CN111393409A - Protein degradation targeting chimera compound, application and preparation method thereof - Google Patents
Protein degradation targeting chimera compound, application and preparation method thereof Download PDFInfo
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- CN111393409A CN111393409A CN202010226123.2A CN202010226123A CN111393409A CN 111393409 A CN111393409 A CN 111393409A CN 202010226123 A CN202010226123 A CN 202010226123A CN 111393409 A CN111393409 A CN 111393409A
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- 230000008685 targeting Effects 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 230000017854 proteolysis Effects 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- CRAUTELYXAAAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione Chemical compound O=C1C=2C(F)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O CRAUTELYXAAAPW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 17
- UERPUZBSSSAZJE-UHFFFAOYSA-N 3-chlorophthalic anhydride Chemical compound ClC1=CC=CC2=C1C(=O)OC2=O UERPUZBSSSAZJE-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 9
- VWBDYQNOIRKCSH-UHFFFAOYSA-N (3-fluorobenzoyl) 3-fluorobenzoate Chemical compound FC1=CC=CC(C(=O)OC(=O)C=2C=C(F)C=CC=2)=C1 VWBDYQNOIRKCSH-UHFFFAOYSA-N 0.000 claims abstract description 8
- WWJAZKZLSDRAIV-UHFFFAOYSA-N 4-fluoro-2-benzofuran-1,3-dione Chemical compound FC1=CC=CC2=C1C(=O)OC2=O WWJAZKZLSDRAIV-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 3-fluorobenzene anhydride Chemical class 0.000 claims description 37
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000012043 crude product Substances 0.000 claims description 27
- 238000000967 suction filtration Methods 0.000 claims description 22
- 235000003270 potassium fluoride Nutrition 0.000 claims description 17
- 239000011698 potassium fluoride Substances 0.000 claims description 17
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 14
- 238000005660 chlorination reaction Methods 0.000 claims description 13
- 230000002797 proteolythic effect Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229920005862 polyol Polymers 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 14
- 102000004169 proteins and genes Human genes 0.000 abstract description 13
- 102000044159 Ubiquitin Human genes 0.000 abstract description 6
- 108090000848 Ubiquitin Proteins 0.000 abstract description 6
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000012065 filter cake Substances 0.000 description 30
- 238000001035 drying Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000004537 pulping Methods 0.000 description 10
- 238000009987 spinning Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 108010026668 snake venom protein C activator Proteins 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 description 2
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 2
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003446 ligand Substances 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
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
Abstract
The invention provides a novel protein degradation targeting chimera compound, application and a preparation method thereof. Wherein the protein degradation targeting chimera compound is 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione. The preparation method comprises the following steps: step S1, carrying out fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride; step S2, the 3-fluorobenzoic anhydride and 3-amino-2, 6-piperidedione hydrochloride are subjected to condensation reaction to obtain the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione. According to the protein degradation targeting chimera, the compound has the advantages of moderate molecular size, good leaving performance of fluorine, small molecular weight and stable performance, can effectively draw a target protein close to E3 ubiquitin enzyme, and can be effectively used for preparing a targeting drug. The preparation method is simple, the three wastes are less, and the raw materials are low in price, so that the preparation cost is low, and the preparation method is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a protein degradation targeting chimera compound, application and a preparation method thereof.
Background
Protein degradation TArgeting Chimera (PROTAC), a bifunctional small molecule with one end being a ligand binding to the target protein and the other end being a ligand binding to E3 ubiquitin ligase, linked by a chain. The PROTAC can draw a target protein and E3 enzyme in vivo, so that the target protein is labeled with ubiquitin, further ubiquitinated to modify the target protein, and then degraded through ubiquitin-proteasome pathway.
At present, PROTACs have become a hot spot of pharmaceutical research due to higher specificity and targeting degradation function and good safety. By reversibly degrading the target protein by using the ubiquitin-proteasome system existing in the cell, the drug resistance phenomenon caused by the mutation of the gene locus of the target protein is avoided, and the problem that a small molecule inhibitor cannot be obtained due to the lack of a proper locus of part of oncogenic proteins is solved. Meanwhile, the more diverse E3 ubiquitin ligases also provide multiple possibilities for PROTACs design.
