CN113563280A - Synthetic method of 2-cyanophenothiazine - Google Patents
Synthetic method of 2-cyanophenothiazine Download PDFInfo
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- CN113563280A CN113563280A CN202110869328.7A CN202110869328A CN113563280A CN 113563280 A CN113563280 A CN 113563280A CN 202110869328 A CN202110869328 A CN 202110869328A CN 113563280 A CN113563280 A CN 113563280A
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- cyanophenothiazine
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- nickel
- ligand
- mercaptobenzonitrile
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- XZSIGWOVDPSPMG-UHFFFAOYSA-N 10h-phenothiazine-2-carbonitrile Chemical compound C1=CC=C2NC3=CC(C#N)=CC=C3SC2=C1 XZSIGWOVDPSPMG-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000010189 synthetic method Methods 0.000 title claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- CJEDABGJILXBLL-UHFFFAOYSA-N 3-amino-4-sulfanylbenzonitrile Chemical compound NC1=CC(C#N)=CC=C1S CJEDABGJILXBLL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003446 ligand Substances 0.000 claims abstract description 24
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000002815 nickel Chemical class 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- ZYZGPMFOTXMGRA-UHFFFAOYSA-N 1-bromoimidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=C(Br)N=CN21 ZYZGPMFOTXMGRA-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 4
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 4
- 229940078494 nickel acetate Drugs 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 4
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 claims description 4
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 claims description 4
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 4
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- -1 amine compounds Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical group [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- YJCZGTAEFYFJRJ-UHFFFAOYSA-N n,n,3,5-tetramethyl-1h-pyrazole-4-sulfonamide Chemical compound CN(C)S(=O)(=O)C=1C(C)=NNC=1C YJCZGTAEFYFJRJ-UHFFFAOYSA-N 0.000 claims description 3
- OUZIIFOEMPAZKX-UHFFFAOYSA-N n-[2-(2-chlorophenyl)sulfanylethyl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]sulfonylpropanamide Chemical compound C=1C=C(C(F)(F)F)C=NC=1S(=O)(=O)C(C)(C)C(=O)NCCSC1=CC=CC=C1Cl OUZIIFOEMPAZKX-UHFFFAOYSA-N 0.000 claims description 3
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 3
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-UHFFFAOYSA-L 0.000 claims description 3
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 17
- 239000012043 crude product Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- BBOLNFYSRZVALD-UHFFFAOYSA-N 1,2-diiodobenzene Chemical compound IC1=CC=CC=C1I BBOLNFYSRZVALD-UHFFFAOYSA-N 0.000 description 1
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical compound ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 description 1
- FXRMUJPWDOLCLX-UHFFFAOYSA-N 4-bromo-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1Br FXRMUJPWDOLCLX-UHFFFAOYSA-N 0.000 description 1
- XBLPHYSLHRGMNW-UHFFFAOYSA-N 4-chloro-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1Cl XBLPHYSLHRGMNW-UHFFFAOYSA-N 0.000 description 1
- LKOWKPGBAZVHOF-UHFFFAOYSA-N 4-fluoro-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1F LKOWKPGBAZVHOF-UHFFFAOYSA-N 0.000 description 1
- PZAMZPVQVFOYHP-UHFFFAOYSA-N 4-iodo-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1I PZAMZPVQVFOYHP-UHFFFAOYSA-N 0.000 description 1
- QWFHFNGMCPMOCD-UHFFFAOYSA-N 6-bromopyridine-2-carbaldehyde Chemical compound BrC1=CC=CC(C=O)=N1 QWFHFNGMCPMOCD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a synthetic method of 2-cyanophenothiazine, which comprises the following steps: step 1, reacting 4-halogen-3-nitrobenzonitrile serving as a raw material in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile; and 2, in the presence of nickel salt, ligand and alkali, reacting 3-amino-4-mercaptobenzonitrile with a compound C to generate 2-cyanophenothiazine, and synthesizing the 2-cyanophenothiazine by using cheap and easily available 4-halogen-3-nitrobenzonitrile as a raw material through fewer two steps. The reagent used in the reaction process is cheap and easy to obtain, and the reaction process has the advantages of short steps, simple and convenient operation, high yield, safe operation and no pollution, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis and fine chemicals, in particular to a method for synthesizing 2-cyanophenothiazine.
