CN115572262A - Isoquinoline derivative and preparation method thereof - Google Patents
Isoquinoline derivative and preparation method thereof Download PDFInfo
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- CN115572262A CN115572262A CN202211330720.5A CN202211330720A CN115572262A CN 115572262 A CN115572262 A CN 115572262A CN 202211330720 A CN202211330720 A CN 202211330720A CN 115572262 A CN115572262 A CN 115572262A
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- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims description 73
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 41
- 229940125904 compound 1 Drugs 0.000 claims description 30
- 239000012043 crude product Substances 0.000 claims description 30
- 239000013067 intermediate product Substances 0.000 claims description 27
- 229940126214 compound 3 Drugs 0.000 claims description 25
- 229940125782 compound 2 Drugs 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 18
- 239000007789 gas Substances 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
- 235000019253 formic acid Nutrition 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 10
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- KSONICAHAPRCMV-UHFFFAOYSA-N 5-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2C(=O)CCC2=C1 KSONICAHAPRCMV-UHFFFAOYSA-N 0.000 claims description 9
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- 238000005893 bromination reaction Methods 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 238000006900 dealkylation reaction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 4
- 238000006146 oximation reaction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 3
- 230000020335 dealkylation Effects 0.000 claims description 3
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000002537 isoquinolines Chemical class 0.000 abstract description 33
- IQEHNPFLYOSKCB-UHFFFAOYSA-N 1,3,6-trichloroisoquinoline Chemical compound ClC1=NC(Cl)=CC2=CC(Cl)=CC=C21 IQEHNPFLYOSKCB-UHFFFAOYSA-N 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- ZZAYRMTWLXJWLQ-UHFFFAOYSA-N ClC1=NC(Br)=CC2=CC(Br)=CC=C12 Chemical compound ClC1=NC(Br)=CC2=CC(Br)=CC=C12 ZZAYRMTWLXJWLQ-UHFFFAOYSA-N 0.000 abstract description 6
- CVOZBLQWQILGIW-UHFFFAOYSA-N 3-amino-2h-isoquinolin-1-one Chemical class C1=CC=C2C(=O)NC(N)=CC2=C1 CVOZBLQWQILGIW-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 238000004537 pulping Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000004982 aromatic amines Chemical class 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- -1 3,6-dibromo-2H-isoquinoline-1-one Chemical compound 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- VYCKDIRCVDCQAE-UHFFFAOYSA-N isoquinolin-3-amine Chemical class C1=CC=C2C=NC(N)=CC2=C1 VYCKDIRCVDCQAE-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- AOYFZKCRCRAFIY-UHFFFAOYSA-N 5-bromo-2-hydroxyimino-3h-inden-1-one Chemical compound BrC1=CC=C2C(=O)C(=NO)CC2=C1 AOYFZKCRCRAFIY-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- ICXAPFWGVRTEKV-UHFFFAOYSA-N 2-[4-(1,3-benzoxazol-2-yl)phenyl]-1,3-benzoxazole Chemical compound C1=CC=C2OC(C3=CC=C(C=C3)C=3OC4=CC=CC=C4N=3)=NC2=C1 ICXAPFWGVRTEKV-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008094 contradictory effect Effects 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
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The invention aims to provide an isoquinoline derivative and a preparation method thereof, and in the invention, another isoquinoline derivative 1-chloro-3,6-dibromo isoquinoline containing halogen element combination, which is not reported, is provided, the structural formula of which is shown in a formula 1, and the isoquinoline derivative is beneficial to expanding the application of introducing an isoquinoline skeleton and replaces 1,3,6-trichloroisoquinoline in the synthesis of 3-aminoisoquinoline-1-one derivatives. Meanwhile, the method for preparing the isoquinoline derivative is simple and ensures the yield and the purity of the product.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an isoquinoline derivative and a preparation method thereof.
Background
1,3,6-trihaloisoquinoline is an important structural unit for constituting natural products such as papaverine, morphine, berberine and the like, and can also be used as an important nitrogenous heterocyclic medicine intermediate to be widely applied to the fields of medicines, pesticides and the like. The 1,3,6-trichloroisoquinoline is a core basic framework for preparing a cell division cycle factor 25B (Cdc 25B) inhibitor, and the 3-aminoisoquinoline derivative constructed by taking 1,3,6-trichloroisoquinoline-1-ketone as a mother nucleus can selectively target Cdc25B and specifically inhibit the growth of tumor cells.
