CN116444526A - Application of iodination reagent in Ruidexivir fragment - Google Patents
Application of iodination reagent in Ruidexivir fragment Download PDFInfo
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- 238000006192 iodination reaction Methods 0.000 title claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 14
- 239000012634 fragment Substances 0.000 title claims abstract description 14
- 230000026045 iodination Effects 0.000 title claims abstract description 12
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims abstract description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000001632 sodium acetate Substances 0.000 claims abstract description 4
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims abstract description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims abstract description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims abstract description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000005416 organic matter Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical group N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960001997 adefovir Drugs 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 2
- 239000012336 iodinating agent Substances 0.000 claims 8
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 18
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 9
- 239000007800 oxidant agent Substances 0.000 abstract description 7
- 230000001590 oxidative effect Effects 0.000 abstract description 7
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- -1 pyrrolo [1,2-b ] pyridazine-4-amine compound Chemical class 0.000 description 8
- 238000004321 preservation Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RZDNUSWOUZKGEC-UHFFFAOYSA-N pyrrolo[1,2-b]pyridazin-4-amine Chemical compound NC1=CC=NN2C=CC=C12 RZDNUSWOUZKGEC-UHFFFAOYSA-N 0.000 description 2
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 241001115401 Marburgvirus Species 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 241000711466 Murine hepatitis virus Species 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides an application of iodination reagent in Ruidexivir fragments, wherein a compound with a structure of a formula B is prepared by reacting a compound with a structure of a formula A with iodine chloride under the action of an organic solvent and alkali;wherein the alkali is one of sodium acetate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium carbonate. The invention solves the problems that the existing iodination reaction of the Ruidexivir fragment has low utilization rate of iodine atoms, so that a large amount of waste liquid is generated in the synthesis process, thereby improving the atomic utilization rate of iodination reagent, reducing the discharge of byproducts of the iodination reagent, reducing the use of oxidant and the discharge of waste liquid, reducing the production cost and reducing the effect of subsequent pollution treatment.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to application of an iodination reagent in a Ruidexivir fragment.
Background
Remdesivir (Remdesivir) is a drug developed by Ji Lide science, a nucleoside analog with antiviral activity, and has an EC50 value of 74nM for SARS-CoV and MERS-CoV in HAE cells and 30nM for murine hepatitis virus in delayed brain tumor cells. The broad-spectrum antiviral activity of rad Wei Juyou, which shows effects on a variety of emerging viral pathogens, including ebola virus, marburg virus, middle East Respiratory Syndrome (MERS), and atypical pneumonia (SARS) virus, in vitro and in vivo studies in animal models. The U.S. Food and Drug Administration (FDA) approved the antiviral drug, adefovir, of gilid science for the treatment of new coronary hospitalized patients, and became the first formally available new coronary therapeutic in the united states, month 22 of 2020.
At present, in the iodination reaction of the Ruidexivir fragment, three existing processes are mainly adopted, namely Iodinated Succinimide (NIS), iodine simple substance or sodium iodide matched with an oxidant. Wherein, the molecular weight 224.99 and the atom utilization rate of the iodinated succinimide (NIS) process are 56.4 percent. The elemental iodine process has molecular weight of 253.81 and atomic utilization of 50.0%. The process of matching the iodine simple substance or sodium iodide with the oxidant can theoretically improve the utilization rate of iodine atoms to 100 percent, but the use of the oxidant can lower the overall atomic utilization rate. Therefore, the three methods adopted at present are not high in utilization rate of iodine atoms, and a large amount of waste liquid is generated in the synthesis process, so that the method is not beneficial to environmental protection.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides application of an iodination reagent in a Ruidexivir fragment, which solves the problem of low utilization rate of iodine atoms existing in the prior art.
The invention provides an application of iodination reagent in Ruidexivir fragment, wherein the compound with the structure of formula B is prepared by reacting the compound with the structure of formula A with iodine chloride under the action of organic solvent and alkali,
wherein the alkali is one of sodium acetate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium carbonate.
