CN115557936A - Preparation method and application of pomalidomide derivative capable of being used as feed additive - Google Patents
Preparation method and application of pomalidomide derivative capable of being used as feed additive Download PDFInfo
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- CN115557936A CN115557936A CN202211301550.8A CN202211301550A CN115557936A CN 115557936 A CN115557936 A CN 115557936A CN 202211301550 A CN202211301550 A CN 202211301550A CN 115557936 A CN115557936 A CN 115557936A
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- dione
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- dichloromethane
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- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical class O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 239000003674 animal food additive Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 12
- 108010046334 Urease Proteins 0.000 claims abstract description 7
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims abstract description 4
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 122
- 238000003756 stirring Methods 0.000 claims description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 93
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 63
- 239000000243 solution Substances 0.000 claims description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 34
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000012074 organic phase Substances 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 28
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 150000001540 azides Chemical class 0.000 claims description 21
- VXDTWULFGNROJV-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-iodoisoindole-1,3-dione Chemical compound O=C1C=2C(I)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O VXDTWULFGNROJV-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 16
- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 14
- 239000012141 concentrate Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 229940095102 methyl benzoate Drugs 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 10
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 claims description 8
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical group NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 claims description 8
- JXYITCJMBRETQX-UHFFFAOYSA-N 4-ethynylaniline Chemical group NC1=CC=C(C#C)C=C1 JXYITCJMBRETQX-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KVRCAGKHAZRSQX-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindole-1,3-dione Chemical compound O=C1C=2C([N+](=O)[O-])=CC=CC=2C(=O)N1C1CCC(=O)NC1=O KVRCAGKHAZRSQX-UHFFFAOYSA-N 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 6
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 5
- -1 2- (2-azidoethoxy) ethoxy Chemical group 0.000 claims description 5
- OJEKEINAGFAPKG-UHFFFAOYSA-N 2-[2-(2-azidoethoxy)ethoxy]acetaldehyde Chemical compound [N-]=[N+]=NCCOCCOCC=O OJEKEINAGFAPKG-UHFFFAOYSA-N 0.000 claims description 5
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 5
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 5
- 229910052750 molybdenum Inorganic materials 0.000 claims description 5
- 239000011733 molybdenum Substances 0.000 claims description 5
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- 239000004304 potassium nitrite Substances 0.000 claims description 5
- 235000010289 potassium nitrite Nutrition 0.000 claims description 5
- 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 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
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- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
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- 239000007787 solid Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
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- ZHWGWSYNZIZTFL-UHFFFAOYSA-N 2-[2-(2-azidoethoxy)ethoxy]ethanamine Chemical compound NCCOCCOCCN=[N+]=[N-] ZHWGWSYNZIZTFL-UHFFFAOYSA-N 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
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- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical class O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
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- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims 2
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Abstract
The invention discloses a preparation method and application of pomalidomide derivatives capable of being used as feed additives, belonging to the technical field of synthesis of feed additives. The technical scheme provided by the invention has the key points that: the pomalidomide derivative has the structure
The invention synthesizes the pomalidomide derivative with a novel structure by a novel method, and researches on the inhibition of urease in bovine stomach are carried out, and part of compounds are shown at a certain concentrationThe compound has obvious inhibition effect on urease and IDO1 enzyme, can improve the immunity of organisms, and is expected to be applied to feed additives.
Description
Technical Field
The invention belongs to the technical field of synthesis of feed additives, and particularly relates to a preparation method and application of pomalidomide derivatives capable of serving as feed additives.
Background
Immune Modulators (IMiD) can increase the production of IL-2 of T lymphocytes and reduce the production of proinflammatory cytokines, and the effects of the IMiD can be widely applied to the clinical treatment of diseases such as tumors and the like. Pomalidomide (Pomalidomide) is a third-generation immunomodulatory drug (IMiD) developed by Celgene corporation of America, and is a drug modified and synthesized on the basis of the chemical structure of the first-generation IMiD thalidomide, and can enhance the immune reaction mediated by T cells and natural killer cells, inhibit the generation of monocyte proinflammatory cytokines, induce tumor cell apoptosis, and is widely concerned in the treatment of various malignant tumors and immunological diseases. Compared with the first-generation and second-generation IMiDs, pomalidomide has stronger pharmacology, smaller toxicity and better patient tolerance, and has good anti-angiogenesis, anti-tumor chemical book and anti-inflammatory response effects which are widely accepted in the early clinical research of Multiple Myeloma (MM). At present, few reports on the treatment of the pomalidomide in the aspect of melanoma are reported, and the molecular structure of pomalidomide is expected to be modified, so that the pomalidomide has an inhibitory effect on the melanoma.
The Urea (Urea) structural fragment is an important dominant framework in pharmaceutical chemistry, and compounds containing Urea structures generally have multiple biological activities and become one of the most commonly used dominant fragments in drug design. Structurally, the urea is linked by two amino groups through an intermediate carbonyl group. The carbonyl group can accept two hydrogen bonds as a hydrogen bond acceptor, and the proton on the N atom can provide a 2-4 hydrogen bond (depending on the substituent of the N atom) as a hydrogen bond donor. Urea has an ultra-strong hydrogen bond forming ability, and can form an intermolecular hydrogen bond through NH of one molecule and carbonyl oxygen atom of the other molecule, thereby forming an organized structure such as a chain, a band, an alpha or beta layer and the like. Therefore, the introduction of the urea structural fragment in the design and optimization of the drug molecule can improve the activity, increase the selectivity, regulate the physicochemical property, help to overcome the metabolic stability, remove toxic pharmacophore and the like. The company designs an IDO1 inhibitor with a urea structure, which can improve the immunity of the organism, inhibit the activity of urease and be used as a feed additive for improving the immunity.