At present, the method for constructing the 3-aminoisoquinoline-1-ketone derivative by using 1,3,6-trichloroisoquinoline as a parent nucleus is less, and report that in 2015 Kara M.George Rosenker and the like, buchwald-Hartwig arylamine reaction is completed at the position 3 of isoquinoline through palladium catalysis regioselectivity, then a biphenyl intermediate is constructed at the position 6 of isoquinoline by utilizing Suzuki cross-coupling reaction, and finally demethylation is carried out under an acidic condition to obtain the 3-aminoisoquinoline derivative. The scheme has low overall yield, and the 3-bit Buchwald-Hartwig arylamine reaction has poor selectivity, and the biggest problem is that the initial raw material 1,3,6-trichloroisoquinoline has no disclosed synthesis scheme, has high autonomous synthesis difficulty and high market price, cannot realize the production of more than kilogram levels of 3-aminoisoquinoline-1-one derivatives, and greatly limits the research progress of Cdc25B related diseases.
Disclosure of Invention
The invention aims to provide an isoquinoline derivative and a preparation method thereof, and aims to provide an isoquinoline derivative containing another halogen element combination and expand the application of the isoquinoline derivative in the introduction of an isoquinoline skeleton.
In order to achieve the above object, the present invention provides an isoquinoline derivative, wherein the isoquinoline derivative is represented by formula 1:
in addition, the present invention also provides a method for preparing the above isoquinoline derivatives, the method comprising:
reacting compound 1 represented by formula 2 with POCl 3 Carrying out chlorination reaction to obtain the isoquinoline derivative;
alternatively, the compound 1 is obtained by carrying out dealkylation reaction on a compound 2 shown in a formula 3 and formic acid;
wherein, in formula 3, R 1 One selected from methyl, ethyl or tert-butyl.
Alternatively, the compound 2 is synthesized from a compound 3 shown in the formula 4 and a base by using a Williams method;
wherein the base is selected from one of alkali methoxide, alkali ethoxide or alkali tert-butoxide.
Alternatively, the compound 2 is prepared by the following steps:
dissolving the compound 3 and the alkali in a solvent, reacting at 100-140 ℃ for 1-3 hours, and distilling after the reaction is finished to obtain a crude product 1, wherein the molar ratio of the compound 3 to the alkali is 1: (1 to 5)
After purification of the crude 1, the compound 2 is obtained.
Alternatively, the compound 3 is the compound 4 shown in the formula 5, which is dissolved in a saturated solvent of hydrogen chloride, and POBr is added 3 Carrying out Beckmann rearrangement and bromination reaction to obtain the product;
alternatively, the step of preparing compound 3 comprises:
dissolving the compound 4 in saturated 1,2-dichloroethane solution of hydrogen chloride, and adding POBr in batches at-5-2 DEG C 3 After the addition, stirring for 1-3 hours at 75-85 ℃ for reaction, and after the reaction is finished, distilling to obtain a crude product 2;
and quenching the crude product 2 by using ice water, filtering, extracting the filtrate by using ethyl acetate, and then drying and concentrating the filtrate in sequence to obtain the compound 3.
Alternatively, the compound 1 is prepared by the following steps:
reacting compound 4 represented by formula 5 with PBr 5 Obtaining an intermediate product after the reaction;
the intermediate product and HBr complete bromination reaction to obtain the compound 1;
alternatively, the compound 4 shown in the formula 5 is reacted with PBr 5 The step of obtaining an intermediate product after the reaction comprises:
PBr is prepared from 5 Slowly adding the mixture into the solution containing the compound 4 at the temperature of between 2 ℃ below zero and 2 ℃, reacting for 12 to 20 hours at the temperature of between 10 and 40 ℃ after adding, and distilling to obtain an intermediate product, wherein the compound 4 and PBr are mixed 5 In a molar ratio of 1: (1-2); and/or the presence of a gas in the gas,
the step of reacting the intermediate product with HBr to obtain the compound 1 comprises:
dissolving the intermediate product to obtain an intermediate product solution, introducing dry HBr gas into the intermediate product solution at the temperature of 5-10 ℃, stopping introducing the gas after the intermediate product solution changes from beige to brown, reacting at the temperature of 10-40 ℃ for 10-20 hours, then stirring at the temperature of 40-70 ℃ for 1-3 hours until the reaction is finished to obtain a crude product 3, and sequentially diluting, washing, drying, filtering and concentrating the crude product 3 to obtain the compound 1.
Alternatively, the compound 4 is prepared by the following steps:
dissolving 5-bromo-1-indanone, slowly adding concentrated hydrochloric acid, dropwise adding butyl nitrite at 40 ℃, preserving heat for 2-3 hours, completing oximation reaction, filtering after the reaction is finished, and drying to obtain the compound 4.