However, the polypeptide PROTACs molecules are still large and difficult to enter cells.
Disclosure of Invention
In view of this, the invention provides a novel 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione (PROTAC) compound, which has a moderate molecular size and is easy to enter cells, has a good leaving performance of fluoride ions, and meets the characteristics of a bifunctional small molecule.
The invention also provides an application of the PROTAC compound in preparation of targeted drugs.
The invention also provides a preparation method of the PROTAC compound, the synthesis method is simple and convenient, the three wastes are less, and the 3-chlorophthalic anhydride and the 3-amino-2, 6-piperidedione hydrochloride which are used as raw materials are supplied by the market in large quantities and have low price.
In order to solve the technical problems, the invention adopts the following technical scheme:
a proteolytic degradation targeting chimeric compound according to an embodiment of the first aspect of the invention, which is 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Further, the structural formula of the protein degradation targeting chimera compound is shown as the following formula (1).
According to the second aspect of the invention, the application is the application of the protein degradation targeting chimera compound in the preparation of targeting drugs. In other words, the protein degradation targeting chimera compound is applied to the preparation of targeting drugs. The targeted drug may be, for example, a tumor targeted drug or the like.
A method of making a proteolytic targeting chimeric compound according to an embodiment of the third aspect of the invention, said proteolytic targeting chimeric compound being 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione, said method of making comprising the steps of:
step S1, carrying out fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride;
step S2, the 3-fluorobenzoic anhydride and 3-amino-2, 6-piperidedione hydrochloride are subjected to condensation reaction to obtain the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione.
Further, the step S1 may include:
step S11, dissolving 3-chlorophthalic anhydride in sulfolane, and adding a chlorinating agent to perform chlorination reaction;
and step S12, after the chlorination reaction is finished, carrying out the fluorination reaction with potassium fluoride to generate the 3-fluorophthalic anhydride.
Further, in the step S11, the chlorinating agent is oxalyl chloride, and the chlorination reaction is performed at 80 to 120 ℃.
Further, in the step S12, after the chlorination reaction is completed, the reaction mixture is cooled to room temperature and oxalyl chloride is removed by rotary evaporation, and thereafter anhydrous potassium fluoride is added and the temperature is raised to 80 to 120 ℃ to perform the fluorination reaction.
Further, the step S1 further includes:
in step S13, after the fluorination reaction is completed, the 3-fluorobenzene anhydride thus produced is purified.
Further, in the step S2, the condensation reaction is performed at 5 to 20 ℃ in the presence of a base, wherein the base is one or more selected from sodium polyol, potassium polyol, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
Further, in the step S2, after the condensation reaction is finished, the solvent is removed, and a crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione is obtained by suction filtration, and then the crude product is decolorized, slurried with petroleum ether, suction filtration and dried to obtain the purified proteolytic targeting chimera compound.
The technical scheme of the invention at least has one of the following beneficial effects:
according to the novel protein degradation targeting chimera disclosed by the embodiment of the invention, the compound is moderate in molecular size, the leaving performance of a fluorine example is good, the molecular weight is small, and the performance is stable;
according to the novel protein degradation targeting chimera disclosed by the embodiment of the invention, the target protein and the E3 ubiquitin enzyme can be effectively drawn close, so that the target protein is labeled with the ubiquitin tag, and then the target protein is subjected to ubiquitination modification to realize degradation, so that the novel protein degradation targeting chimera can be effectively used for preparing a targeting drug;
according to the preparation method of the protein degradation targeting chimera, the synthesis method is simple and convenient, the three wastes are less, and the 3-chlorophthalic anhydride and the 3-amino-2, 6-piperiddione hydrochloride which are used as raw materials are widely sold and have low price, so that the preparation cost is low, and the preparation method is suitable for industrial large-scale production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention are clearly and completely described below. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
First, a protein degradation targeting chimera compound according to an embodiment of the present invention is described in detail, and is a novel protein degradation targeting chimera compound, specifically 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Further, the structural formula can be represented by the following formula (1).