The pomalidomide molecular structure is frequently used for connecting a ligand of E3 ligase in a PROTAC molecule at present, and plays a very important role in researching the development of a very hot protease degradation drug, so that an ether chain structure is introduced into the pomalidomide structure according to a PROTAC molecular design method, and then the other end of the ether chain is connected with urea compounds with different substituents, and the compound molecule is expected to inhibit the activity of urease in a protein degradation mode and be used for a feed additive.
Disclosure of Invention
The invention aims to provide a preparation method and application of pomalidomide derivative serving as a feed additive.
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the pomalidomide derivative is characterized by comprising the following specific steps of:
1. adding a certain amount of methyl benzoate and calcium carbonate into a dichloroethane solution, stirring, slowly dropwise adding the dichloroethane solution dissolved with iodine chloride, heating to reflux and stirring for a period of time after dropwise adding, cooling and filtering the reaction solution, adding anhydrous magnesium sulfate, stirring and filtering, adding a certain amount of 3-aminopiperidine-2, 6-dione hydrochloride, triethylamine and N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for a period of time at room temperature, concentrating, washing the concentrate for a plurality of times with diethyl ether, adding the concentrate into toluene, adding triphenylphosphine and iodine simple substance, heating to reflux, removing water in the reaction system through a water separator, adding a certain amount of palladium acetate and triethylamine, stirring for a period of time under the protection of nitrogen, adding anhydrous formic acid, keeping the nitrogen atmosphere, adjusting the temperature of the reaction system to 80 ℃, stopping the reaction after the reaction is finished, filtering the reaction solution hot, adding water, extracting for a plurality of times with dichloromethane after stirring, combining organic phases, and concentrating to obtain 2- (2, 6-dioxo-piperidin-3-yl) -4-iodo-isoindoline-1, 3-dione.
2. Adding a certain amount of methyl benzoate and calcium carbonate into a dichloroethane solution, stirring, slowly dropwise adding the dichloroethane solution dissolved with a certain amount of iodine chloride, heating to reflux and stirring for a period of time after dropwise adding, cooling and filtering the reaction solution, adding anhydrous magnesium sulfate, stirring and filtering, adding a certain amount of 3-aminopiperidine-2, 6-dione hydrochloride, triethylamine and N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for a period of time at room temperature, concentrating, washing the concentrate with diethyl ether for a plurality of times, adding the concentrate into glycerol, placing into a high-pressure reaction kettle, adding a certain amount of triphenylphosphine palladium chloride, molybdenum acetylacetonate and an alkaline substance, uniformly stirring, removing air in the reaction kettle in vacuum, introducing carbon monoxide to make the pressure in the reaction kettle reach a certain value, slowly heating to a certain temperature, keeping the pressure in the reaction kettle constant, filtering the reaction solution after the reaction is finished, adding water into the reaction system while the reaction system is hot, adding dichloromethane, stirring, filtering the reaction solution, separating an organic phase, extracting a water phase with dichloromethane, merging the organic phases, separating and purifying by silica gel column chromatography to obtain 2- (2, 6-3-dioxopiperidine) -3-indole-1-3-indole-base.
3. Adding a certain amount of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione, copper powder and potassium nitrite into N, N-dimethylformamide, stirring at room temperature under the protection of nitrogen for a period of time, adding 50mL of N, N-dimethylformamide in which N, N-dimethylethylenediamine, zinc iodide and cuprous iodide are dissolved, keeping the nitrogen protection atmosphere, slowly heating to a certain temperature, pouring the reaction liquid into water after the reaction is completed, filtering the reaction liquid, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain 2- (2, 6-dioxo-piperidine-3-yl) -4-nitroisoindoline-1, 3-dione.
4. Adding a certain amount of 2- (2, 6-dioxopiperidine-3-yl) -4-nitroisoindoline-1, 3-dione and palladium acetate into a mixed solution of N, N-dimethylformamide, ethanol, tetrahydrofuran and acetone in a high-pressure reaction kettle, stirring, introducing hydrogen into the reaction kettle, replacing gas in a reaction system for three times, heating the reaction kettle to 50 ℃, stirring for reacting till the raw materials completely react, pouring a reaction liquid into water, filtering the reaction liquid, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain the 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione.
5. Adding a certain amount of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione and 2- (2- (2- (2-azidoethoxy) ethoxy) ethyoxyl) ethane-1-amine into N, N-dimethylformamide, stirring to dissolve, then adding N, N-diisopropylethylamine, stirring to react at room temperature until the raw material 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione completely reacts, stirring the reaction liquid, pouring into water, continuously stirring for a period of time, then extracting the reaction system for multiple times by dichloromethane, combining organic phases, drying by anhydrous sodium sulfate, concentrating in vacuum, and separating by silica gel column chromatography to obtain the azide intermediate compound.