The invention provides another isoquinoline derivative 1-chloro-3,6-dibromo isoquinoline containing halogen element combination, which is not reported, and the structural formula of the isoquinoline derivative is shown as a formula 1, the isoquinoline derivative is beneficial to expanding the application of introducing an isoquinoline skeleton, and 1,3,6-trichloroisoquinoline is replaced in the synthesis of 3-aminoisoquinoline-1-one derivatives. Meanwhile, the method for preparing the isoquinoline derivative is simple and ensures the yield and the purity of the product.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other related drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a hydrogen spectrum of 1-chloro-3,6-dibromoisoquinoline;
FIG. 2 is a mass spectrum of 1-chloro-3,6-dibromo isoquinoline;
FIG. 3 is a liquid phase diagram and mass ESI of the product of example 1.
The implementation, functional features and advantages of the present invention will be further described with reference to the accompanying drawings.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments.
It should be noted that those who do not specify specific conditions in the examples were performed under the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. In addition, the meaning of "and/or" appearing throughout includes three juxtapositions, exemplified by "A and/or B", including either A or B or both A and B. In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
At present, the method for constructing the 3-aminoisoquinoline-1-ketone derivative by taking 1,3,6-trichloroisoquinoline as a parent nucleus is less, and report that Buchwald-Hartwig arylamine reaction is completed at the position 3 of isoquinoline by palladium catalysis regioselectivity in 2015 by Kara M.George Rosenker and the like, a biphenyl intermediate is constructed at the position 6 of isoquinoline by Suzuki cross-coupling reaction, and finally, the 3-aminoisoquinoline derivative is obtained by demethylation under acidic condition, wherein the reaction route is shown as follows:
the scheme has low overall yield and poor selectivity during the 3-bit Buchwald-Hartwig arylamine reaction, the initial raw material 1,3,6-trichloroisoquinoline has no disclosed synthesis scheme, the autonomous synthesis difficulty is high, the market price is high, the production of 3-aminoisoquinoline-1-ketone derivatives above kilogram level cannot be realized, and the research progress of Cdc25B related diseases is greatly limited.
In order to introduce an isoquinoline skeleton more conveniently, the invention provides an isoquinoline derivative, wherein the isoquinoline derivative is shown as a formula 1, a hydrogen spectrum is shown as a figure 1, and a mass spectrum is shown as a figure 2:
the invention provides another isoquinoline derivative 1-chloro-3,6-dibromo isoquinoline containing halogen element combination, which is not reported, and has a structural formula shown in formula 1, the isoquinoline derivative is beneficial to expanding the application of introducing an isoquinoline skeleton, and 1,3,6-trichloroisoquinoline is replaced in the synthesis of 3-aminoisoquinoline-1-one derivatives.
In addition, the present invention also provides a method for preparing the above isoquinoline derivatives, the method comprising:
reacting compound 1 represented by formula 2 with POCl 3 Carrying out chlorination reaction to obtain the isoquinoline derivative;
the invention provides a synthetic method of isoquinoline derivative 1-chloro-3,6-dibromo isoquinoline, which is simple and convenient to operate, easy to obtain raw materials, low in cost and has the potential of industrial mass production.
It should be noted that, under the premise of the purpose of the reaction, the specific reaction conditions and steps can be adjusted according to the needs. In the invention, the specific steps are as follows: dissolving compound 1 in 1-1.2 ml of POCl 3 Performing the following steps;
reacting for 1-3 hours at the reaction temperature of 100-150 ℃, and distilling to obtain a crude product;
and dissolving the crude product, and then washing, drying, filtering and concentrating the product in sequence to obtain the isoquinoline derivative. By adopting the steps, the product concentration and the product purity can be further improved, and the product yield can be more than 70%.
In some embodiments, compound 2 of formula 3 of compound 1 is obtained after completing the dealkylation reaction with formic acid;
wherein, in formula 3, R 1 One selected from methyl, ethyl or tert-butyl. Compound 2 can be prepared using the above method.
It should be noted that, under the premise of the purpose of the reaction, the specific reaction conditions and steps can be adjusted according to the needs. In the invention, the specific steps are as follows:
dissolving the compound 2 in formic acid, wherein 5-10 ml of formic acid is dissolved in each mmol of the compound 2, reacting at 10-40 ℃ for 0.2-3 hours after dissolution, distilling, extracting, and concentrating to obtain the compound 1. By adopting the specific steps, the yield and the purity of the compound 1 can be further improved.
In some embodiments, compound 2 is synthesized from compound 3 represented by formula 4 with a base using the williamson method;
wherein the base is selected from one of alkali methoxide, alkali ethoxide or alkali tert-butoxide. Compound 2 can be prepared using the above method.
It should be noted that specific reaction conditions and steps can be adjusted as required for the purpose of the reaction. And in some embodiments, the compound 2 is prepared by: dissolving the compound 3 and the alkali in a solvent, reacting at 100-120 ℃ for 1-3 hours, and distilling after the reaction is finished to obtain a crude product 1, wherein the molar ratio of the compound 3 to the alkali is 1: (1-5).