Further, the polar solvent is an alcohol solvent, a ketone solvent, an ester solvent, a dipolar solvent, a polar solvent, a halogenated hydrocarbon, water or a mixed solvent of any two or more solvents.
Further, the alcohol solvent is methanol, ethanol or isopropanol; the ketone solvent is acetone, butanone, cyclopentanone or cyclohexanone; the ester solvent is ethyl acetate or isopropyl acetate; the dipolar solvent is DMF, DMSO or DMAC; the polar solvent is acetonitrile, acetic acid or propionic acid; the halohydrocarbon is dichloromethane, trichloromethane or tetrachloromethane.
Further, the mass fraction of the structural compound of the formula A in the organic solvent is 2-20%.
Further, the molar ratio of the compound of the formula A to the base to the iodine chloride is 1:0-3:0.95-1.10.
Further, the reaction comprises the steps of:
s1, uniformly stirring a solvent, alkali and a compound with a structure shown in a formula A to obtain a mixture I;
s2, dropwise adding iodine chloride into the mixture I to obtain a mixture II;
s3, distilling the mixture II under reduced pressure, and recrystallizing to obtain an organic matter III;
and S4, carrying out suction filtration and drying on the organic matter III to obtain the compound with the structure shown in the formula B.
Further, in the step S2, the dripping temperature is 0-20 ℃, and after the dripping is finished, the heat preservation reaction is carried out for 1-3 hours.
Further, in the step S3, the temperature of the reduced pressure distillation is 20-70 ℃.
Further, in the step S4, the drying temperature is 40-60 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention adopts the iodine chloride process to carry out the iodination reaction, the utilization rate of iodine atoms reaches 78.2 percent, and the utilization rate of the atoms of the iodination reagent is improved. The method reduces the discharge of byproducts of iodizing reagent, reduces the use of oxidant and the discharge of waste liquid, reduces the production cost and reduces the subsequent pollution treatment.
Drawings
FIG. 1 is a process flow diagram of the present invention.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following description, taken in conjunction with the accompanying drawings, and not to the limitation of the present invention.
As shown in fig. 1, the process of the present invention is implemented in a flowchart, and the steps described in the figures can be performed.
Example 1
Preparation of a compound of formula B:
s1, adding 133.15g of pyrrolo [1,2-b ] pyridazine-4-amine compound with a structure shown in a formula A into a four-port reaction bottle, adding 650g of acetone, adding 53.0g of sodium carbonate, starting stirring, and uniformly mixing to obtain a mixture I.
S2, dissolving 162.35g of iodine chloride in 320g of dichloromethane to obtain an iodine chloride solution, dropwise adding the iodine chloride solution into the mixture I, controlling the internal temperature of a reaction bottle to be 0-20 ℃, and carrying out heat preservation reaction for 3 hours after the dropwise addition to obtain a mixture II, wherein the obtained liquid phase of the mixture II is detected, and the iodine chloride content is less than or equal to 1%.
S3, carrying out reduced pressure distillation on the mixture II at the temperature of 20-70 ℃ until no solvent exists, and obtaining an organic matter III.
S4, adding water into the organic matter III, pulping for 3 hours, crystallizing, carrying out suction filtration on an organic phase after crystallizing, drying a product obtained after suction filtration at 40-60 ℃, and obtaining the compound 7-iodopyrrolo [1,2-B ] pyridazine-4-amine with the structure of formula B, wherein 246.10g of the compound with the structure of formula B is detected, and the yield is 95.0% and the purity is 98.1%.
Example 2
Preparation of a compound of formula B:
s1, adding 133.15g of pyrrolo [1,2-b ] pyridazine-4-amine compound with a structure shown in a formula A into a four-port reaction bottle, adding 650g of methanol, adding 82.03g of sodium acetate, and stirring and uniformly mixing to obtain a mixture I.