6. Adding a certain amount of 2- (2- (2- (2-azidoethoxy) ethoxy) ethane-1-aldehyde and acetic acid into N, N-dimethylformamide, stirring for dissolving, then adding 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione, stirring for a period of time at room temperature, cooling a reaction system to 0 ℃, slowly dropwise adding N, N-dimethylformamide dissolved with sodium triacetoxyborohydride or sodium borohydride, heating to room temperature after dropwise adding, monitoring by TLC that raw materials are completely reacted, then pouring a reaction solution into water, extracting for multiple times by using dichloromethane, combining organic phases, concentrating, adding ethanol for dissolving, heating to reflux under the protection of nitrogen, reacting for a period of time to 0 ℃, separating out solids, and drying after suction filtration to obtain an azide intermediate compound.
7. Adding a certain amount of azide intermediate compound and 4-aminophenylacetylene or 3-aminophenylacetylene into a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol, adding cuprous iodide, protecting with nitrogen, heating to 80 ℃, carrying out reflux reaction for a period of time, extracting with dichloromethane, combining organic phases, adding phenyl isocyanate compounds, stirring for a period of time, filtering with diatomite, carrying out vacuum concentration on the filtrate, and carrying out silica gel column chromatography separation with dichloromethane and methanol (V/V = 15) to obtain the target compound.
The invention has the technical advantages that: according to the invention, pomalidomide and urea compounds are connected through long ether chains, the urea structure can be used as an IDO1 inhibitor, pomalidomide can be used as a ligand of E3 ubiquitin enzyme, the obtained micromolecules can degrade the IDO1 enzyme activity and have an inhibition effect on urease, a simple and efficient method for generating nitrobenzene by iodobenzene is developed, and a method for condensation connection of aldehyde group and aniline is developed, so that the method is suitable for industrial mass production.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the objective compound prepared in example 1.
FIG. 2 is a nuclear magnetic hydrogen spectrum of the objective compound prepared in example 12.
FIG. 3 is a nuclear magnetic hydrogen spectrum of the objective compound produced in example 13.
FIG. 4 is a nuclear magnetic hydrogen spectrum of the objective compound produced in example 18.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be understood that the scope of the subject matter of the present invention is limited to the examples below, and any technique realized based on the above contents of the present invention falls within the scope of the present invention.
Example 1
Adding 1.4g of methyl benzoate and 3g of calcium carbonate into 100mL of dichloroethane solution in a reaction bottle with a stirring device, slowly dropwise adding 100mL of dichloroethane solution dissolved with 4g of iodine chloride after stirring, heating to reflux and stirring for 1.5h after dropwise adding, then cooling and filtering the reaction solution, adding 10g of anhydrous magnesium sulfate, stirring for 20min and filtering, adding 1.7g of 3-aminopiperidine-2, 6-dione hydrochloride and 1g of triethylamine and 2g of N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for 15h at room temperature, washing the concentrate for multiple times by 50mL of diethyl ether after concentrating, then adding the concentrate into 100mL of toluene, adding 2.6g of triphenylphosphine and 3g of iodine simple substance, heating to reflux, removing water in a reaction system through a water separator, then adding 0.23g of palladium acetate and 1g of triethylamine, stirring for 30min under the protection of nitrogen, then adding 1.5g of anhydrous formic acid, keeping the nitrogen atmosphere, adjusting the temperature of the reaction system to 80 ℃, reacting for 5h, stopping the reaction, filtering the reaction liquid while hot, adding 100mL of water into filtrate, extracting for multiple times by 50mL of dichloromethane after stirring, combining organic phases, concentrating in vacuum, washing by petroleum ether, and drying to obtain 3.59g of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione; 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.24(d,J＝4.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.54(t,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),5.13(dd,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),2.89-2.81(m,1H),2.59-2.47(m,2H),2.06-2.00(m,1H)。
example 2
Adding 1.4g of methyl benzoate and 3g of calcium carbonate into 100mL of dichloroethane solution in a reaction bottle with a stirring device, slowly dropwise adding 100mL of dichloroethane solution dissolved with 4g of iodine chloride after stirring, heating to reflux and stirring for 1.5h after dropwise adding, then cooling and filtering the reaction solution, adding 10g of anhydrous magnesium sulfate, stirring for 20min and filtering, adding 1.7g of 3-aminopiperidine-2, 6-dione hydrochloride into the filtrateAnd 1g of triethylamine and 2g of N, N' -dicyclohexylcarbodiimide, stirring and reacting for 15h at room temperature, washing the concentrate for multiple times by using 50mL of diethyl ether after concentrating, adding the concentrate into 150mL of glycerol, placing the concentrate into a high-pressure reaction kettle, adding 0.28g of palladium chloride triphenylphosphine and 0.65g of molybdenum acetylacetonate as well as 1.8g of N, N-dimethylethanolamine, uniformly stirring, removing air in the reaction kettle in vacuum, introducing carbon monoxide to ensure that the pressure in the reaction kettle reaches 1.5MPa, slowly heating to 120 ℃, keeping the pressure in the reaction kettle unchanged, reacting for 5h, stopping the reaction, filtering the reaction liquid, adding 100mL of water into the reaction system while the reaction system is hot, adding 50mL of dichloromethane, filtering the reaction liquid after stirring, separating an organic phase from a filtrate, extracting an aqueous phase for multiple times by using 50mL of dichloromethane, combining the organic phases, concentrating, and purifying by silica gel column chromatography to obtain 3.11g of 2- (2, 6-dioxo-piperidin-3-yl) -4-iodo-isoindole-1, 3-dione; 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.24(d,J＝4.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.54(t,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),5.13(dd,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),2.89-2.81(m,1H),2.59-2.47(m,2H),2.06-2.00(m,1H)。