The preparation method of the protein degradation targeting chimera compound can comprise the following steps:
and step S1, carrying out fluorination reaction on the 3-chlorophthalic anhydride to generate the 3-fluorophthalic anhydride.
Specifically, the reaction equation can be represented by the following formula (2):
more specifically, it can be prepared by first performing a chlorination reaction and then performing a fluorination reaction to produce 3-fluorophenylanhydride. That is, the fluorination process may comprise the steps of:
and step S11, dissolving 3-chlorophthalic anhydride in sulfolane, and adding a chlorinating agent to perform chlorination reaction.
Further, the chlorinating agent is oxalyl chloride, and the chlorination reaction is carried out at 80-120 ℃, and the reaction time may be, for example, 2-6 hours.
And step S12, after the chlorination reaction is finished, carrying out the fluorination reaction with potassium fluoride to generate the 3-fluorophthalic anhydride.
More specifically, after completion of the chlorination reaction, the reaction mixture was cooled to room temperature and oxalyl chloride was removed therefrom by rotary evaporation, after which anhydrous potassium fluoride was added and the temperature was raised to 80 to 120 ℃ to conduct the fluorination reaction. The reaction time may be, for example, 4 to 10 hours.
After the fluorination reaction, preferably, the following steps can be further included:
in step S13, after the fluorination reaction is completed, the 3-fluorobenzene anhydride thus produced is purified.
As a specific method for purification and purification, a method which is conventional in the field of chemical synthesis can be used. Preferably, the purification and purification are carried out, for example, by the following method:
after the fluorination reaction is finished, cooling to room temperature, filtering to remove inorganic salt (namely potassium fluoride), pouring the filtrate into ice water to separate out solid, continuously stirring and filtering to obtain a filter cake, and drying the filter cake to obtain a crude product of the 3-fluorobenzene anhydride;
then, the crude 3-fluorobenzene anhydride is dissolved and cleaned by dichloromethane, and then is dried (for example, the drying can be carried out by vacuum drying, anhydrous magnesium sulfate drying and the like), and is filtered, the filter cake is rotated until solid is separated out, petroleum ether is added into the filter cake for pulping, and is filtered, and the filter cake is dried in vacuum, so that the refined 3-fluorobenzene anhydride is obtained.
Step S2, the 3-fluorobenzoic anhydride and 3-amino-2, 6-piperidedione hydrochloride are subjected to condensation reaction to obtain the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione.
After 3-fluorobenzoic anhydride is obtained, the 3-fluorobenzoic anhydride and 3-amino-2, 6-piperidyl diketone hydrochloride are subjected to condensation reaction to obtain the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-diketone.
The reaction formula is shown as the following formula (3):
specifically, the condensation reaction may be carried out in the presence of a base at 5 to 20 ℃. Wherein, the alkali can be one or more selected from sodium polyol, potassium polyol, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. The sodium polyol may be, for example, sodium ethoxide, sodium t-butoxide, etc., and similarly, the potassium polyol may be, for example, potassium ethoxide, potassium t-butoxide, etc.
Further, the condensation reaction can be carried out, for example, as follows: dissolving 3-fluorobenzene anhydride in ethanol, adding 3-amino-2, 6-piperidedione hydrochloride, cooling the reaction system to below 10 ℃ through an ice bath, slowly adding sodium ethoxide in batches, and heating and refluxing after the sodium ethoxide is added to perform condensation reaction.
Further, after the condensation reaction is completed, the product may be purified.
Specifically, after the condensation reaction is finished, removing the solvent, performing suction filtration to obtain a crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, and then decoloring the crude product, pulping by using petroleum ether, performing suction filtration and drying to obtain the purified protein degradation targeting chimera compound.
