CN115626903A - Preparation method of EED inhibitor intermediate - Google Patents
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- CN115626903A CN115626903A CN202211442899.3A CN202211442899A CN115626903A CN 115626903 A CN115626903 A CN 115626903A CN 202211442899 A CN202211442899 A CN 202211442899A CN 115626903 A CN115626903 A CN 115626903A
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an EED inhibitor intermediate. The preparation method takes a compound I2,5-difluorobromobenzene as a starting material to be substituted with N, N-dimethylformamide to generate a compound II; the compound II and ethyl glycolate undergo cyclization to obtain a compound III; hydrolyzing the compound III under the alkaline condition to obtain a compound IV; decarboxylating the compound IV to obtain a compound V; the compound V and N, N-dimethylformamide are substituted to obtain a compound VI; carrying out reductive amination on the compound VI under the action of a reducing agent to obtain a compound VII; catalytically hydrogenating the compound VII to obtain a compound VIII; and removing the protecting group of the compound VIII under an acidic condition to obtain an EED inhibitor intermediate. The synthesis route is novel, the operation is simple, the generation of a large amount of isomers is avoided, the yield is high, the cost is low, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an EED inhibitor intermediate.
Background
EZH2, a histone lysine N-methyltransferase, is also a subunit of polycomb inhibition complex PRC2, is highly expressed in a variety of human cancers and promotes carcinogenesis and malignancy, and targeted inhibition of EZH 2's methyltransferase activity has been demonstrated to be a successful cancer treatment strategy. Nevertheless, secondary mutations in EZH2 can lead to acquired resistance and its homology EZH1 also has methyltransferase activity, all of which result in limited EZH2 inhibitor activity. Embryonic ectodermal developmental proteins (EEDs) are part of the PRC2 complex and can activate the methyltransferase activity of EZH2, and thus allosterically targeting EEDs is also an effective approach. EED inhibitors have great therapeutic potential in a variety of solid and hematological tumors. The compound MAK683 is the first inhibitor aiming at subunit EED entering into clinical tests, can selectively combine EED protein, is expected to overcome tumor drug resistance by adjusting tumor epigenetics and tumor microenvironment, realizes complete and durable tumor regression, and has clinically proven anticancer efficacy.
The structure of the MAK683 compound is shown in figure 1. The preparation method of the MAK683 compound is disclosed in the patent document WO2017221100A1, and the specific synthetic route is shown in figure 2.
The synthesis difficulty of the MAK683 compound lies in the preparation of a key intermediate 8, and the existing preparation method has the following problems. First, compound 2 produces compound 3 with an isomer ratio of about 1.8, which results in low yield and difficult purification, and column chromatography separation and purification are required, thus being unsuitable for industrial production. Secondly, the compound 5 is prepared by using virulent zinc cyanide when preparing the compound 6. Thirdly, compound 6 to compound 7 requires high pressure hydrogenation in an autoclave with a high risk factor.
Therefore, there is a need to develop an efficient method for preparing compound 8, which provides an aid for the development of novel EED inhibitors.
Disclosure of Invention
In view of the drawbacks of the prior art in the synthesis of compound 8, the present invention provides a new method for synthesizing compound 8, i.e. the present invention aims to provide a method for preparing an intermediate of an EED inhibitor, so as to solve the above problems.
The invention provides a preparation method of an EED inhibitor intermediate, which has the advantages of novel synthetic route, simple and convenient operation, good safety and environmental friendliness and is suitable for commercial production. The preparation method of the intermediate of the EED inhibitor provided by the invention is shown in figure 3 and comprises the following steps.
Step A: the compound I and DMF are subjected to substitution reaction under the action of organic base to generate a compound II.
And B, step B: under the action of alkali, the compound II and methyl glycolate are subjected to cyclization reaction in an organic solvent to generate a compound III.
Step C: and hydrolyzing the compound III under the action of alkali to generate a compound IV.
Step D: and decarboxylating the compound IV in an organic solvent under the action of alkali to generate a compound V.
Step E: and carrying out substitution reaction on the compound V and DMF under the action of organic base to generate a compound VI.
Step F: and carrying out reduction amination reaction on the compound VI and tert-butyl carbamate under the action of a reducing agent to generate a compound VII.
G: and (3) carrying out catalytic hydrogenation on the compound VII under the action of a catalyst to obtain a compound VIII.
Step H: and removing the Boc protecting group from the compound VIII under an acidic condition to obtain a target compound 8, namely an EED inhibitor intermediate.