example 3
Adding 1.4g of methyl benzoate and 3g of calcium carbonate into 100mL of dichloroethane solution in a reaction bottle with a stirring device, slowly dropwise adding 100mL of dichloroethane solution dissolved with 4g of iodine chloride after stirring, heating to reflux and stirring for 1.5h after dropwise adding, then cooling and filtering the reaction solution, adding 10g of anhydrous magnesium sulfate, stirring for 20min and filtering, adding 1.7g of 3-aminopiperidine-2, 6-dione hydrochloride and 1g of triethylamine and 2g of N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for 15h at room temperature, washing the concentrate for multiple times by 50mL of diethyl ether after concentrating, adding 150mL of glycerol, placing into a high-pressure reaction kettle, adding 0.28g of triphenylphosphine palladium chloride, 0.6g of molybdenum acetylacetonate and 1.7g of potassium tert-butoxide, uniformly stirring, then removing air in the reaction kettle in vacuum, then introducing carbon monoxide, and enabling the internal pressure of the reaction kettle to be uniform, introducing carbon monoxide into the reaction kettleHeating to 95 ℃ slowly until the pressure in the reaction kettle is kept constant, reacting for 12h, stopping the reaction, filtering the reaction solution, namely adding 100mL of water into the reaction system while the reaction system is hot, then adding 50mL of dichloromethane, stirring, filtering the reaction solution, separating the filtrate into an organic phase, extracting the aqueous phase for multiple times by using 50mL of dichloromethane, combining the organic phases, concentrating, and separating and purifying by silica gel column chromatography to obtain 3.65g of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione; 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.24(d,J＝4.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.54(t,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),5.13(dd,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),2.89-2.81(m,1H),2.59-2.47(m,2H),2.06-2.00(m,1H)。
example 4
In a reaction flask with a stirring device, 3.9g of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione, 0.19g of copper powder and 1.7g of potassium nitrite are added to 150mL of N, N-dimethylformamide, stirring is carried out at room temperature for 1h under nitrogen protection, then N, N-dimethylethylenediamine 1.8g and zinc iodide 0.32g and cuprous iodide 50mL are added, nitrogen protection is maintained, the temperature is slowly raised to 120 ℃ and the reaction is carried out for 6.5h, then the reaction solution is filtered, the filtrate is placed at 0 ℃, 50mL of an ethanol solution containing nitrosamine 0.7g is added under nitrogen protection according to laboratory dangerization product usage rules, attention is paid to keeping nitrogen and low temperature during dropwise addition, stirring is carried out for 30min after dropwise addition is finished, the unreacted reactant is further converted, then the reaction solution is poured into 200mL of water, the reaction solution is filtered by stirring, 100mL of dichloromethane, the extraction is carried out, the organic phase is combined with 2- (2.6-dioxo-piperidine-3-yl) -4-isoindoline-1, 14g of 2-nitro-2-3-dione is separated by chromatography for a plurality of times, 2- (3-nitro-diketone), 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.32(d,J＝8.0Hz,1H),8.20(d,J＝4.0Hz,1H),8.08(t,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),5.16(dd,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),2.89-2.81(m,1H),2.60-2.48(m,2H),2.06-2.01(m,1H)。
example 5
In a reaction flask with a stirring device, 3.9g of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione, 0.38g of copper powder and 1.7g of potassium nitrite are added to 150mL of N, N-dimethylformamide, stirring is carried out at room temperature for 1h under nitrogen protection, then 2.7g of N, N-dimethylethylenediamine dissolved in N, N-dimethylethylenediamine, 0.32g of zinc iodide and 0.19g of cuprous iodide are added to 50mL of N, N-dimethylformamide, the temperature is slowly raised to 120 ℃ under nitrogen protection, the reaction solution is filtered after 4h of reaction, the filtrate is placed at 0 ℃, 50mL of ethanol solution dissolved with 0.7g of nitrosamine is added under nitrogen protection, attention is paid to the maintenance of nitrogen and low temperature during the dropwise addition, stirring is carried out for 30min after the dropwise addition, then the reaction solution is poured into 200mL of water, the reaction solution is filtered under stirring, then 100mL of dichloromethane is extracted for a plurality of times, the organic phase is combined, the organic phase is concentrated and separated by silica gel column chromatography to obtain 2- (2, 6-piperidine-3-yl) -4-isoindoline-1, 3-dione, 76g, 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.32(d,J＝8.0Hz,1H),8.20(d,J＝4.0Hz,1H),8.08(t,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),5.16(dd,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),2.89-2.81(m,1H),2.60-2.48(m,2H),2.06-2.01(m,1H)。
example 6
In a high-pressure reaction kettle, adding 3g of 2- (2, 6-dioxopiperidine-3-yl) -4-nitroisoindoline-1, 3-dione and 0.23g of palladium acetate into a mixed solution of 5mL of N, N-dimethylformamide, 10mL of ethanol, 50mL of tetrahydrofuran and 50mL of acetone, stirring, introducing hydrogen into the reaction kettle, replacing gas in a reaction system for three times, heating the reaction kettle to 50 ℃ under the pressure of 0.5MPa, stirring for reaction for 2 hours, monitoring the reaction of raw materials by TLC, pouring the reaction liquid into 100mL of water, filtering the reaction liquid, extracting the reaction liquid by 50mL of dichloromethane for multiple times, combining organic phases, concentrating, and performing silica gel column chromatography to obtain 2.47g of 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione.