After purification of the crude 1, the compound 2 is obtained. By adopting the specific steps, the yield and the purity of the compound 2 can be further improved.
In some embodiments, the compound 3 is a compound 4 represented by formula 5 dissolved in a saturated solution of hydrogen chloride, and POBr is added 3 Carrying out Beckmann rearrangement and bromination reaction to obtain the product; compound 3 can be prepared by the above steps.
It should be noted that, under the premise of the purpose of the reaction, the specific reaction conditions and steps can be adjusted according to the needs. In some embodiments, the step of preparing compound 3 comprises:
dissolving the compound 4 in saturated 1,2-dichloroethane solution of hydrogen chloride, and adding POBr in batches at-5 DEG C 3 After the addition, stirring for 1-3 hours at 75-85 ℃ for reaction, and after the reaction is finished, distilling to obtain a crude product 2;
and quenching the crude product by using ice water, filtering, extracting the filtrate by using ethyl acetate, and then drying and concentrating the filtrate in sequence to obtain the compound 3. The purity and yield of compound 3 can be further improved by the above steps.
Specifically, in some embodiments, 5 to 8L of 1,2-dichloroethane are added per mole of the compound 4;
in some embodiments, 2mol to 2.2mol of POBr is added per mole of said compound 4 3 。
In some embodiments, the compound 1 is prepared by the steps of:
reacting compound 4 represented by formula 5 with PBr 5 Obtaining an intermediate product after reaction;
the intermediate product and HBr complete bromination reaction to obtain the compound 1;
the compound 1 is prepared by adopting the steps, so that the reaction route can be further shortened, and the reaction efficiency is improved.
According to the technical scheme provided by the invention, 5-bromo-1-indanone and butyl nitrite are used as initial raw materials, oximation reaction is firstly carried out to construct 5-bromo-2-oximino-1-indanone, beckmann rearrangement, bromination reaction, alkylation, dealkylation and other processes are carried out to construct a key intermediate 3,6-dibromo-2H-isoquinoline-1-one, and chlorination reaction is finally carried out to construct a target product 1-chloro-3,6-dibromide isoquinoline.
In some embodiments, the compound 4 of formula 5 is reacted with PBr 5 The step of obtaining an intermediate product after the reaction comprises:
PBr (poly-p-phenylene benzobisoxazole) is prepared 5 Slowly adding the mixture into the solution containing the compound 4 at the temperature of between 5 ℃ below zero and 5 ℃, reacting for 12 to 20 hours at the temperature of between 10 and 40 ℃ after adding, and distilling to obtain an intermediate product, wherein the compound 4 and PBr are mixed 5 In a molar ratio of 1: (1-3). With the above conditions, the purity and yield of compound 1 can be further improved.
In some embodiments, the step of obtaining compound 1 after reacting the intermediate product with HBr comprises:
dissolving the intermediate product to obtain an intermediate product solution, introducing dry HBr gas into the intermediate product solution at the temperature of 5-10 ℃, stopping introducing the gas after the intermediate product solution changes from beige to brown yellow, reacting at the temperature of 10-50 ℃ for 10-20 hours, then stirring at the temperature of 40-70 ℃ for 1-3 hours until the reaction is finished to obtain a crude product 3, and sequentially diluting, washing, drying, filtering and concentrating the crude product 3 to obtain the compound 1. With the above conditions, the purity and yield of compound 1 can be further improved.
In some embodiments, the compound 4 is prepared by the steps of:
dissolving 5-bromo-1-indanone, slowly adding concentrated hydrochloric acid, dropwise adding butyl nitrite at 35-45 ℃, reacting for 2-3 hours under heat preservation, filtering after the reaction is finished, and drying to obtain the compound 4.
Compound 4 can be prepared using the above procedure, and certain purity and yield are ensured.
In some embodiments, the compound 5-bromo-1-indanone is reacted with butyl nitrite in a molar ratio of 1: (1-3).
In summary, in the technical scheme provided by the invention, 5-bromo-1-indanone and butyl nitrite are used as starting raw materials, oximation reaction is firstly carried out to construct 5-bromo-2-oximino-1-indanone, beckmann rearrangement, bromination reaction, alkylation, dealkylation and other processes are carried out to construct the key intermediate 3,6-dibromo-2H-isoquinoline-1-one, and finally chlorination reaction is carried out to construct the target product 1-chloro-3,6-dibromide isoquinoline.
The technical solutions of the present invention are further described in detail below with reference to specific examples and drawings, it should be understood that the following examples are merely illustrative of the present invention and are not intended to limit the present invention.
