obtain the hydrochloride of compound I；
(5) compound I is continued to be dissociated with sodium hydroxide, and be extracted with dichloromethane, Boc2O is added dropwise, reaction overnight, adds
Water separates methylene chloride, and saturated sodium-chloride washs 2 times, and anhydrous sodium sulfate is dry, and concentration crosses column purification, obtains off-white powder
45g。
Column purification uses the silica gel of 100-200 mesh for filler in step (5), eluant, eluent PE (petroleum ether): EA (acetic acid second
Ester)=40:1-20:1, obtain crude product.
The present invention prepares 4- bromine isoindoline (hydrochloride) by Material synthesis of the bromo- 2- methyl-benzoic acid of 3-, not only raw material
It is at low cost, and the preparation process is simple, and synthesis yield is high, has industrial applications promotional value.
4- bromine isoindoline (hydrochloride) is further carried out tertiary butyl oxycarbonyl modification by the present invention simultaneously, in application
Modification base is sloughed, reaction is added, can be further improved the purity and utilization rate of raw material, reduces raw material investment.
Specific embodiment
In order to better understand the present invention, we in conjunction with specific embodiments further explain the present invention below
It states.
In the present invention unless there are special declaration, otherwise reagent is commercially available.
PE is petroleum ether in the present invention, and EA is ethyl acetate.
Embodiment 1
2L MeOH is added in 5L reaction flask, raw material 150g is added, concentrated sulfuric acid 10mL is added dropwise, back flow reaction is overnight, TLC
Fully reacting is detected, is concentrated under reduced pressure, adds water, is extracted 2 times with EA, organic phase is merged, saturated sodium carbonate washes 2 times, saturated sodium-chloride
It washes 2 times, anhydrous sodium sulfate is dry, and concentration obtains crude product 120g, is directly thrown into the preparation process of embodiment 2.
Embodiment 2
CCl is added in 5L reaction flask4Compound IV 120g is added in 1.5L, and 2g AIBN is added, NBS is added portionwise
1.1eq under nitrogen protection, is warming up to 85 DEG C of back flow reactions and stays overnight.TLC detects raw material fully reacting.Reaction solution is cooled to room temperature,
It pours into sodium thiosulfate solution, separates organic phase, water phase is extracted with MTBE, and organic phase uses sodium thiosulfate solution respectively
Washing 3 times, saturated sodium-chloride water solution wash 2 times, and anhydrous sodium sulfate is dry, concentration.Residue column chromatographic isolation and purification, elution
Agent PE (petroleum ether): EA (ethyl acetate)=40:1-20:1 obtains crude product, then crude product is evaporated under reduced pressure, 2Torr, 168 DEG C of outer temperature,
120 DEG C of interior temperature.Obtain colourless liquid compound III 110g.
Embodiment 3
The compound III that embodiment 2 obtains is added in the methanolic ammonia solution of freshly prepd 10M, is stirred overnight.To nothing
When white solid is precipitated, filtering drains, obtains off-white color product 60g,1H NMR(400MHz,DMSO)δ8.85(s,1H),7.84
(d, J=7.8Hz, 1H), 7.73 (d, J=7.4Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 4.34 (s, 2H)
Nuclear-magnetism identifies such white products, confirms as compound ii.
Embodiment 4
The compound ii obtained in embodiment 3 is dissolved in 2L THF, 0 DEG C is cooled to, sodium borohydride is added in four batches
After stirring is stablized, boron trifluoride ether 2.0eq is added dropwise, then be warming up to 70 DEG C of back flow reactions 8 hours in 2.5eq, TLC tracking.Cooling
To 0 DEG C, methanol quenching reaction is added dropwise, then 6M hydrochloric acid is added dropwise, adjusts pH to 3-4, then be warming up to 70 DEG C of back flow reactions 8 hours.It is cooling
To room temperature, filtering, mother liquor concentrations obtain product hydrochloride.