Example 7
In a reaction flask with a stirring device, 3.9g of 2- (2, 6-dioxo-piperidin-3-yl) -4-iodo-isoindole-1, 3-dione and 2.2g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethan-1-amine were added to 100mL of N, N-dimethylformamide, and after stirring and dissolving, 2.5g of N, N-diisopropylethylamine was added thereto, and after stirring at room temperature for 40min, TLC-monitored completion of the reaction of the raw material, 2- (2, 6-dioxo-piperidin-3-yl) -4-iodo-isoindole-1, 3-dione, the reaction solution was stirred and poured into water to continue stirring for a while, then the reaction system was extracted with dichloromethane for a plurality of times, the organic phases were combined, dried over anhydrous sodium sulfate, vacuum-concentrated, and then subjected to silica gel column chromatography to obtain 4.36g of an azide intermediate compound.
Example 8
Adding 2.2g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethane-1-aldehyde and 10mL of acetic acid into 100mL of N, N-dimethylformamide in a reaction bottle with a stirring device, stirring to dissolve, then adding 2.8g of 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione into the reaction bottle, stirring for 30min at room temperature, then cooling the reaction system to 0 ℃, slowly dropwise adding 100mL of N, N-dimethylformamide dissolved with 3.1g of sodium triacetoxyborohydride, heating to room temperature after dropwise adding, monitoring the complete reaction of raw materials by TLC, then pouring the reaction solution into 200mL of water, extracting for multiple times by using 80mL of dichloromethane, combining organic phases, adding ethanol to dissolve after concentration, heating to reflux under the protection of nitrogen, reacting for 2h, cooling to 0 ℃, precipitating solids, and drying to obtain 4.49g of the azide intermediate.
Example 9
Adding 2.2g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethane-1-aldehyde and 10mL of acetic acid into 100mL of N, N-dimethylformamide in a reaction bottle with a stirring device, stirring to dissolve, then adding 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione 2.8g, stirring for 30min at room temperature, cooling the reaction system to 0 ℃, slowly adding N, N-dimethylformamide containing 1.1g of sodium borohydride in 70mL, heating to room temperature after adding completely, monitoring the complete reaction of raw materials by TLC, then pouring the reaction liquid into 200mL of water, extracting for multiple times by using 80mL of dichloromethane, combining organic phases, adding ethanol after concentrating, heating to reflux under the protection of nitrogen, reacting for 2h, cooling to 0 ℃, precipitating solids, and then drying to obtain 4.16g of azide intermediate compound.
Example 10
In a reaction flask with a stirring device, adding 4.8g of azide intermediate compound and 1.4g of 4-aminophenylacetylene into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1; 1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),9.86-9.70(m,1H),8.42(s,1H),7.76(d,J＝4.0Hz,2H),7.69(d,J＝4.0Hz,2H),7.64(d,J＝4.0Hz,2H),7.58-7.54(m,3H),7.11(d,J＝4.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.57(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),5.07-5.04(m,1H),4.54(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.85(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.58–3.50(m,12H),2.90-2.85(m,1H),2.63-2.57(m,1H),2.04–1.98(m,1H),1.88-1.80(m,1H)。
example 11
In a reaction flask with a stirring device, adding 4.8g of azide intermediate compound and 1.4g of 3-aminophenylacetylene into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1; 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.58(s,1H),8.35(d,J＝8.0Hz,1H),7.42(t,J 1 ＝4.0Hz,J 2 ＝8.0Hz,1H),7.27-7.18(m,5H),6.96–6.89(m,2H),6.75(d,J＝12.0Hz,2H),6.46–6.42(m,1H),5.62(s,1H),4.94(dd,J 1 ＝8.0Hz,J 2 ＝4.0Hz,1H),4.45–4.40(m,2H),3.74(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.60(s,3H),3.45-3.41(m,7H),3.29–3.26(m,4H),2.82–2.72(m,1H),2.46-2.38(m,2H),1.91(d,J＝8.0Hz,1H)。
example 12
In a reaction flask equipped with a stirring device, 4.8g of azide intermediate compound and 1.4g of 3-aminophenylacetylene were added to distilled water, tetrahydrofuran and tert-butanolTo 200mL of the mixed solvent (volume ratio of three: 1), 0.19g of cuprous iodide was added, the mixture was heated to 80 ℃ under nitrogen protection, reflux reaction was carried out for 7h, tlc monitored that the raw materials were completely reacted, the reaction was stopped, 50mL of dichloromethane was used for extraction for 4 times, the organic phases were combined, 2.2g of 4-bromophenyl isocyanate was added, the mixture was stirred for a while, and then filtered through celite, the filtrate was concentrated in vacuo, and the target compound was isolated by silica gel column chromatography using dichloromethane and methanol (V/V = 15). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),8.86(s,2H),8.50(s,1H),8.07(s,1H),7.57(t,J 1 ＝8.0Hz,J 2 ＝8.0Hz,1H),7.49–7.45(m,5H),7.42-7.35(m,2H),7.11-7.05(m,2H),6.59(s,1H),5.09(dd,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),4.59(s,2H),3.89(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.60–3.53(m,10H),3.44(s,2H),2.96-2.87(m,1H),2.62–2.52(m,2H),2.07–2.02(m,1H)。
Example 13
In a reaction flask with a stirring device, 4.8g of azide intermediate compound and 1.4g of 3-aminophenylacetylene are added into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1.