Example 1
The present embodiment provides a method for preparing an isoquinoline derivative as shown in formula 1, which is performed as follows:
1)
5-bromo-1-indanone (shown in formula 6) (500g, 2369mmol) is dissolved in methanol (4500 mL), concentrated hydrochloric acid (213 mL) is slowly added, butyl nitrite (308mL, 2.62mol) is added dropwise at 40 ℃, and the reaction is finished after the temperature is kept and the stirring is continued for 2.5 hours. The temperature of the reaction is reduced to 20 to 30 ℃, and 500g of white solid, namely the compound 4, is obtained after filtration and drying, as shown in the formula 5 (A) 1 H NMR(400MHz,DMSO-d 6 ) δ 12.73 (s, 1H), 7.90 (p, J =1.1hz, 1h), 7.68 (d, J =1.1hz, 2h), 3.79 (d, J =1.0hz, 2h)), yield 70.1%.
2)
Compound 4 (24g, 100mmol) was dissolved in a saturated 1,2-dichloroethane solution of hydrogen chloride (500 mL) and POBr was added portionwise at 0 deg.C 3 (57.3 g, 200mmol), and the reaction was terminated by stirring at 80 ℃ for 2 hours. Cooling downDistilling under reduced pressure to 20-30 deg.C to remove 1,2-dichloroethane, quenching the crude product with ice water, filtering, extracting the filtrate with ethyl acetate, drying, concentrating, and pulping to obtain 21g of white solid (shown in formula 4) ((formula 4)) 1 H NMR(400MHz,DMSO-d 6 ) δ 8.34 (d, J =2.0hz, 1h), 8.24 (d, J =0.8hz, 1h), 8.10 (dt, J =9.1,0.7hz, 1h), 7.97 (dd, J =9.0,1.9hz, 1h)), yield 57.5%.
(3)
Compound 3 (3.65g, 10 mmol) was dissolved in toluene (20 mL), and sodium methoxide (1.08g, 20 mmol) was added thereto, followed by stirring at 110 ℃ for 2 hours to complete the reaction. Cooling to 20-30 deg.C, distilling under reduced pressure to remove toluene, dissolving the obtained crude product with ethyl acetate, washing with water and saturated saline solution respectively, drying, filtering, and concentrating to obtain 2.5g white solid compound, i.e. compound 2 (shown in formula 3, R1 is CH) 3 )( 1 H NMR (400mhz, chloroform-d) δ 8.07 (dt, J =8.8,0.7hz, 1h), 7.83 (d, J =1.9hz, 1h), 7.63 (dd, J =8.9,1.9hz, 1h), 7.37 (d, J =0.8hz, 1h), 7.29 (s, 1H), 4.16 (s, 3H)), yield 78.8%.
(4)
Compound 2 (1.83g, 5 mmol) in step 3) was dissolved in formic acid (30 mL) and the reaction was terminated by stirring at 25 ℃ for 0.5 hour. Distilling under reduced pressure to remove formic acid, and pulping to obtain 1g of white solid (compound 1 (shown in formula 2) ((II) 1 H NMR(500MHz,DMSO-d 6 ) δ 12.35 (s, 1H), 8.04 (d, J =8.5hz, 1h), 7.91 (d, J =2.0hz, 1h), 7.65 (dd, J =8.5,2.0hz, 1h), 6.88 (s, 1H)), yield 66.2%.
5)
Taking out the compound1 (17g, 56.5mmol) in POCl 3 (60 mL), after the addition, the reaction was stirred at 120 ℃ for 2 hours. Cooling to 20-30 deg.C, and distilling under reduced pressure to remove POCl 3 Dissolving the crude product with ethyl acetate, washing with saturated saline water and saturated aqueous solution of sodium bicarbonate, drying, filtering, concentrating, and pulping to obtain 15g white solid (shown in formula 1) ((formula 1)) 1 H NMR(500MHz,DMSO-d 6 ) δ 8.38 (d, J =2.0hz, 1h), 8.25 (d, J =0.8hz, 1h), 8.19 (d, J =9.0hz, 1h), 7.99 (dd, J =9.0,1.9hz, 1h)), yield 75%.
Example 2
The present embodiment provides a method for preparing an isoquinoline derivative shown in formula 1, and the operation of the method for preparing an isoquinoline derivative shown in formula 1 is as follows:
1) 5-bromo-1-indanone (shown in formula 6) (500g, 2369mmol) is dissolved in methanol (5000 mL), then concentrated hydrochloric acid (220 mL) is slowly added, butyl nitrite (833mL, 7.11mol) is added dropwise at 35 ℃, and the reaction is finished after the temperature is kept and the stirring is continued for 2 hours. The reaction is cooled to 20-30 ℃, and the compound 4 (shown in formula 5) is obtained after filtration and drying, with the yield of 71.5%.