S2, dissolving 162.35g of iodine chloride in 320g of dichloromethane to obtain an iodine chloride solution, dropwise adding the iodine chloride solution into the mixture I, controlling the internal temperature of a reaction bottle to be 0-20 ℃, and carrying out heat preservation reaction for 3 hours after the dropwise addition to obtain a mixture II, wherein the obtained liquid phase of the mixture II is detected, and the iodine chloride content is less than or equal to 1%.
S3, carrying out reduced pressure distillation on the mixture II at the temperature of 20-70 ℃ until no solvent exists, and obtaining an organic matter III.
S4, adding water into the organic matter III, pulping for 3 hours, crystallizing, carrying out suction filtration on an organic phase after crystallizing, drying a product obtained after suction filtration at 40-60 ℃, and obtaining the compound 7-iodopyrrolo [1,2-B ] pyridazine-4-amine with the structure of formula B, wherein 249.10g of the compound with the structure of formula B is detected, and the yield is 96.2% and the purity is 98.4%.
Example 3
Preparation of a compound of formula B:
s1, adding 133.15g of pyrrolo [1,2-b ] pyridazine-4-amine with a structure shown in a formula A into a four-port reaction bottle, adding 650g of acetonitrile, adding 69.1g of potassium carbonate, starting stirring, and uniformly mixing to obtain a mixture I.
S2, dissolving 154.23g of iodine chloride in 320g of chloroform to obtain an iodine chloride solution, dropwise adding the iodine chloride solution into the mixture I, controlling the internal temperature of a reaction bottle to be 0-20 ℃, and carrying out heat preservation reaction for 3 hours after the dropwise addition to obtain a mixture II, wherein the obtained liquid phase of the mixture II is detected, and the iodine chloride content is less than or equal to 1%.
S3, carrying out reduced pressure distillation on the mixture II at the temperature of 20-70 ℃ until no solvent exists, and obtaining an organic matter III.
S4, adding water into the organic matter III, pulping for 3 hours, crystallizing, carrying out suction filtration on an organic phase after crystallizing, drying a product obtained after suction filtration at 40-60 ℃, and obtaining the compound 7-iodopyrrolo [1,2-B ] pyridazine-4-amine with the structure of formula B, wherein 245.58g of the compound with the structure of formula B is detected, and the yield is 94.8% and the purity is 98.8%.
Example 4
Preparation of a compound of formula B:
s1, adding 133.15g of pyrrolo [1,2-b ] pyridazine-4-amine with a structure shown in a formula A into a four-port reaction bottle, adding 650g of acetonitrile, adding 138.2g of potassium carbonate, starting stirring, and uniformly mixing to obtain a mixture I.
S2, dissolving 170.47g of iodine chloride in 320g of acetic acid to obtain an iodine chloride solution, dropwise adding the iodine chloride solution into the mixture I, controlling the internal temperature of a reaction bottle to be 0-20 ℃, and carrying out heat preservation reaction for 3 hours after the dropwise addition to obtain a mixture II, wherein the obtained liquid phase of the mixture II is detected, and the iodine chloride content is less than or equal to 1%.
S3, carrying out reduced pressure distillation on the mixture II at the temperature of 20-70 ℃ until no solvent exists, and obtaining an organic matter III.
S4, adding water into the organic matter III, pulping for 3 hours, crystallizing, carrying out suction filtration on an organic phase after crystallizing, drying a product obtained after suction filtration at 40-60 ℃, and obtaining the compound 7-iodopyrrolo [1,2-B ] pyridazine-4-amine with the structure of formula B, wherein 238.84g of the compound with the structure of formula B is detected, and the yield is 92.2% and the purity is 98.1%.
Example 5
Preparation of a compound of formula B:
s1, adding 133.15g of pyrrolo [1,2-b ] pyridazine-4-amine compound with a structure shown in a formula A into a four-port reaction bottle, adding 650g of DMF, adding 69.1g of potassium carbonate, starting stirring, and uniformly mixing to obtain a mixture I.