Example 14
In a reaction flask with a stirring device, 4.8g of azide intermediate compound and 1.4g of 3-aminophenylacetylene are added into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1.
Example 15
In a reaction flask with a stirring device, 4.8g of azide intermediate compound and 1.4g of 3-aminophenylacetylene are added into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1.
Example 16
In a reaction flask with a stirring device, 4.8g of azide intermediate compound and 1.4g of 4-aminophenylacetylene are added into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1.
Example 17
In a reaction flask with a stirring device, 4.8g of azide intermediate compound and 1.4g of 4-aminophenylacetylene are added into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1.
Example 18
Adding 4.8g of azide intermediate compound and 1.4g of 4-aminophenylacetylene into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1; 1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),8.84(s,1H),8.81(s,1H),8.41(s 1H),7.75(d,J＝8.0Hz,2H),7.57-7.52(m,3H),7.47-7.43(m,5H),7.11(d,J＝4.0Hz,1H),7.04(d,J＝4.0Hz,1H),6.58(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),5.07-5.04(m,1H),4.54(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.85(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.58–3.51(m,10H),3.43-3.41(m,2H),2.91–2.85(m,1H),2.60-2.55(m,1H),2.04–2.01(m,1H)。
example 19
Adding 4.8g of azide intermediate compound and 1.4g of 4-aminophenylacetylene into 200mL of a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol (the volume ratio of the three is 1; 1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),8.83(s,1H),8.80(s,1H),8.41(s 1H),7.75(d,J＝8.0Hz,2H),7.57-7.49(m,5H),7.34(d,J＝4.0Hz,2H),7.11(d,J＝4.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.57(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,1H),5.07-5.04(m,1H),4.54(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.85(t,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),3.58–3.50(m,10H),3.42(dd,J 1 ＝4.0Hz,J 2 ＝4.0Hz,2H),2.91–2.85(m,1H),2.60-2.57(m,1H),2.03–2.01(m,1H)。
example 20
After cell recovery, heLa cells were plated at 5x10 per well 4 Inoculating into 96-well plate, adding DMEM culture solution into the well, putting the 96-well plate into 5% 2 Was cultured overnight in a 37 ℃ incubator. After 24 hours, human IFN-. Gamma.was added (diluted with culture broth) and test compound solutions (diluted with culture broth to different concentrations of 0.1,1, 10,0.3,3, 30. Mu.M)Add to each well 20 μ L per well. Putting 96-well plates into 5% CO 2 Was cultured overnight in a 37 ℃ incubator. After 48 hours, 140 μ L of supernatant was removed from each well and transferred to a new 96 well plate. 20 μ L6.1N of trichloroacetic acid was added to each well, mixed and incubated at 50 ℃ for 30 minutes. The reaction mixture was then centrifuged at 2500rpm for 10 minutes and 100. Mu.L of the supernatant per well was transferred to another 96-well plate and mixed with 100. Mu.L of a 2% (w/v) solution of p-dimethylaminobenzaldehyde in acetic acid. The content of the L-kynurenine-derived yellow product was measured at 480nm using a microplate reader. Three experiments were performed with the same batch of cells at different passage numbers for each drug, and compound IC was calculated using Graphpad Prism 5.0 using non-linear regression 50 The value is obtained. ICs of examples 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19 50 Respectively have values of>100，>100，3.5，30.82，>100，>100，>100，>100，50.2，>100μM。
Example 21
We chose the compound obtained in examples 12, 13 and 18 which had the best activity against IDO1 to perform in vitro urease inhibition experiments: selecting cattle of about 12 months, feeding for 1h, collecting 400mL rumen fluid by a special rumen fluid collector through an artificial rumen fistula, and filtering through 4 layers of gauze for later use. After adding the corresponding reagents into each culture tube according to the amount in the following table, 4 drops of liquid paraffin are added dropwise and placed on a constant temperature water bath oscillator at (39.0 +/-0.5) DEG C for slight shaking. After 8 hours of incubation, a portion of the tubes from each group was removed and 4 drops of saturated mercuric chloride solution were added immediately and shaken well to terminate the reaction. The ammonia nitrogen content of each tube is measured by a Kjeldahl half-trace-saturated magnesium oxide distillation method. We can find that the compound obtained from example 12 has more and more significant urease inhibiting activity and very significant inhibiting effect with the prolonging of time; and has low toxicity and IC to human kidney epithelial cell line 293T cells through CCK8 experiments 50 Value of>100μM。
| Group of | | Test | 1 | Test | 2 groups |
| Rumen fluid/mL | 5 | 5 | 5 | ||
| Artificial saliva/mL | 5 | 5 | 5 | ||
| Soluble starch/mg | 6 | 6 | 6 | ||
| Urea nitrogen/mg | 5 | 5 | 5 | ||
| EXAMPLE 12 product/ |
0 | 4 | 8 | ||
| Example 13 product/ |
0 | 4 | 8 | ||
| Example 18 product/ |
0 | 4 | 8 |
Inhibition (%) = (control group ammonia content-test group ammonia content) ÷ control group ammonia content × 100%
| Numbering | Time (h) | Inhibition rate of | Test | 1 group | Test | 2 group inhibition rate |
| Example 12 product | 8 | 0％ | 42.77％ | 61.53％ | ||
| Example 13 product | 8 | 0％ | 28.64％ | 39.76％ | ||
| Example 18 product | 8 | 0％ | 20.49％ | 27.25％ |
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (9)
1. A preparation method and application of pomalidomide derivative used as feed additive are characterized in that the molecular structure of pomalidomide derivative is as follows:
wherein R is methoxy, bromine, chlorine, or fluorine atom.