2) Dissolving Compound 4 (24g, 100mmol) in a saturated 1,2-dichloroethane solution of hydrogen chloride (800 mL), adding POBr in portions at 5 deg.C 3 (58.3 g, 205mmol), and after the addition was completed, the reaction was stirred at 85 ℃ for 2 hours to terminate. Cooling to 20-30 deg.C, distilling under reduced pressure to remove 1,2-dichloroethane, quenching the obtained crude product with ice water, filtering, extracting the filtrate with ethyl acetate, drying, concentrating, and pulping to obtain white solid, i.e. compound 3 (shown in formula 4), with yield of 56.8%.
(3) Compound 3 (3.65g, 10mmol) was dissolved in toluene (30 mL), and sodium ethoxide (0.68g, 10mmol) was added thereto, and the mixture was stirred at 115 ℃ for 3 hours to complete the reaction. Cooling to 20-30 deg.C, distilling under reduced pressure to remove toluene, dissolving the obtained crude product with ethyl acetate, washing with water and saturated saline solution respectively, drying, filtering, and concentrating to obtain white solid compound, i.e. compound 2 (shown in formula 3, R1 is CH) 3 CH 2 -) in a yield of 79.2%.
(4) Compound 2 (1.9g, 5mmol) obtained in 3) was dissolved in formic acid (50 mL), and the reaction was terminated by stirring at 10 ℃ for 3 hours. Distilling under reduced pressure to remove formic acid, and pulping to obtain white solid, namely the compound 1 (shown in formula 2), with the yield of 64.7%.
5) Compound 1 (20g, 66.5mmol) was dissolved in POCl 3 (70 mL), after the addition, the reaction was stirred at 150 ℃ for 1 hour. Cooling to 20-30 deg.C, and distilling under reduced pressure to remove POCl 3 The obtained crude product is dissolved by ethyl acetate, washed by saturated salt solution and saturated sodium bicarbonate water solution respectively, dried, filtered, concentrated and pulped to obtain white solid, namely the product, shown as the formula 1, with the yield of 72 percent.
Example 3
The present embodiment provides a method for preparing an isoquinoline derivative as shown in formula 1, which is performed as follows:
1) Dissolving 5-bromo-1-indanone (shown in formula 6) (500g, 2369mmol) in methanol (5000 mL), slowly adding concentrated hydrochloric acid (221 mL), dropwise adding butyl nitrite (310mL, 2.65mol) at 45 ℃, keeping the temperature, and continuously stirring uniformly for 2 hours to finish the reaction. The reaction is cooled to 20-30 ℃, and the compound 4 is obtained after filtration and drying, as shown in formula 5, and the yield is 66.2%.
2) The compound 4 (24g, 100mmol) was dissolved in a saturated 1,2-dichloroethane solution of hydrogen chloride (700 mL) and POBr was added in portions at 5 deg.C 3 (60.2g, 210mmol), and after the addition, the reaction was stirred at 75 ℃ for 3 hours to complete the reaction. Cooling to 20-30 deg.C, distilling under reduced pressure to remove 1,2-dichloroethane, quenching the obtained crude product with ice water, filtering, extracting the filtrate with ethyl acetate, drying, concentrating, and pulping to obtain white solid, i.e. compound 3 (shown in formula 4), with yield of 57.3%.
(3) Compound 3 (3.65g, 10mmol) was dissolved in toluene (30 mL), and sodium t-butoxide (4.81g, 50mmol) was added thereto, and the mixture was stirred at 100 ℃ for 3 hours to complete the reaction. Cooling to 20-30 deg.C, distilling under reduced pressure to remove toluene, dissolving the obtained crude product with ethyl acetate, washing with water and saturated saline solution respectively, drying, filtering, and concentrating to obtain white solid compound, i.e. compound 2, as shown in formula 3, R1 is C (CH) 3 ) 3 -。
(4) Compound 2 (2.04g, 5 mmol) obtained in 3) was dissolved in formic acid (35 mL) and stirred at 40 ℃ for 0.2 hour to complete the reaction. Distilling under reduced pressure to remove formic acid, and pulping to obtain white solid, namely the compound 1, as shown in the formula 2, with the yield of 61%.
5) Compound 1 (20g, 66.5mmol) was dissolved in POCl 3 (70 mL), and after the addition, the reaction was stirred at 100 ℃ for 3 hours. Cooling to 20-30 deg.C, and distilling under reduced pressure to remove POCl 3 Dissolving the obtained crude product with ethyl acetate, washing with saturated saline water and saturated sodium bicarbonate water solution respectively, drying, filtering, concentrating, and pulping to obtain white solid, i.e. the product shown in formula 1, with the yield of 72.5%.