Background
2-cyanophenothiazine (CAS number 38642-74-9) is an important organic synthesis intermediate, and the medicine prepared from it has multiple medicinal functions, especially has important effects in lowering blood pressure, tranquilizing mind, relieving pain and resisting cancer, and the demand of international market for the intermediate is large. The structural formula of the 2-cyanophenothiazine is shown in the specification
The compound is prepared by using 2-chlorophenothiazine and cuprous cyanide as raw materials and reacting in organic solvent with high boiling point, such as quinoline or N-methylpyrrolidone, and the like under the catalysis of iodine or sodium iodide and potassium iodide.
Although the above methods are relatively mature, they have high requirements for raw materials and environment. In the high-temperature reaction process, the 2-cyanophenothiazine product is hydrolyzed into the amide body by a trace amount of water in the raw material or the environment, the impurity is difficult to remove from the product by a solvent recrystallization method, and the product yield is greatly influenced by repeated recrystallization although the content of the amide body can be reduced. Therefore, the industrial synthetic route of 2-chlorophenothiazine is yet to be optimized, and particularly a new synthetic route using new raw materials is yet to be developed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for synthesizing 2-cyanophenothiazine.
The technical scheme for solving the problems comprises the following steps: a method for synthesizing 2-cyanophenothiazine comprises the following steps:
step 1, reacting 4-halogen-3-nitrobenzonitrile serving as a raw material in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
and 2, reacting the 3-amino-4-mercaptobenzonitrile with the compound C in the presence of nickel salt, a ligand and alkali to generate the 2-cyanophenothiazine. The reaction synthesis route is as follows:
x in the structural formula of 4-halogen-3-nitrobenzonitrile1Compound C formula wherein X2，X3One selected from F, Cl, Br and I.
Further, in step 1, the sulfide is selected from Na2S，NaHS，K2S，KHS，(NH4)2S，NH4HS，Na2SO3The reaction temperature is 20-100 ℃.
Further, the mass ratio of the sulfide to the 4-halogen-3-nitrobenzonitrile is (3-4): 1.
further, in the step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel trifluoromethanesulfonate, and the reaction temperature is 80-100 ℃.
Further, the mass ratio of the nickel salt to the 3-amino-4-mercaptobenzonitrile is 2-5: 100.
further, in step 2, the ligand is selected from compounds of the following structures:
in the ligand structure, R1R2, R3, R4, R5, R6 and R7 are selected from any one of a hydrogen atom, a linear chain or branched chain alkyl group and an aryl group.
Further, the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
further, the synthesis of the ligand comprises two steps: firstly, bromo-pyridine aldehyde ketone derivatives, formaldehyde and amine compounds are condensed under an acidic condition to generate bromo-2-azaindolizine; and step two, coupling bromo-2-azaindolizine and an imidazole derivative to obtain a ligand. The reaction synthesis route is as follows:
the invention has the following beneficial effects:
the invention provides a synthesis method of 2-cyanophenothiazine, which takes cheap and easily-obtained 4-halogen-3-nitrobenzonitrile as a raw material and realizes the synthesis of 2-cyanophenothiazine by fewer two steps. The reagent used in the reaction process is cheap and easy to obtain, and the reaction process has the advantages of short steps, simple and convenient operation, high yield, safe operation and no pollution, and is suitable for industrial production.
Detailed Description
The technical solution provided by the present invention is explained in detail with reference to specific embodiments below.