According to the preparation method of the protein degradation targeting chimera, the synthesis method is simple and convenient, the three wastes are less, and the 3-chlorophthalic anhydride and the 3-amino-2, 6-piperiddione hydrochloride which are used as raw materials are widely sold and have low price, so that the preparation cost is low, and the preparation method is suitable for industrial large-scale production.
In addition, the prepared novel protein degradation targeting chimera has the advantages of moderate molecular size, good leaving performance of fluorine, small molecular weight and stable performance, and can effectively draw the target protein and E3 ubiquitin enzyme close to enable the target protein to be labeled with ubiquitin tag, and further ubiquitin-modify the target protein, so that the target protein degradation is realized, and the novel protein degradation targeting chimera can be effectively used for preparing targeted drugs.
Hereinafter, the method for producing the proteolytic targeting chimera compound of the present invention will be described in more detail with reference to specific examples.
Example 1:
adding 500ml sulfolane into a 1L three-neck flask, then adding 180g of 3-chlorophthalic anhydride, cooling to below 10 ℃ in an ice bath, dropwise adding 300g of oxalyl chloride, heating to about 100 ℃ after dropwise adding, reacting for 3 hours, cooling to room temperature, carrying out rotary evaporation to remove weeding acyl chloride, then adding 180g of anhydrous potassium fluoride, adding potassium fluoride completely, heating the system to 100 ℃ for reacting for 6 hours, cooling to room temperature, carrying out suction filtration to remove inorganic salts, slowly pouring the filtrate into 900ml of ice water, precipitating a large amount of solid, continuing stirring for 2 hours, carrying out suction filtration to obtain a filter cake, and carrying out vacuum drying to obtain a crude product of the 3-fluorobenzoic anhydride.
Dissolving the crude product of the 3-fluorobenzene anhydride with 800ml of dichloromethane, drying the mixture by anhydrous magnesium sulfate, carrying out suction filtration, spinning a filter cake until a solid is separated out, adding petroleum ether 2L into the filter cake, continuing stirring for 1 hour, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain 90g of the pure product of the 3-fluorobenzene anhydride.
Adding 500ml of ethanol and 90g of 3-fluorobenzene anhydride into a 1L three-neck flask, then adding 93g of 3-amino-2, 6-piperidedione hydrochloride, cooling to below 10 ℃ in an ice bath, slowly adding 42g of sodium ethoxide in batches, finishing the addition, heating and refluxing for 24 hours, stopping the reaction, spinning off the ethanol, then adding a mixed solution of 200ml of water and 100ml of dichloromethane into the system, pulping, and performing suction filtration to obtain a brown solid, namely a crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Dissolving the crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione in ethyl 2L acetate, decoloring with appropriate amount of activated carbon, filtering off the activated carbon to obtain yellow filtrate, spin-drying the yellow filtrate to obtain a large amount of off-white solid, adding 200ml of petroleum ether, pulping, filtering, and drying the filter cake in vacuum to obtain the pure product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione 126g with the total molar yield of 46.3%.
The reaction product was characterized by nmr and the data were as follows:
HNMR(400MHz,DMSO)：11.16(s,1H),7.95(td,J＝7.9,4.6Hz,1H), 7.84–7.68(m,2H),5.17(dd,J＝12.8,5.4Hz,1H),2.97–2.80(m,1H),2.61(d, J＝18.4Hz,1H),2.14–1.99(m,1H)
example 2:
adding 500ml sulfolane into a 1L three-neck flask, then adding 180g of 3-chlorophthalic anhydride, cooling to below 10 ℃ in an ice bath, dropwise adding 360g of phosphorus oxychloride, heating to about 100 ℃ after the dropwise addition, reacting for 3 hours, cooling to room temperature, removing the phosphorus oxychloride by rotary evaporation, then adding 180g of anhydrous potassium fluoride, adding potassium fluoride, heating the system to 100 ℃ for reacting for 6 hours, cooling to room temperature, filtering to remove inorganic salts, slowly pouring the filtrate into 900ml of ice water, separating out a large amount of solids, continuing stirring for 2 hours, performing suction filtration to obtain a filter cake, and performing vacuum drying to obtain a crude product of the 3-fluorobenzoic anhydride.
