CN105111209B - Aza-indoline compound and method for preparing same - Google Patents
Aza-indoline compound and method for preparing same Download PDFInfo
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- CN105111209B CN105111209B CN201510627125.1A CN201510627125A CN105111209B CN 105111209 B CN105111209 B CN 105111209B CN 201510627125 A CN201510627125 A CN 201510627125A CN 105111209 B CN105111209 B CN 105111209B
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- azaindole
- indoline compound
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- -1 Aza-indoline compound Chemical class 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title abstract description 7
- BYRJSCNPUHYZQE-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC=C(C(F)(F)F)C=N1 BYRJSCNPUHYZQE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 41
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 4
- 238000005679 Batcho-Leimgruber synthesis reaction Methods 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000006396 nitration reaction Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 239000002994 raw material Substances 0.000 abstract description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 14
- 208000006673 asthma Diseases 0.000 abstract description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 6
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 abstract 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 201000005702 Pertussis Diseases 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 241000736199 Paeonia Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- HYXDULZRFHVIDQ-UHFFFAOYSA-N ethyl acetate;methane Chemical compound C.CCOC(C)=O HYXDULZRFHVIDQ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to an aza-indoline compound and a method for preparing the same. The aza-indoline compound is 6-trifluoromethyl-2, 3-pyrroline [2, 3-b] pyridine, and 2-hydroxyl-5-trifluoromethyl pyridine is synthesized by means of 9-step reaction to obtain the aza-indoline compound. The aza-indoline compound and the method have the advantages that the aza-indoline compound is a novel phosphodiesterase inhibitor and has a broad application prospect in the aspect of diseases such as asthma; raw materials for the aza-indoline compound prepared by the aid of the method are inexpensive and are easily available, the method for synthesizing the raw materials is simple and is a novel method for synthesizing the raw materials to obtain the aza-indoline compound, and requirements of large-scale industrial production can be met.
Description
Technical field
The present invention relates to production of chemicals field, especially a kind of azaindole quinoline compound and preparation method thereof.
Background technology
Azaindole quinoline compound is the intermediate (preparation of the key preparing phosphodiesterase (pde) inhibitor
of azaindolines and benzoyl substituted azaindolines:precursors of
triazabenzo[cd]azulen-9-one pde4inhibitors.tetrahedron letters(2011),52(41),
5292-5296).Azaindole quinoline compound is widely present in the drug molecule with biologically active, exists in treatment and prepayment
Heart failure, asthma, it is with a wide range of applications in the disease such as impotence.Make parent can carry out further synthesizing more of this compound
Complicated derivative, provides condition for broadly studying such compound property.
Content of the invention
The technical problem to be solved is to provide a kind of azaindole quinoline compound.
Another technical problem to be solved by this invention is to provide the preparation method of above-mentioned azaindole quinoline compound.
For solving above-mentioned technical problem, the technical scheme is that
A kind of azaindole quinoline compound, 6- trifluoromethyl -2,3- pyrrolin [2,3-b] pyridine, its structural formula is ()
It is shown,
Preferably, above-mentioned azaindole quinoline compound, 6- trifluoromethyl -2, the nuclear-magnetism of 3- pyrrolin [2,3-b] pyridine
Resonance hydrogen modal data be 3.216-3.173 (t, 2h), 3.742-3.699 (t, 2h), 6.888-6.884 (d, 1h), 8.080 (s,
1h).
The preparation method of above-mentioned azaindole quinoline compound, with 2- hydroxyl -5- trifluoromethyl pyridine as initiation material, passes through
9 steps are synthesized target compound, specifically comprise the following steps that
(1) nitration is carried out to compound 12- hydroxyl -5- trifluoromethyl pyridine and obtain compound 2；
(2) compound 2 chloro of phenolic hydroxyl group under POCl3 effect obtains compound 3；
(3) compound 3 dimethyl malenate under sodium hydride effect replaces chlorine and obtains compound 4；
(4) compound 4 dimethyl malenate substituted compound decarboxylation under acidity obtains compound 5；
(5) compound 5 carries out leimgruber-batcho synthetic method, and the first step synthesizes compound 6；
(6) compound 6 passes through leimgruber-batcho synthetic method, and second step reduction nitro synthesis of indole obtains chemical combination
Thing 7；
(7) on compound 7 azaindole, boc carries out separating-purifying and obtains compound 8；
(8) compound 8 passes through pd (oh)2Reduction, generates compound 9 azaindole quinoline；
(9) compound 9 by tfa except boc group obtains target compound 10；Wherein,
Intermediate compound 6 in the preparation method of above-mentioned azaindole quinoline compound, its structural formula is shown in (),
Intermediate compound 7 in the preparation method of above-mentioned azaindole quinoline compound, its structural formula is shown in (),
Intermediate compound 8 in the preparation method of above-mentioned azaindole quinoline compound, its structural formula is shown in (),
Intermediate compound 9 in the preparation method of above-mentioned azaindole quinoline compound, its structural formula is shown in (),
The concrete reaction equation of the preparation method of above-mentioned azaindole quinoline compound is as follows:
The invention has the beneficial effects as follows:
Above-mentioned azaindole quinoline compound 6- trifluoromethyl -2,3- pyrrolin [2,3-b] pyridine is a kind of new phosphorus
Acid diesters enzyme inhibitor, is with a wide range of applications in the diseases such as asthma；Its preparation method raw material is cheap and easily-available, synthesis side
Method is simple, is a kind of completely new approach of synthesis azepine sulfonylindoline compounds, the needs of suitable scale industrial production.