A method for synthesizing 2-cyanophenothiazine comprises the following steps:
step 1, reacting 4-halogen-3-nitrobenzonitrile serving as a raw material in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
and 2, reacting the 3-amino-4-mercaptobenzonitrile with the compound C in the presence of nickel salt, a ligand and alkali to generate the 2-cyanophenothiazine. The reaction synthesis route is as follows:
the structural formula of the 4-halogen-3-nitrobenzonitrile is shown as the following, X1One selected from F, Cl, Br and I;
the structural formula of the 3-amino-4-mercapto benzonitrile is shown as follows,
the structural formula of the compound c is shown as the following, X2，X3One selected from F, Cl, Br and I;
in step 1, the sulfide is selected from Na2S，NaHS，K2S，KHS，(NH4)2S，NH4HS，Na2SO3In the preparation method, the mass ratio of the sulfide to the 4-halogen-3-nitrobenzonitrile is (3-4): 1, the reaction temperature is 20-100 ℃;
in the step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel trifluoromethanesulfonate, and the mass ratio of the nickel salt to the 3-amino-4-mercaptobenzonitrile is 2-5: 100, the reaction temperature is 80-100 ℃;
in step 2, the base is selected from DBU, KOButPotassium tert-butoxide, sodium methoxide, NaH, Cs2CO3、K3PO4In the method, the mass ratio of the alkali to the 3-amino-4-mercaptobenzonitrile is 2-4: 1;
in step 2, the ligand is selected from compounds of the following structure:
in the ligand structure, R1，R2，R3，R4，R5，R6，R7Any one selected from a hydrogen atom, a linear or branched alkyl group and an aryl group; the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
the synthesis of the ligand comprises two steps: firstly, bromo-pyridine aldehyde ketone derivatives, formaldehyde and amine compounds are condensed under an acidic condition to generate bromo-2-azaindolizine; and step two, coupling bromo-2-azaindolizine and an imidazole derivative to obtain a ligand. The reaction synthesis route is as follows:
preparing a ligand: in the first step, aniline (0.4mL,4.3mmol), 35% aqueous formaldehyde (0.49mL,6.5mmol), 2.94M HCl in ethanol (1.5mL,4.3mmol), 6-bromopyridine-2-carbaldehyde (4.3mmol), and ethanol (7.2mL) were added to a reaction vessel, and the reaction was stirred at room temperature for 15 minutes. Then decompressing and distilling off the solvent, dissolving the obtained crude product in hot acetonitrile, filtering while the crude product is hot, and recrystallizing the crude product through acetonitrile/tetrahydrofuran to obtain corresponding bromo-2-azaindolizine M1 which is an orange solid;
and secondly, dissolving bromo-2-azaindolizine M1(2mmol) and imidazole (2.4mmol) in acetonitrile (10mL), adding palladium acetate (0.1mmol) and potassium phosphate (2.4mmol), heating to 80 ℃, reacting for 8 hours, filtering while hot, and recrystallizing the obtained crude product by acetonitrile/tetrahydrofuran to obtain the corresponding ligand L1.
The reaction synthesis route is as follows:
example 1
Dissolving 4-chloro-3-nitrobenzonitrile (18.3g, 100mmol) in water (100mL), stirring, adding NaHS (6.2g, 110mmol), heating to 85 deg.C, reacting for 3h, cooling the reaction mixture to room temperature, adding Na while stirring2SO3(27.7g, 220mmol) and then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid for about 2 hours, and finally isolated by extraction with 1, 2-dichloroethane (200mL) and the organic mixture was MgSO 24Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL of toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃, separating out a solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile with the yield of 81%.