Dissolving the crude product of the 3-fluorobenzene anhydride with 800ml of dichloromethane, drying the solution by anhydrous magnesium sulfate, carrying out suction filtration, spinning a filter cake until a solid is separated out, adding petroleum ether 2L into the filter cake, continuing stirring for 1 hour, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain 92g of the pure product of the 3-fluorobenzene anhydride.
Adding 500ml of ethanol and 92g of 3-fluorobenzene anhydride into a 1L three-neck flask, then adding 93g of 3-amino-2, 6-piperidedione hydrochloride, cooling to below 10 ℃ in an ice bath, slowly adding 43g of sodium ethoxide in batches, finishing the addition, heating and refluxing for 24 hours, stopping the reaction, spinning off the ethanol, then adding a mixed solution of 200ml of water and 100ml of dichloromethane into the system, pulping, and performing suction filtration to obtain a brown solid, namely a crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Dissolving the crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione in ethyl 2L acetate, decoloring with appropriate amount of activated carbon, filtering off the activated carbon to obtain yellow filtrate, spin-drying the yellow filtrate to obtain a large amount of off-white solid, adding 200ml of petroleum ether, pulping, filtering, and drying the filter cake in vacuum to obtain 121g of pure 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, wherein the total molar yield is 44.4%.
The reaction product was characterized by nmr and the data were as follows:
HNMR(400MHz,DMSO)：11.16(s,1H),7.95(td,J＝7.9,4.6Hz,1H), 7.84–7.68(m,2H),5.17(dd,J＝12.8,5.4Hz,1H),2.97–2.80(m,1H),2.61(d, J＝18.4Hz,1H),2.14–1.99(m,1H)
example 3:
adding 500ml sulfolane into a 1L three-neck flask, then adding 180g of 3-chlorophthalic anhydride, cooling to below 10 ℃ in an ice bath, dropwise adding 280g of thionyl chloride, heating to about 100 ℃ after dropwise adding, reacting for 3 hours, cooling to room temperature, removing thionyl chloride by rotary evaporation, then adding 180g of anhydrous potassium fluoride, adding potassium fluoride, heating the system to 100 ℃ for reacting for 6 hours, cooling to room temperature, filtering to remove inorganic salts, slowly pouring the filtrate into 900ml of ice water, separating out a large amount of solids, continuing stirring for 2 hours, filtering to obtain a filter cake, and drying in vacuum to obtain a crude product of the 3-fluorobenzene anhydride.
Dissolving the crude product of the 3-fluorobenzene anhydride with 800ml of dichloromethane, drying the solution by anhydrous magnesium sulfate, carrying out suction filtration, spinning a filter cake until a solid is separated out, adding petroleum ether 2L into the filter cake, continuing stirring for 1 hour, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain 99g of a pure product of the 3-fluorobenzene anhydride.
Adding 500ml of ethanol and 92g of 3-fluorobenzene anhydride into a 1L three-neck flask, then adding 93g of 3-amino-2, 6-piperidedione hydrochloride, cooling to below 10 ℃ in an ice bath, slowly adding 43g of sodium ethoxide in batches, finishing the addition, heating and refluxing for 24 hours, stopping the reaction, spinning off the ethanol, then adding a mixed solution of 200ml of water and 100ml of dichloromethane into the system, pulping, and performing suction filtration to obtain a brown solid, namely a crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Dissolving the crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione in ethyl 2L acetate, decoloring with appropriate amount of activated carbon, filtering off the activated carbon to obtain yellow filtrate, spin-drying the yellow filtrate to obtain a large amount of off-white solid, adding 200ml of petroleum ether, pulping, filtering, and drying the filter cake in vacuum to obtain 131g of pure 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, wherein the total molar yield is 48.1%.