Brief description
Fig. 1 is 6- trifluoromethyl -2, the hnmr spectrogram of 3- pyrrolin [2,3-b] pyridine.
Specific embodiment
In order that those skilled in the art is better understood from technical scheme, with reference to specific embodiment
Technical scheme of the present invention is described in further detail.
Embodiment 1
6- trifluoromethyl -2, the preparation method of 3- pyrrolin [2,3-b] pyridine, specifically comprise the following steps that
(1) 100g compound 1 is dissolved in the 400ml concentrated sulfuric acid and adding in 2l there-necked flask, be heated to interior temperature and rise to 80 degree；Will
110g red fuming nitric acid (RFNA) dropping funel slowly drops to reaction system, and system starts to warm up, and now from heating bath, reaction bulb is gone to sky
Gas bath, controls rate of addition, makes to keep internal temperature at that in the range of 80-85 degree, (temperature is high, and yield can reduce, and can use cold bath
Suitably temperature control), drip off (40-60 minute) within about 50 minutes, then (40-60 minute was equal in 50 minutes for oil bath insulation reaction
Can)；The most of raw material reaction of tlc display is complete, stops heating, is quickly down to room temperature, and reactant liquor is poured on 1000g trash ice muddy
Turbid liquid, then uses ethyl acetate (ea) to extract (500ml*2), organic phase is washed one time with saturated salt again, and drying is concentrated to give crude product,
This crude product is added in dichloromethane (dcm) (80ml), stirs 5min, dissolving unreacted raw material on a small quantity, filter, filter cake is first used
A small amount of dcm washes, then with ea and petroleum ether, filtration cakes torrefaction, obtains compound 2, is faint yellow solid.Tlc information: ultraviolet shows
Color, raw material rf=0.5, product rf=0.1.Solvent: ea/1-2 drips ammoniacal liquor or dcm/meoh=10/1 adds 1-2 again and drips ammoniacal liquor.
Record 35 grams of product, faint yellow solid, yield 28%.
(2) 52g compound 2 is added in 150ml POCl3, under stirring, be slowly added into 21g quinoline, control charging speed
Degree, makes interior temperature be less than 50 degree, compound 2 slowly dissolves simultaneously, and argon gas protects system, oil bath heating, and outer temperature sets 120 degree,
After 20-30 minute, system starts to flow back, and keeps system micro-boiling to react 1.5 hours.Tlc display raw material reaction finishes, and stops heating,
By system reduced pressure concentration, remove POCl3, then use ea (400ml) to dissolve, wash removing quinoline with 2n hcl (200ml*2)
Quinoline, then it is washed till neutrality with saturated sodium bicarbonate solution, organic phase drying is concentrated to give compound 3.Tlc information: raw material rf=0.1,
Product rf=0.7.Solvent: pe/ea/=15/1.Record 50 grams of product, brown oil, yield 88%.
(3) 50g compound 3 and 52.5g dimethyl malenate are dissolved in 500ml anhydrous tetrahydro furan, argon gas is protected, body
System's dry ice ethanol is cooled to -10 to -20 degree, is dividedly in some parts 15.9g sodium hydride, controls interior temperature at 0 degree about simultaneously.After finishing
Naturally it is warmed to room temperature, continue reaction overnight 16 hours.Tlc display raw material reaction finishes, and reactant liquor is poured into saturated ammonium chloride molten
Reaction is quenched in liquid (500ml), is then extracted with ethyl acetate (500ml*2), merge organic phase, washing once, is dried, is spin-dried for
Solvent obtains compound 4 (crude product).Tlc information: raw material rf=0.7, product rf=0.15.Solvent: pe/ea/=15/1.Survey
Obtain 97 grams of crude products, red oil.