Nickel bromide (0.4g, 2mmol) and ligand L1(1.5g, 5mmol) were dissolved in DMF (200mL), potassium tert-butoxide (24.6g, 220mmol) was added, and after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15g, 100mmol) and o-dichlorobenzene (16.2g, 110mmol) were added, the reaction was warmed to 100 ℃ for 10 hours, then 100mL of water was added to quench the reaction, and extraction separation was performed with dichloromethane (300 mL). The organic mixture was over MgSO4The crude product was added to 100mL of toluene, refluxed at elevated temperature for 30 minutes, and then cooled to 5 ℃ to precipitate a yellow solid. The resulting yellow solid was filtered under vacuum, washed with cold ether and dried to give pure 2-cyanophenothiazine in 88% yield.
Example 2
4-fluoro-3-nitrobenzonitrile (16.6g, 100mmol) was dissolved in water (100mL), stirring was turned on, and K was added2S (12.1g, 110mmol), heating to 80 ℃ for reaction for 3h, and reactingThe reaction mixture was cooled to room temperature and Na was added with stirring2SO3(27.7g, 220mmol) and then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid for about 2 hours, and finally isolated by extraction with 1, 2-dichloroethane (200mL) and the organic mixture was MgSO 24Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL of toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃, separating out a solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile with the yield of 78%.
Nickel chloride (0.26g, 2mmol) and ligand L1(1.9g, 5mmol) were dissolved in DMF (200mL), cesium carbonate (72g, 220mmol) was added, and after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15g, 100mmol) and o-dibromobenzene (26g, 110mmol) were added, and the reaction was warmed to 80 ℃ for 10 hours, followed by quenching with 100mL of water, and extraction separation was performed with dichloromethane (300 mL). The organic mixture was over MgSO4The crude product was added to 100mL of toluene, refluxed at elevated temperature for 30 minutes, and then cooled to 5 ℃ to precipitate a yellow solid. The resulting yellow solid was filtered under vacuum, washed with cold ether and dried to give pure 2-cyanophenothiazine in 90% yield.
Example 3
4-bromo-3-nitrobenzonitrile (22.7g, 100mmol) was dissolved in water (100mL), stirring was turned on, and Na was added2S (8.6g, 110mmol), heating to 60 ℃ for 2h, cooling the reaction mixture to room temperature, adding Na while stirring2SO3(27.7g, 220mmol) and then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid for about 2 hours, and finally isolated by extraction with 1, 2-dichloroethane (200mL) and the organic mixture was MgSO 24Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL of toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃, separating out a solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile with the yield of 83%.
Nickel sulfate (0.3g, 2mmol) and ligandL1(1.9g, 5mmol) was dissolved in DMF (200mL), DBU (33.4g, 220mmol) was added, and after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15g, 100mmol) and o-diiodobenzene (36.3g, 110mmol) were added, and the reaction was warmed to 80 ℃ for 6 hours, then 100mL of water was added to quench the reaction, and extraction separation was performed with dichloromethane (300 mL). The organic mixture was over MgSO4The crude product was added to 100mL of toluene, refluxed at elevated temperature for 30 minutes, and then cooled to 5 ℃ to precipitate a yellow solid. The resulting yellow solid was filtered under vacuum, washed with cold ether and dried to give pure 2-cyanophenothiazine in 87% yield.
Example 4
4-iodo-3-nitrobenzonitrile (27.4g, 100mmol) was dissolved in water (100mL), stirring was turned on, and (NH) was added4)2S (7.5g, 110mmol), heating to 40 ℃ for 2h, cooling the reaction mixture to room temperature, adding Na while stirring2SO3(27.7g, 220mmol) and then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid for about 2 hours, and finally isolated by extraction with 1, 2-dichloroethane (200mL) and the organic mixture was MgSO 24Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL of toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃, separating out a solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile with the yield of 84%.