Sodium hydroxide solution is added into the solution containing compound I, and is extracted with dichloromethane, Boc is added dropwise2O, reaction
Overnight, add water, separate methylene chloride, saturated sodium-chloride washs 2 times, and anhydrous sodium sulfate is dry, concentration, residue column chromatography for separation
Purifying, using the silicagel column of 100-200 mesh, eluant, eluent uses PE (petroleum ether): EA (ethyl acetate)=40:1-20:1 is obtained
Off-white powder 45g.1H NMR (400MHz, DMSO-d6) δ ppm 7.51-7.46 (dd, J=7.8,0.6Hz, 1H), 7.38-
730 (m, 1H), 7.29-7.21 (m, 1H), 4.73-4.63 (d, 2H), 4.56-4.47 (d, 2H), 1.50-1.42 (d, 9H)
Embodiment 5
It prepares in accordance with the following steps:
(1) 2L MeOH is added in 5L reaction flask, raw material 150g is added, concentrated sulfuric acid 10mL is added dropwise, back flow reaction is overnight,
TLC detects fully reacting, is concentrated under reduced pressure, adds water, is extracted 2 times with EA, merges organic phase, and saturated sodium carbonate is washed 2 times, is saturated chlorination
Sodium is washed 2 times, and anhydrous sodium sulfate is dry, and concentration obtains compound IV crude product 120g；
(2) CCl is added in 5L reaction flask4Compound IV 120g is added in 1.5L, 2g AIBN is added, gradually NBS
1.1eq under nitrogen protection, is warming up to 85 DEG C of back flow reactions and stays overnight.TLC detects raw material fully reacting.Reaction solution is cooled to room temperature,
It pours into sodium thiosulfate solution, separates organic phase, water phase is extracted with MTBE, and organic phase uses sodium thiosulfate solution respectively
Washing 3 times, saturated sodium-chloride water solution wash 2 times, and anhydrous sodium sulfate is dry, concentration.Residue is divided by the way of column chromatography
From purifying, using the silica filler column of 100-200 mesh as chromatographic column, using PE:EA=40:1-20:1 as eluant, eluent, then will be thick
Product vacuum distillation, 2Torr, 168 DEG C of outer temperature, 120 DEG C of interior temperature.Obtain colourless liquid compound III 110g；
(3) compound III 110g is added in methanolic ammonia solution, is stirred overnight.To there is no white solid precipitation, mistakes
Filter, obtains white solid, i.e. compound II 60g；
(4) compound II 60g is dissolved in organic solvent, is cooled to 0 DEG C, be gradually added sodium borohydride 2.5eq, stirred
After stabilization, boron trifluoride ether 2.0eq is added dropwise, then be warming up to 70 DEG C, back flow reaction 8 hours, TLC was monitored to fully reacting.Drop
Temperature is added dropwise methanol quenching reaction, is then added dropwise hydrochloric acid to 0 DEG C, after adjusting pH to 3-4,70 DEG C back flow reaction 8 hours.It is cooled to room
Temperature, filtering, mother liquor concentrations obtain compound I；
Continue that sodium hydroxide is added into the solution containing compound I, be then extracted with dichloromethane, Boc2O is added dropwise, instead
It answers 8 hours, adds water, separate methylene chloride, saturated sodium-chloride washs 2 times, and anhydrous sodium sulfate is dry, and concentration, residue uses column
The mode of chromatography isolates and purifies, and using the silica filler column of 100-200 mesh as chromatographic column, is used as and is washed using PE:EA=40:1-20:1
De- agent, obtains off-white powder 45g, purity 97%.1H NMR (400MHz, DMSO-d6) δ ppm 7.51-7.46 (dd, J=
7.8,0.6Hz, 1H), 7.38-730 (m, 1H), 7.29-7.21 (m, 1H), 4.73-4.63 (d, 2H), 4.56-4.47 (d, 2H),
1.50-1.42(d,9H)。
Embodiment 6
Respectively investigate the present invention be prepared compound I withStability.
The results show thatWith higher stability.
The foregoing is a specific embodiment of the present invention.It should be pointed out that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as
Protection scope of the present invention.
Claims (10)
1.A kind of application as HCV virus NS3/4A inhibitor synthetic intermediate.
2. application according to claim 1, it is characterised in that: describedIt is converted intoParticipate in the synthesis of HCV virus NS3/4A inhibitor.
3. a kind of synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate, which is characterized in that this method synthetic route is such as
Under:
4. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 3, which is characterized in that
The synthetic method specifically: compound II is dissolved in organic solvent, is cooled to 0 DEG C, sodium borohydride 2.5eq is gradually added, stirs
It mixes after stablizing, boron trifluoride ether 2.0eq is added dropwise, then be warming up to 70 DEG C, back flow reaction to fully reacting；It is cooled to 0 DEG C, is added dropwise
Then 6M hydrochloric acid is added dropwise in methanol quenching reaction, after adjusting pH to 3-4,70 DEG C of back flow reactions；It is cooled to room temperature, filters, mother liquor is dense
Contracting, obtains the hydrochloride of compound I；
It is further preferred that sodium hydrate aqueous solution is added into the HCI solution of compound I, shake up, and is added organic molten
Agent extraction, obtains compound I；
Preferably, the compound II is dissolved in tetrahydrofuran solvent；
As a kind of perferred technical scheme, it adopts and is extracted with dichloromethane；
As a preferred technical solution, by TLC technical monitoring whether fully reacting；
Preferably, adjust pH to 3-4 after, 70 DEG C back flow reaction 8 hours.
5. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 3, it is characterised in that:
The synthetic method of the compound II, synthetic route are as follows:
6. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 5, which is characterized in that
The synthetic method specifically: compound III is added in excess of ammonia methanol solution, is stirred；To there is no white solid analysis
Out, it filters, obtains white solid, i.e. compound II；
Preferably, the concentration of the ammonia methanol is 10M.
7. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 5, which is characterized in that
The synthetic method of the compound III, synthetic route are as follows:
8. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 7, it is characterised in that:
The synthetic method specifically: be firstly added reaction dissolvent in reaction flask, compound IV is then added, compound IV is added later
The azodiisobutyronitrile (AIBN) of mass fraction 2% is gradually added N-bromosuccinimide (NBS) 1.1eq, nitrogen protection
Under, 85 DEG C of back flow reactions are warming up to fully reacting；Reaction solution is cooled to room temperature, and is poured into sodium thiosulfate solution, is separated
Organic phase, water phase are extracted with methyl tertiary butyl ether(MTBE) (MTBE), separate methyl tertiary butyl ether(MTBE) phase, after merging with organic phase, use respectively
Sodium thiosulfate solution and saturated sodium-chloride water solution washing, then dry with anhydrous sodium sulfate, concentration obtains colourless liquid
Close object III；
It is further preferred that further include purification step after concentration, specifically: it is purified by the way of first being chromatographed using column, then by crude product
Vacuum distillation, 2Torr, 168 DEG C of outer temperature, 120 DEG C of interior temperature；
Preferably, the reaction dissolvent is CCl4；
It is further preferred that detecting whether fully reacting by TLC；
Preferably, it is washed 3 times using sodium thiosulfate solution, is washed 2 times with saturated sodium-chloride water solution；
It is further preferred that column chromatographic purifying is to be eluted with the silicagel column of 100-200 mesh using PE:EA=40:1-20:1.
9. the synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate according to claim 6, it is characterised in that:
The synthetic method of the compounds Ⅳ, synthetic route are as follows:
And it may further be preferable that the synthetic method specifically: compound V is added in methanol (MeOH) solution first,
Then the concentrated sulfuric acid is added dropwise, back flow reaction is complete, after reduced pressure, adds water, is extracted with ethyl acrylate (EA), and divide and takes organic phase,
Washing, dry, concentration obtains compound IV；
Wherein preferred, washing includes once washing and secondary washing, and wherein once washing is washed using saturated sodium carbonate solution,
Secondary washing is washed using saturated sodium chloride solution；
It is further preferred that each substance adding proportion is in the synthesis, and when the additional amount of compound V is 150g, methanol solution
Additive amount be 2L, the additive amount of the corresponding concentrated sulfuric acid is 10mL；
Preferably, fully reacting is detected whether by TLC.
10. a kind of synthetic method of HCV virus NS3/4A inhibitor synthetic intermediate, which is characterized in that preparation route is as follows:
Further preferred, it further comprises the steps of:
And it may further be preferable that the preparation method the following steps are included:
(1) compound V is added in methanol (MeOH) solution first, the concentrated sulfuric acid is then added dropwise, back flow reaction is overnight, TLC prison
It surveys to fully reacting, after reduced pressure, adds water, extracted with ethyl acrylate (EA), divide and take organic phase, wash, dry, concentration,
Obtain compound IV；
(2) CCl is added in reaction flask4, compound IV is added, the AIBN of compound IV2% (mass fraction) is added later, point
Four crowdes of addition NBS 1.1eq under nitrogen protection, are warming up to 85 DEG C of back flow reactions 10 hours.TLC detects raw material fully reacting.Instead
It answers liquid to be cooled to room temperature, pours into sodium thiosulfate solution, separate organic phase, water phase is extracted with MTBE, and organic phase is used respectively
Sodium thiosulfate solution washs 3 times, and saturated sodium-chloride water solution washs 2 times, and anhydrous sodium sulfate is dry, concentration.First use column
Chromatographic purifying, then crude product is evaporated under reduced pressure, 2Torr, 168 DEG C of outer temperature, 120 DEG C of interior temperature；Obtain colourless liquid compound III.
(3) compound III is added in methanolic ammonia solution, is stirred；To there is no white solid precipitation, it is solid to obtain white for filtering
Body, i.e. compound II；
(4) compound II is dissolved in organic solvent, is cooled to 0 DEG C, be gradually added sodium borohydride 2.5eq, after stirring is stablized, drop
Add boron trifluoride ether 2.0eq, then be warming up to 70 DEG C, back flow reaction 8 hours, TLC was monitored to fully reacting；It is cooled to 0 DEG C, drop
Add methanol quenching reaction, be then added dropwise hydrochloric acid, after adjusting pH to 3-4,70 DEG C back flow reaction 8 hours；But to room temperature, filtering, mother liquor
Concentration, obtains the hydrochloride of compound I；
(5) sodium hydroxide solution is added in the hydrochloride of Xiang Hanyou compound I, is then extracted with dichloromethane, divide and take dichloromethane
Alkane phase, and Boc is added dropwise2O adds water, separates methylene chloride phase, after being washed with saturated sodium-chloride, anhydrous sodium sulfate after standing reaction
It is dry, it is concentrated, purifying obtains compoundPreferably, the purifying is column chromatographic purifying side
Formula；
It is further preferred that column chromatographic purifying is to be eluted with the silicagel column of 100-200 mesh using PE:EA=40:1-20:1.
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