Example 4
The present embodiment provides a method for preparing an isoquinoline derivative as shown in formula 1, which is performed as follows:
1) It was operated as in example 1, step 1);
2)
dissolving compound 4 (24g, 100mmol) in dry dichloromethane (1L), slowly adding PBr at 0 deg.C 5 (65g, 150mmol), and after addition, the reaction was terminated after stirring at room temperature for 16 hours. Concentrating under reduced pressure to remove dichloromethane, dissolving the crude product again with 1,4-dioxane (1L), introducing dry HBr gas at 5-10 deg.C, stopping introducing gas when the reaction solution changes from beige to brown, reacting at 30 deg.C for 16 hr, and stirring at 60 deg.C for 2 hr until the reaction is finished. Cooling the reaction solution to room temperature, diluting with ethyl acetate, washing with saturated sodium chloride solution and saturated sodium bicarbonate solution, drying, filtering, and concentrating to obtain 25g brown yellow solid V, compound 1 shown in formula 2 (b), (b) 1 H NMR(500MHz,DMSO-d 6 ) δ 12.35 (s, 1H), 8.04 (d, J =8.5hz, 1h), 7.91 (d, J =2.0hz, 1h), 7.65 (dd, J =8.5,2.0hz, 1h), 6.88 (s, 1H)), yield 82.5%.
3) The procedure was as in example 1, step 5).
Example 5
This example provides a method for preparing isoquinoline derivatives as shown in formula 1, which operates substantially as in example 4, with the only difference that the operation of step 2) is:
dissolving compound 4 (24g, 100mmol) in dry dichloromethane (1L), slowly adding PBr at 2 deg.C 5 (80g, 185mmol), and after the addition was completed, the reaction was stirred at room temperature for 20 hours. Concentrating under reduced pressure to remove dichloromethane, dissolving the crude product again with 1,4-dioxane (1L), introducing gas HBr at 5-10 deg.C, stopping introducing gas when the reaction solution changes from beige to brown yellow, reacting at 50 deg.C for 10 hr, and stirring at 70 deg.C for 1 hr until the reaction is finished. The reaction solution is cooled to room temperature, diluted by ethyl acetate, washed by saturated brine and saturated sodium bicarbonate water respectively, dried, filtered and concentrated to obtain a brown yellow solid, namely the compound 1, as shown in the formula 2, and the yield is 79.3%.
Example 6
This example provides a method for preparing isoquinoline derivatives as shown in formula 1, which operates substantially as in example 4, with the only difference that the operation of step 2) is:
dissolving compound 4 (24g, 100mmol) in dry dichloromethane (1L), slowly adding PBr at 2 deg.C 5 (130g, 300mmol), and after the addition was completed, the reaction was stirred at room temperature for 20 hours.
Concentrating under reduced pressure to remove dichloromethane, dissolving the crude product again with 1,4-dioxane (1L), introducing dry HBr gas at 5-10 deg.C, stopping introducing gas when the reaction solution changes from beige to brown, reacting at 40 deg.C for 10 hr, and stirring at 70 deg.C for 1 hr until the reaction is finished. The reaction solution is cooled to room temperature, diluted by ethyl acetate, washed by saturated brine and saturated sodium bicarbonate water respectively, dried, filtered and concentrated to obtain a brown yellow solid, namely the compound 1, as shown in the formula 2, and the yield is 79.3%.
Example 7
This example provides a method for preparing isoquinoline derivatives as shown in formula 1, which operates substantially as in example 4, with the only difference that the operation of step 2) is:
dissolving compound 4 100mmol in dry dichloromethane (1L), slowly adding PBr at 2 deg.C 5 (43g, 100mmol), and after the addition was completed, the reaction was stirred at room temperature for 20 hours. Concentrating under reduced pressure to removeDichloromethane, directly dissolving the obtained crude product with 1,4-dioxane (1L), introducing and drying at 5-10 ℃ to obtain HBr gas, stopping introducing when the reaction liquid changes from beige to brown yellow, reacting at 10 ℃ for 20 hours, and then stirring at 40 ℃ for 3 hours until the reaction is finished. The reaction solution is cooled to room temperature, diluted by ethyl acetate, washed by saturated brine and saturated sodium bicarbonate water respectively, dried, filtered and concentrated to obtain a brown yellow solid, namely the compound 1, as shown in the formula 2, and the yield is 76.5%.
It should be noted that, in the experiment of the present invention, each step is independently performed, and the yield of the product in each step is independent of each other, i.e. the batch product in the example does not represent the direct application to the next step, but represents the product that can be produced by expanding or reducing the raw material under the process.