The reaction product was characterized by nmr and the data were as follows:
HNMR(400MHz,DMSO)：11.16(s,1H),7.95(td,J＝7.9,4.6Hz,1H), 7.84–7.68(m,2H),5.17(dd,J＝12.8,5.4Hz,1H),2.97–2.80(m,1H),2.61(d, J＝18.4Hz,1H),2.14–1.99(m,1H)
example 4:
adding 500ml sulfolane into a 1L three-neck flask, then adding 180g of 3-chlorophthalic anhydride, cooling to below 10 ℃ in an ice bath, dropwise adding 280g of thionyl chloride, heating to about 100 ℃ after dropwise adding, reacting for 3 hours, cooling to room temperature, removing thionyl chloride by rotary evaporation, then adding 180g of anhydrous potassium fluoride, adding potassium fluoride, heating the system to 100 ℃ for reacting for 6 hours, cooling to room temperature, filtering to remove inorganic salts, slowly pouring the filtrate into 900ml of ice water, separating out a large amount of solids, continuing stirring for 2 hours, filtering to obtain a filter cake, and drying in vacuum to obtain a crude product of the 3-fluorobenzene anhydride.
Dissolving the crude product of the 3-fluorobenzene anhydride with 800ml of dichloromethane, drying the solution by anhydrous magnesium sulfate, carrying out suction filtration, spinning a filter cake until a solid is separated out, adding petroleum ether 2L into the filter cake, continuing stirring for 1 hour, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain 99g of a pure product of the 3-fluorobenzene anhydride.
500ml of acetonitrile and 92g of 3-fluorobenzene anhydride are added into a 1L three-neck flask, then 93g of 3-amino-2, 6-piperidedione hydrochloride is added, the temperature is reduced to below 10 ℃ in an ice bath, 67g of sodium carbonate is slowly added in batches, the addition is finished, the temperature is increased and the reflux reaction is carried out for 24 hours, the reaction is stopped, the acetonitrile is dried in a spinning mode, then a mixed solution of 200ml of water and 100ml of dichloromethane is added into the system, the mixture is pulped and is filtered in a suction mode, and a brown solid crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione.
Dissolving the crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione in ethyl 2L acetate, decoloring with appropriate amount of activated carbon, filtering off the activated carbon to obtain yellow filtrate, spin-drying the yellow filtrate to obtain a large amount of off-white solid, adding 200ml of petroleum ether, pulping, filtering, and drying a filter cake in vacuum to obtain 123g of pure 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, wherein the total molar yield is 45.2%.
The reaction product was characterized by nmr and the data were as follows:
HNMR(400MHz,DMSO)：11.16(s,1H),7.95(td,J＝7.9,4.6Hz,1H), 7.84–7.68(m,2H),5.17(dd,J＝12.8,5.4Hz,1H),2.97–2.80(m,1H),2.61(d, J＝18.4Hz,1H),2.14–1.99(m,1H)
example 5:
adding 500ml sulfolane into a 1L three-neck flask, then adding 180g of 3-chlorophthalic anhydride, cooling to below 10 ℃ in an ice bath, dropwise adding 280g of thionyl chloride, heating to about 100 ℃ after dropwise adding, reacting for 3 hours, cooling to room temperature, removing thionyl chloride by rotary evaporation, then adding 180g of anhydrous potassium fluoride, adding potassium fluoride, heating the system to 100 ℃ for reacting for 6 hours, cooling to room temperature, filtering to remove inorganic salts, slowly pouring the filtrate into 900ml of ice water, separating out a large amount of solids, continuing stirring for 2 hours, filtering to obtain a filter cake, and drying in vacuum to obtain a crude product of the 3-fluorobenzene anhydride.