(4) 97g compound 4 is added in the 10000ml4n hydrochloric acid of 10 times of volumes, oil bath temperature control 120-125 degree, it is heated to
Back flow reaction is overnight (16 hours, reaction is very slowly it is necessary to overnight could react).Tlc shows and finishes, system is down to room temperature, so
Afterwards reactant liquor is poured in 1000ml cold water, extract (500ml*3) with ea, organic phase merges, in being washed till with saturated sodium bicarbonate
Property or alkalescence (400ml*2), organic phase be dried, be spin-dried for solvent and obtain red oil.This grease is proceeded to quiet in 50ml test tube
Put, layering, the colourless transparent liquid on upper strata is separated (mineral oil in upper step sodium hydride), the red liquid of lower floor is product
Compound 5.Tlc information: raw material rf=0.3, product rf=0.7.Solvent: petrol ether/ethyl acetate (pe/ea)=5/1.Survey
Obtain 35 grams of product, red oil, yield 77%.
(5) 30g compound 5 is added in 180ml Dimethylformamide dimethyl acetal (dmfdma), 110 degree of oil bath temperature control,
It is heated to back flow reaction 1 hour, condenser pipe adds water but do not circulate, make the methyl alcohol of generation quick by the drying tube of condenser pipe upper end
Volatilization removes.Tlc shows and finishes, and reduced pressure concentration removes solvent, obtains compound 6, is red oil, becomes red solid after cooling
Body.Tlc information: raw material rf=0.7, product rf=0.5；Solvent: pe/ea/=5/1.Record 38 grams of product, Red oil
Thing, crude product.
(6) 65g iron powder is added in 2 liters of there-necked flask, add in 2n hydrochloric acid, 100 degree of oil bath temperature control, 15 points of backflow activation
Clock.Add acetic acid 40ml and ethanol (150ml), 95 degree of oil bath temperature control, continue backflow 30 minutes.Compound 6 is dividedly in some parts instead
Answer in system, control charging rate, about 40-60 minute adds, continue 1 hour of back flow reaction.Tlc shows and finishes, and adds
Ethyl acetate (400ml), continues backflow 10 minutes, is filtered with diatomite while hot, filter cake hot ethanol and ethyl acetate are washed twice,
Filtrate is peony, concentrates and removes solvent, and residue is diluted with water (200ml) and ethyl acetate (300ml), then the hydrogen with 2-3n
Sodium hydroxide solution adjusts ph=8-9 (by the acetate separate out of product), is filtered to remove the molysite such as iron hydroxide again, and chlorine cake is used
Hot ethyl acetate washs, and filtrate layered separates organic phase, aqueous phase is extracted with ethyl acetate once again, merges organic phase, is dried,
Reduced pressure concentration removes solvent, obtains compound 7.Tlc information: ultraviolet colour developing, raw material rf=0.5, product rf=0.2.Solvent:
Pe/ea/=5/1.Record 17.8 grams of product, brown solid, yield: 66% (two steps).
(7) 9g compound 7 is dissolved in 100ml dichloromethane, adds 13.7g boc acid anhydrides and 6.4g triethylamine, room
Temperature is stirred overnight (16h).Tlc display reaction completely, is directly added into silica gel mixed sample after cooling, cross pillar purifying (pe/ea) and must change
Compound 8.Tlc information: ultraviolet colour developing, raw material rf=0.2, product rf=0.6.Solvent: pe/ea/=3/1.Record product 8.5
Gram, white solid, yield 62%.
(8) 4g compound 8 is dissolved in 100ml ethanol, adds 1g palladium dydroxide, autoclave hydrogen exchange 5 times, so
After be warming up to 50 degree, react overnight under 1 MPa of Hydrogen Vapor Pressure.Tlc and lcms shows reaction completely, reactant liquor diatomite mistake
Filter, filtrate concentrates and then too short pillar purifies (pe/ea) and obtains clean product Compound 9.Tlc information: raw material rf=0.60, product
Rf=0.55.Solvent: pe/ea/=3/1.Record 4.3 grams of product, yellow oil, yield 100%.
(9) 4.3g compound 9 is dissolved in 25ml dichloromethane, under argon gas protection, slowly drips 10ml trifluoroacetic acid,
Finish rear room temperature reaction 3.5 hours.Tlc display reaction completely, concentrates below 40 degree of reactant liquor and removes solvent, then use anhydrous dichloro
Twice (50ml*2), the molten saturated sodium bicarbonate solution of residue is adjusted to alkaline ph=8, then be extracted with ethyl acetate methane band
(50ml*2), organic phase merges, washing, is dried, 40 degree obtain compound 10, as target product with drop-down dry solvent.Tlc believes
Breath: raw material rf=0.55, product rf=0.3.Solvent: pe/ea/=3/1.Record 2.3 grams of product, yellow solid powder is pure
Degree is more than 96%, yield 82%.As shown in figure 1,6- trifluoromethyl -2, the hnmr (cdcl of 3- pyrrolin [2,3-b] pyridine3)
Spectrogram, its hydrogen modal data is: 3.216-3.173 (t, 2h), 3.742-3.699 (t, 2h), 6.888-6.884 (d, 1h), 8.080
(s,1h).