2. The preparation method of pomalidomide derivative as feed additive in claim 1, wherein the preparation method comprises the following steps: adding a certain amount of methyl benzoate and calcium carbonate into a dichloroethane solution, stirring, slowly dropwise adding the dichloroethane solution dissolved with iodine chloride, heating to reflux and stirring for a period of time after dropwise adding, cooling and filtering the reaction solution, adding anhydrous magnesium sulfate, stirring and filtering, adding a certain amount of 3-aminopiperidine-2, 6-dione hydrochloride and triethylamine and N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for a period of time at room temperature, concentrating, washing the concentrate with diethyl ether for a plurality of times, adding the concentrate into toluene, adding triphenylphosphine and iodine simple substance, heating to reflux, removing water in the reaction system through a water separator, adding a certain amount of palladium acetate and triethylamine, stirring for a period of time under the protection of nitrogen, adding anhydrous formic acid, maintaining the nitrogen atmosphere, adjusting the temperature of the reaction system to 80 ℃, stopping the reaction after the reaction is finished, filtering the reaction solution while hot, adding water, extracting with dichloromethane for a plurality of times after stirring, combining organic phases, and concentrating to obtain 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione; the feeding amount molar ratio of the methyl benzoate to the calcium carbonate to the iodine chloride is 1: 2.5-3: 2 to 2.5; the molar ratio of the fed amounts of the methyl benzoate, the 3-aminopiperidine-2, 6-dione hydrochloride, the triethylamine and the N, N' -dicyclohexylcarbodiimide is 1:1:1:2; the molar ratio of the methyl benzoate to the triphenylphosphine to the elemental iodine to the palladium acetate to the triethylamine added for the second time is 1:1.2:1.2:0.1:1; the feeding amount molar ratio of the methyl benzoate to the anhydrous formic acid is 1:3.
3. the preparation method of pomalidomide derivative as feed additive in claim 1, wherein the preparation method comprises the following steps: adding a certain amount of methyl benzoate and calcium carbonate into a dichloroethane solution, stirring, slowly dropwise adding the dichloroethane solution dissolved with a certain amount of iodine chloride, heating to reflux and stirring for a period of time after dropwise adding, cooling and filtering the reaction solution, adding anhydrous magnesium sulfate, stirring and filtering, adding a certain amount of 3-aminopiperidine-2, 6-dione hydrochloride, triethylamine and N, N' -dicyclohexylcarbodiimide into the filtrate, stirring and reacting for a period of time at room temperature, concentrating, washing the concentrate with diethyl ether for a plurality of times, adding the concentrate into glycerol, placing into a high-pressure reaction kettle, adding a certain amount of triphenylphosphine palladium chloride, molybdenum acetylacetonate and an alkaline substance, uniformly stirring, removing air in the reaction kettle in vacuum, introducing carbon monoxide to make the pressure in the reaction kettle reach a certain value, slowly heating to a certain temperature, keeping the pressure in the reaction kettle constant, filtering the reaction solution after the reaction is finished, adding water into the reaction system while the reaction system is hot, adding dichloromethane, stirring, filtering the reaction solution, separating an organic phase, extracting a water phase with dichloromethane, merging the organic phases, separating and purifying by silica gel column chromatography to obtain 2- (2, 6-3-dioxopiperidine) -3-indole-1-3-indole-yl-indole-1-indole base; the mass ratio of the methyl benzoate to the triphenylphosphine palladium chloride is 1:0.2; (ii) a The feeding amount molar ratio of the methyl benzoate to the molybdenum acetylacetonate to the alkaline substance is 1:0.2:1 to 2; the alkaline substance is N, N-dimethylethanolamine or potassium tert-butoxide; the pressure in the reaction kettle is 1-1.5 MPa; the reaction temperature is 100-120 ℃.