Nickel acetate (0.36g, 2mmol) and ligand L1(1.7g, 5mmol) were dissolved in DMF (200mL) and K was added3PO4(46.6g, 220mmol), and after stirring the reaction at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15g, 100mmol) and 2-bromochlorobenzene (21g, 110mmol) were added, the reaction was warmed to 90 ℃ for 8 hours, then 100mL of water was added to quench the reaction, and the reaction was separated by extraction with dichloromethane (300 mL). The organic mixture was over MgSO4The crude product was added to 100mL of toluene, refluxed at elevated temperature for 30 minutes, and then cooled to 5 ℃ to precipitate a yellow solid. The resulting yellow solid is filtered under vacuum, washed with cold diethyl ether and dried to give pure 2-cyanoPhenothiazine in 86% yield.
The above description is only a preferred embodiment of the present invention, and not intended to limit the present invention in other forms, and any person skilled in the art may apply the above modifications or changes to the equivalent embodiments with equivalent changes, without departing from the technical spirit of the present invention, and any simple modification, equivalent change and change made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the technical spirit of the present invention.
Claims (8)
1. A synthetic method of 2-cyanophenothiazine is characterized by comprising the following steps: the method comprises the following steps:
step 1, reacting 4-halogen-3-nitrobenzonitrile serving as a raw material in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
and 2, reacting the 3-amino-4-mercaptobenzonitrile with the compound C in the presence of nickel salt, a ligand and alkali to generate the 2-cyanophenothiazine. The reaction synthesis route is as follows:
x in the structural formula of 4-halogen-3-nitrobenzonitrile1Compound C formula wherein X2，X3One selected from F, Cl, Br and I.
2. A process as claimed in claim 1 for the synthesis of 2-cyanophenothiazines, wherein: in step 1, the sulfide is selected from Na2S，NaHS，K2S，KHS，(NH4)2S，NH4HS，Na2SO3The reaction temperature is 20-100 ℃.
3. A process as claimed in claim 1 or claim 2, wherein the synthesis of 2-cyanophenothiazine comprises: the mass ratio of the sulfide to the 4-halogen-3-nitrobenzonitrile is (3-4): 1.
4. a process as claimed in claim 1 for the synthesis of 2-cyanophenothiazines, wherein: in step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel trifluoromethanesulfonate, and the reaction temperature is 80-100 ℃.
5. A process as claimed in claim 1 or claim 4, wherein the synthesis of 2-cyanophenothiazine is as follows: the mass ratio of the nickel salt to the 3-amino-4-mercaptobenzonitrile is 2-5: 100.
6. a process as claimed in claim 1 for the synthesis of 2-cyanophenothiazines, wherein: in step 2, the ligand is selected from compounds of the following structure:
in the ligand structure, R1，R2，R3，R4，R5，R6，R7Selected from any one of a hydrogen atom, a linear or branched alkyl group and an aryl group.
7. A process as claimed in claim 1 or claim 6, wherein the synthesis of 2-cyanophenothiazine is as follows: the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
8. a method of synthesising 2-cyanophenothiazine as claimed in claim 6 wherein: the synthesis of the ligand comprises two steps: firstly, bromo-pyridine aldehyde ketone derivatives, formaldehyde and amine compounds are condensed under an acidic condition to generate bromo-2-azaindolizine; and step two, coupling bromo-2-azaindolizine and an imidazole derivative to obtain a ligand. The reaction synthesis route is as follows:
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| CN102532057A (en) * | 2011-11-17 | 2012-07-04 | 成都理工大学 | Copper catalytic synthesis phenothiazine compound |
| CN111039898A (en) * | 2019-12-26 | 2020-04-21 | 暨明医药科技（苏州）有限公司 | Preparation method of metopimazine intermediate |
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| CN1583732A (en) * | 2004-06-10 | 2005-02-23 | 山西大学 | Preparation of 2-cyanophenthiazine |
| CN102532057A (en) * | 2011-11-17 | 2012-07-04 | 成都理工大学 | Copper catalytic synthesis phenothiazine compound |
| CN111039898A (en) * | 2019-12-26 | 2020-04-21 | 暨明医药科技（苏州）有限公司 | Preparation method of metopimazine intermediate |
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