In the invention, the hydrogen spectrum test method is as follows:
nuclear magnetic data were collected by Bruker AV 600HZ Nuclear magnetic resonance apparatus, tetramethylsilane (Si (CH) 3 ) 4 ) Signal as internal reference (δ =0 ppm); chemical shifts (δ) in parts per million (ppm) and coupling constants (J) in Hz. The following abbreviations are used to characterize peak splits s = mono; br.s. = wide signal; d = two; t = three; m = multiplicity; dd = doublet.
The mass spectrometry method adopted is as follows:
the equipment model is Waters 2767sample manager, waters 2545binary program module, waters 2489UV/Visible detector. The post model is SunAire TM C18 column, 5. Mu.M, 4.6X 50mm. Mobile phase a was methanol and mobile phase B was water (+ 0.035% TFA).
The above is only a preferred embodiment of the present invention, and it is not intended to limit the scope of the invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the scope of the present invention.
Claims (10)
1. An isoquinoline derivative, wherein the isoquinoline derivative is represented by formula 1:
2. a method for producing an isoquinoline derivative according to claim 1 comprising:
reacting compound 1 represented by formula 2 with POCl 3 Carrying out chlorination reaction to obtain the isoquinoline derivative;
3. the method for producing an isoquinoline derivative according to claim 2, wherein the compound 1 is obtained by dealkylation of a compound 2 represented by formula 3 with formic acid;
wherein, in formula 3, R 1 One selected from methyl, ethyl or tert-butyl.
4. The process for producing an isoquinoline derivative according to claim 3, wherein the compound 2 is synthesized from the compound 3 represented by the formula 4 with a base by the williamson method;
wherein the base is selected from one of alkali methoxide, alkali ethoxide or alkali tert-butoxide.
5. The process for preparing isoquinoline derivatives according to claim 4 wherein compound 2 is prepared by the steps of:
dissolving the compound 3 and the alkali in a solvent, reacting at 100-140 ℃ for 1-3 hours, and distilling after the reaction is finished to obtain a crude product 1, wherein the molar ratio of the compound 3 to the alkali is 1: (1-5);
after purification of the crude 1, the compound 2 is obtained.
6. The method for producing an isoquinoline derivative according to claim 4, wherein the compound 3 is a compound 4 represented by the formula 5, dissolved in a saturated solvent of hydrogen chloride, to which POBr is added 3 Carrying out Beckmann rearrangement and bromination reaction to obtain the product;
7. the method for producing an isoquinoline derivative according to claim 6, wherein the step of producing the compound 3 comprises:
dissolving the compound 4 in saturated 1,2-dichloroethane solution of hydrogen chloride, and adding POBr in batches at-5-2 DEG C 3 After the addition, stirring for 1-3 hours at 75-85 ℃ for reaction, and after the reaction is finished, distilling to obtain a crude product 2;
and quenching the crude product 2 by using ice water, filtering, extracting the filtrate by using ethyl acetate, and then drying and concentrating the filtrate in sequence to obtain the compound 3.
8. The process for preparing isoquinoline derivatives according to claim 2, wherein compound 1 is prepared by the steps of:
reacting compound 4 represented by formula 5 with PBr 5 Obtaining an intermediate product after reaction;
the intermediate product and HBr complete bromination reaction to obtain the compound 1;
9. the method for producing an isoquinoline derivative according to claim 8, wherein the compound 4 represented by the formula 5 is reacted with PBr 5 The step of obtaining an intermediate product after the reaction comprises:
PBr is prepared from 5 Slowly adding the mixture into the solution containing the compound 4 at the temperature of between 2 ℃ below zero and 2 ℃, reacting for 12 to 20 hours at the temperature of between 10 and 40 ℃ after adding, and distilling to obtain an intermediate product, wherein the compound 4 and PBr are mixed 5 In a molar ratio of 1: (1-2); and/or the presence of a gas in the gas,
the step of reacting the intermediate product with HBr to obtain the compound 1 comprises:
dissolving the intermediate product to obtain an intermediate product solution, introducing dry HBr gas into the intermediate product solution at the temperature of 5-10 ℃, stopping introducing the gas after the intermediate product solution changes from beige to brown, reacting at the temperature of 10-40 ℃ for 10-20 hours, then stirring at the temperature of 40-70 ℃ for 1-3 hours until the reaction is finished to obtain a crude product 3, and sequentially diluting, washing, drying, filtering and concentrating the crude product 3 to obtain the compound 1.
10. The process for preparing an isoquinoline derivative according to any one of claims 6 to 9, wherein the compound 4 is prepared by the following steps:
dissolving 5-bromo-1-indanone, slowly adding concentrated hydrochloric acid, dropwise adding butyl nitrite at 40 ℃, preserving heat for 2-3 hours, completing oximation reaction, filtering after the reaction is finished, and drying to obtain the compound 4.
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