S2, dissolving 178.59g of iodine chloride in 320g of DMF to obtain iodine chloride solution, dropwise adding the iodine chloride solution into the mixture I, controlling the internal temperature of a reaction bottle to be 0-20 ℃, and carrying out heat preservation reaction for 3 hours after the dropwise addition to obtain a mixture II, wherein the obtained liquid phase of the mixture II is detected, and the iodine chloride content is less than or equal to 1%.
S3, carrying out reduced pressure distillation on the mixture II at the temperature of 20-70 ℃ until no solvent exists, and obtaining an organic matter III.
S4, adding water into the organic matter III, pulping for 3 hours, crystallizing, carrying out suction filtration on an organic phase after crystallizing, drying a product obtained after suction filtration at 40-60 ℃, and obtaining the compound 7-iodopyrrolo [1,2-B ] pyridazine-4-amine with the structure of formula B, wherein 246.87g of the compound with the structure of formula B is detected, and the yield is 95.3% and the purity is 98.7%.
The invention adopts the iodine chloride (ICl) process to carry out the iodination reaction, and the atomic utilization rate of the iodination reagent is improved by calculating the atomic utilization rate to reach 78.2 percent. By calculating the atomic utilization difference, compared with NIS technology, the emission of iodination reagent byproducts is reduced by 22%; compared with the simple iodine process, the method reduces the discharge of 28% of byproducts of the iodizing reagent, and compared with the iodine-adding oxidant process, saves the use of the oxidant and the discharge of three wastes, and compared with the traditional three processes, the method has obvious advantages and innovations.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (9)
1. The application of iodination reagent in Ruidexivir fragment is characterized in that the compound with the structure of formula B is prepared by reacting the compound with the structure of formula A with iodine chloride under the action of organic solvent and alkali;
wherein the alkali is one of sodium acetate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium carbonate.
2. The use of an iodinating agent according to claim 1 in a adefovir dipivoxil fragment, wherein said organic solvent is an alcoholic solvent, a ketone solvent, an ester solvent, a dipolar solvent, a polar solvent, a halogenated hydrocarbon, water or a mixed solvent of any two or more solvents thereof.
3. The use of an iodinating agent according to claim 2 in a fragment of adefovir, wherein the alcoholic solvent is methanol, ethanol or isopropanol; the ketone solvent is acetone, butanone, cyclopentanone or cyclohexanone; the ester solvent is ethyl acetate or isopropyl acetate; the dipolar solvent is DMF, DMSO or DMAC; the polar solvent is acetonitrile, acetic acid or propionic acid; the halohydrocarbon is dichloromethane, trichloromethane or tetrachloromethane.
4. The use of an iodinating agent according to claim 2 in a adefovir dipivoxil fragment, wherein the mass fraction of the compound of formula a in an organic solvent is 2-20%.
5. Use of an iodinating agent according to claim 1 in a fragment of adefovir, wherein the molar ratio of the compound of formula a, the base and iodine chloride is 1:0-3:0.95-1.10.
6. Use of an iodinating agent according to claim 1 in a fragment of adefovir, said reaction comprising the steps of:
s1, uniformly stirring a solvent, alkali and a compound with a structure shown in a formula A to obtain a mixture I;
s2, dropwise adding iodine chloride into the mixture I to obtain a mixture II;
s3, distilling the mixture II under reduced pressure, and recrystallizing to obtain an organic matter III;
and S4, carrying out suction filtration and drying on the organic matter III to obtain the compound with the structure shown in the formula B.
7. The use of an iodinating agent according to claim 6 in a adefovir dipivoxil fragment, wherein in the step S2, the dropping temperature is 0-20 ℃, and the reaction is kept for 1-3 hours after the completion of the dropping.
8. Use of an iodinating agent according to claim 6 in a fragment of adefovir, in said S3 step, distillation under reduced pressure at a temperature of 20-70 ℃.
9. The use of an iodinating agent according to claim 6 in a fragment of adefovir, wherein in said step S4 the drying temperature is 40-60 ℃.
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