Dissolving the crude product of the 3-fluorobenzene anhydride with 800ml of dichloromethane, drying the solution by anhydrous magnesium sulfate, carrying out suction filtration, spinning a filter cake until a solid is separated out, adding petroleum ether 2L into the filter cake, continuing stirring for 1 hour, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain 99g of a pure product of the 3-fluorobenzene anhydride.
500ml of tert-butyl alcohol and 92g of 3-fluorobenzene anhydride are added into a 1L three-neck flask, then 93g of 3-amino-2, 6-piperidedione hydrochloride is added, the temperature is reduced to below 10 ℃ in an ice bath, 71g of potassium tert-butoxide is slowly added in batches, the addition is finished, the temperature is increased, the reflux reaction is carried out for 24 hours, the reaction is stopped, the tert-butyl alcohol is dried in a spinning mode, then a mixed solution of 200ml of water and 100ml of dichloromethane is added into the system, the mixture is pulped and filtered by suction, and a brown solid crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-.
Dissolving the crude product of 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione in ethyl 2L acetate, decoloring with appropriate amount of activated carbon, filtering off the activated carbon to obtain yellow filtrate, spin-drying the yellow filtrate to obtain a large amount of off-white solid, adding 200ml of petroleum ether, pulping, filtering, and drying the filter cake in vacuum to obtain 118g of pure 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, wherein the total molar yield is 43.3%.
The reaction product was characterized by nmr and the data were as follows:
HNMR(400MHz,DMSO)：11.16(s,1H),7.95(td,J＝7.9,4.6Hz,1H), 7.84–7.68(m,2H),5.17(dd,J＝12.8,5.4Hz,1H),2.97–2.80(m,1H),2.61(d, J＝18.4Hz,1H),2.14–1.99(m,1H)
while the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A protein degradation targeting chimera compound, which is characterized in that the protein degradation targeting chimera compound is 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione.
2. The proteolytic targeting chimeric compound according to claim 1, wherein the structural formula of the proteolytic targeting chimeric compound is shown in the following formula (1).
3. Use of the proteolytic degradation targeted chimera compound according to claim 1 or 2 in the preparation of a targeted drug.
4. A preparation method of a protein degradation targeting chimera compound is characterized in that the protein degradation targeting chimera compound is 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione, and the preparation method comprises the following steps:
step S1, carrying out fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride;
step S2, the 3-fluorobenzoic anhydride and 3-amino-2, 6-piperidedione hydrochloride are subjected to condensation reaction to obtain the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione.
5. The method for preparing a proteolytic targeting chimera compound according to claim 4, wherein the step S1 includes:
step S11, dissolving 3-chlorophthalic anhydride in sulfolane, and adding a chlorinating agent to perform chlorination reaction;
and step S12, after the chlorination reaction is finished, carrying out the fluorination reaction with potassium fluoride to generate the 3-fluorophthalic anhydride.
6. The method for preparing a proteolytic targeting chimera compound according to claim 5, wherein the chlorinating agent is oxalyl chloride and the chlorination reaction is performed at 80-120 ℃ in step S11.
7. The method for preparing a proteolytic targeting chimeric compound according to claim 6, wherein in step S12, after the chlorination reaction is completed, the temperature is reduced to room temperature and oxalyl chloride is removed by rotary evaporation, and then anhydrous potassium fluoride is added and the temperature is raised to 80-120 ℃ to perform the fluorination reaction.
8. The method for preparing a proteolytic targeting chimera compound according to any one of claims 4-7, wherein step S1 further includes:
in step S13, after the fluorination reaction is completed, the 3-fluorobenzene anhydride thus produced is purified.
9. The method for preparing a proteolytic targeting chimera compound according to claim 8, wherein the condensation reaction is performed at 5-20 ℃ in the presence of a base selected from one or more of sodium polyol, potassium polyol, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate in step S2.
10. The method of claim 9, wherein in step S2, after the condensation reaction is completed, the solvent is removed, and a crude product of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione is obtained by suction filtration, and then the crude product is decolorized, slurried with petroleum ether, suction filtration and dried to obtain the purified protein degradation target chimera compound.
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