Above-mentioned concrete reaction equation is as follows:
Application test example
Male sd rat, monthly age 4-6 week, body weight 130-160g, it is randomly divided into two big groups (30/big group), often big group again
It is randomly divided into 3 groups (10/group).
First group-asthma group, in every rat abdominal cavity, (100mg containing egg protein inactivates pertussis bar to injections of antigens liquid 1ml
Bacteria vaccine 5*109Individual and aluminium hydroxide dry powder 100mg) sensitization；
Second group-treating asthma group, every rat carries out stomach by 1.2 μ g/kg embodiment 1 gained azaindole quinoline compound
Raise, every 12 hours 1 time, after three days, in every rat abdominal cavity, (100mg containing egg protein inactivates pertussis bar to injections of antigens liquid 1ml
Bacteria vaccine 5*109Individual and aluminium hydroxide dry powder 100mg) sensitization.
Result shows, immediately shows as breathing shortness of breath, four limbs are weak and limp, drumble after first group-asthma group antigen stimulation
Or it is motionless to lie prostrate, and second group-treating asthma group no significant reaction.Show that compound of the present invention has certain suppression to asthma
Make and use.
Above-mentioned retouch in detail to what this kind of azaindole quinoline compound and preparation method thereof was carried out with reference to specific embodiment
State, be illustrative rather than determinate, several embodiments can be included according to limited scope, therefore without departing from this
Changing and modifications under invention general plotting, should belong within protection scope of the present invention.
Claims (1)
1. a kind of preparation method of azaindole quinoline compound, the structural formula of described azaindole quinoline compound is shown in (),
It is characterized in that: with 2- hydroxyl -5- trifluoromethyl pyridine as initiation material, target compound is synthesized by 9 steps, tool
Body step is as follows:
(1) nitration is carried out to compound 1 2- hydroxyl -5- trifluoromethyl pyridine and obtain compound 2；
(2) compound 2 chloro of phenolic hydroxyl group under POCl3 effect obtains compound 3；
(3) compound 3 dimethyl malenate under sodium hydride effect replaces chlorine and obtains compound 4；
(4) compound 4 dimethyl malenate substituted compound decarboxylation under acidity obtains compound 5；
(5) compound 5 carries out leimgruber-batcho synthetic method, and the first step synthesizes compound 6；
(6) compound 6 passes through leimgruber-batcho synthetic method, and second step reduction nitro synthesis of indole obtains compound 7；
(7) on compound 7 azaindole, boc carries out separating-purifying and obtains compound 8；
(8) compound 8 passes through pd (oh)2Reduction, generates compound 9 azaindole quinoline；
(9) compound 9 by tfa except boc group obtains target compound 10；Wherein,
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997045408A1 (en) * | 1996-05-24 | 1997-12-04 | Zeneca Limited | Herbicidal indolines |
| CN103992319A (en) * | 2014-05-27 | 2014-08-20 | 天津市斯芬克司药物研发有限公司 | Pyridine carboxylic acid compounds and preparation method thereof |
| CN104098564A (en) * | 2014-07-30 | 2014-10-15 | 天津市斯芬克司药物研发有限公司 | Pyrazol pyridine compound and preparation method thereof |
-
2015
- 2015-09-28 CN CN201510627125.1A patent/CN105111209B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997045408A1 (en) * | 1996-05-24 | 1997-12-04 | Zeneca Limited | Herbicidal indolines |
| CN103992319A (en) * | 2014-05-27 | 2014-08-20 | 天津市斯芬克司药物研发有限公司 | Pyridine carboxylic acid compounds and preparation method thereof |
| CN104098564A (en) * | 2014-07-30 | 2014-10-15 | 天津市斯芬克司药物研发有限公司 | Pyrazol pyridine compound and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| "Microwave-Assisted Synthesis of Novel (5-Nitropyridin-2-yl)alkyl and (5-Nitropyridin-3-yl)alkyl Carbamates";Christophe Henry et al.;《J. Org. Chem》;20090128;第74卷(第5期);第1932-1938页 * |
| "Preparation of azaindolines and benzoyl substituted azaindolines：precursors of triazabenzo[cd]azulen-9-one PDE4 inhibitors";Matthew Badland et al.;《Tetrahedron Letters》;20110816;第52卷(第41期);第5292-5296页 * |
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