4. The process for preparing pomalidomide derivative as feed additive as claimed in claim 1, wherein the process comprises the following steps: adding a certain amount of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione, copper powder and potassium nitrite into N, N-dimethylformamide, stirring at room temperature for a period of time under the protection of nitrogen, adding a solution of N, N-dimethylformamide in which N, N-dimethylethylenediamine, zinc iodide and cuprous iodide are dissolved, keeping the nitrogen protection atmosphere, slowly heating to a certain temperature, reacting for a period of time, filtering, placing the filtrate at 0 ℃, adding an ethanol solution in which nitrite is dissolved under the protection of nitrogen, keeping nitrogen and low temperature during dropwise adding, stirring, pouring the reaction solution into water, filtering, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain 2- (2, 6-dioxopiperidine-3-yl) -4-nitroisoindoline-1, 3-dione; the feeding amount molar ratio of the 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione to the copper powder to the potassium nitrite is 1:0.3 to 0.6:1.5 to 2; the molar ratio of the 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione to the N, N-dimethylethylenediamine to the zinc iodide to the cuprous iodide is 1:2 to 3:0.1:0.1, preferably 1:3:0.1:0.1; the reaction temperature is 100-120 ℃.
5. The method for preparing pomalidomide derivative as feed additive as claimed in claim 1, wherein the preparation method comprises the following steps: adding a certain amount of 2- (2, 6-dioxopiperidine-3-yl) -4-nitroisoindoline-1, 3-dione and palladium acetate into a mixed solution of N, N-dimethylformamide, ethanol, tetrahydrofuran and acetone in a high-pressure reaction kettle, stirring, introducing hydrogen into the reaction kettle, replacing gas in a reaction system for three times, heating the reaction kettle until the hydrogen pressure reaches a certain value, stirring to react at 50 ℃, pouring a reaction solution into water, filtering the reaction solution, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione; the feeding amount molar ratio of the 2- (2, 6-dioxopiperidine-3-yl) -4-nitroisoindoline-1, 3-dione to the palladium acetate is 1:0.1; the pressure of the reaction kettle is 0.3-0.5 MPa.
6. The process for preparing pomalidomide derivative as feed additive as claimed in claim 1, wherein the process comprises the following steps: adding a certain amount of 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione and 2- (2- (2- (2-azidoethoxy) ethoxy) ethyoxyl) ethane-1-amine into N, N-dimethylformamide, stirring for dissolving, then adding N, N-diisopropylethylamine, stirring for reacting at room temperature until the raw material 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione is completely reacted, stirring the reaction liquid, pouring into water for continuously stirring for a period of time, then extracting the reaction system for multiple times by dichloromethane, combining organic phases, drying by anhydrous sodium sulfate, concentrating in vacuum, and separating by silica gel column chromatography to obtain an azide intermediate compound; the feeding amount molar ratio of the 2- (2, 6-dioxo-piperidine-3-yl) -4-iodo-isoindole-1, 3-dione to the 2- (2- (2- (2-azidoethoxy) ethoxy) ethan-1-amine to the N, N-diisopropylethylamine is 1:1:2.
7. the process for preparing pomalidomide derivative as feed additive as claimed in claim 1, wherein the process comprises the following steps: adding a certain amount of 2- (2- (2- (2-azidoethoxy) ethoxy) ethane-1-aldehyde and acetic acid into N, N-dimethylformamide, stirring for dissolving, then adding 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione, stirring for a period of time at room temperature, cooling a reaction system to 0 ℃, slowly dropwise adding N, N-dimethylformamide dissolved with triacetoxyborohydride or sodium borohydride, heating to room temperature after dropwise adding is finished, monitoring the complete reaction of raw materials by TLC, then pouring a reaction solution into water, extracting for multiple times by using dichloromethane, combining organic phases, concentrating, adding ethanol for dissolving, heating to reflux under the protection of nitrogen, reacting for 2 hours, cooling to 0 ℃, precipitating solids, performing suction filtration and drying to obtain an azide intermediate compound; the molar ratio of the feeding amount of 2- (2- (2- (2-azidoethoxy) ethoxy) ethane-1-aldehyde to 2- (2, 6-dioxopiperidine-3-yl) -4-aminoisoindoline-1, 3-dione to triacetoxyborohydride or sodium borohydride is 1:1:1.2 to 3.
8. The process for preparing pomalidomide derivative as feed additive as claimed in claim 1, wherein the process comprises the following steps: adding a certain amount of azide intermediate compound and 4-aminophenylacetylene or 3-aminophenylacetylene into a mixed solvent of distilled water, tetrahydrofuran and tert-butyl alcohol, adding cuprous iodide, protecting with nitrogen, heating to 80 ℃, carrying out reflux reaction for a period of time, extracting with dichloromethane, combining organic phases, adding phenyl isocyanate compounds, stirring for a period of time, filtering with diatomite, carrying out vacuum concentration on the filtrate, and carrying out silica gel column chromatography separation by using dichloromethane and methanol as eluents to obtain a target compound; the molar ratio of the charge amount of the azide intermediate compound to the charge amount of 4-aminophenylacetylene or 3-aminophenylacetylene to the charge amount of cuprous iodide is 1:1:0.2; the charging amount molar ratio of the azide intermediate compound to the phenyl isocyanate compound is 1:1 to 1.1.
9. Use of pomalidomide derivative as claimed in claim 1 for inhibiting IDO1 enzyme and urease.
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