According to the synthetic route, the preparation method takes 2,5-difluorobromobenzene as a starting material, and obtains the target compound 8 through a series of steps of low-temperature substitution, ring closing, hydrolysis decarboxylation, low-temperature substitution, reductive amination, normal-pressure hydrogenation, hydrolysis deprotection and the like.
The raw materials required by the step operation and the operation flow required by the step operation are all the raw materials and operations commonly used in the production of the medicine, so the synthetic route is an economical and easy synthetic route. In addition, complicated column chromatography is not needed in the steps, so that high yield can be obtained, separation and purification are easy, and safety is high.
In the process of preparing the intermediate 8 of the EED inhibitor by the above reaction, the reaction time of each step can be detected by conventional means, such as monitoring the reaction degree by TLC, and selecting whether to purify or continue the reaction, and after the reaction is finished, selecting whether to purify or directly performing the next reaction according to the need.
The conditions for carrying out the reaction in the above step may be conventional ones, but when the following preferable embodiment is adopted, the reaction yield can be improved, the reaction rate can be increased, and the reaction cost can be reduced.
1. And (C) optimizing the step A.
Preferably, in the reaction step A, the compound I and DMF undergo a substitution reaction under the action of an organic base and an organic solvent to form the compound II.
Wherein the organic base is selected from any one of lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and 2,2,6,6-tetramethyllithium piperidine, preferably lithium diisopropylamide.
Preferably, the organic solvent is one or more selected from tetrahydrofuran, diethyl ether and methyl tert-butyl ether, and tetrahydrofuran is preferably used as the reaction solvent.
The reaction temperature in step A is preferably in the range of-90 ℃ to-70 ℃, more preferably in the range of-78 ℃ to-75 ℃.
Preferably, in step a, the molar ratio of compound I to DMF is 1.5, and the molar ratio of compound I to organic base is 1.
The step A can adopt the following raw material adding sequence and reaction mode:
dissolving the compound I in tetrahydrofuran, cooling to-78 ℃, dropwise adding lithium diisopropylamide, keeping the temperature of-78 ℃ for reacting for 1 hour, adding DMF, keeping the temperature of-78 ℃ for reacting for 1-2 hours.
And B, after the reaction in the step A is finished, adding a saturated ammonium chloride solvent for quenching, adding ethyl acetate for extraction, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound II, wherein the preferable temperature for quenching is-50 ℃.
2. And B, optimizing.
Preferably, in the reaction step B, the compound II and methyl glycolate undergo a ring-combining reaction under the action of alkali and an organic solvent to generate the compound III.
The alkali is selected from any one of sodium hydride, potassium hydride and potassium carbonate, and is preferably sodium hydride.
Preferably, the organic solvent is one or more selected from tetrahydrofuran, diethyl ether and methyl tert-butyl ether, and tetrahydrofuran is preferably used as the reaction solvent.
The reaction temperature in step B is preferably from 50 ℃ to 70 ℃, more preferably from 65 ℃ to 70 ℃. The reaction time in step B is preferably 6 to 10 hours, more preferably 9 to 10 hours.
Preferably, in step B, the molar ratio of compound II to base is 1:2, and the molar ratio of compound II to methyl glycolate is 1:5.
The step B can adopt the following raw material adding sequence and reaction mode:
dissolving the compound II and methyl glycolate in an organic solvent, maintaining the temperature at 20-30 ℃ under the protection of inert gas, adding sodium hydride in batches, and heating to 70 ℃ for reaction for 10 hours.
And B, after the reaction in the step B is finished, adding a saturated ammonium chloride solvent for quenching, adding ethyl acetate for extraction, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of the compound III, wherein the crude product is directly used for the next reaction.
3. And C, optimizing.
Preferably, in the reaction step C, the compound III is hydrolyzed in an organic solvent under the action of a base to form the compound IV.
Among them, any one of sodium hydroxide, potassium hydroxide and lithium hydroxide is used as the base, and lithium hydroxide is preferable.
Preferably, the organic solvent is one or more selected from tetrahydrofuran, methanol, ethanol and water, and preferably a mixed solvent of tetrahydrofuran and water is used as the reaction solvent.
The reaction temperature in step C is preferably 10 ℃ to 50 ℃, more preferably 20 ℃ to 30 ℃.
Preferably, in step C, the molar ratio of the compound III to the base is 1:3, and the volume ratio of the mixed solvent tetrahydrofuran to the water is 3:1.
And C, after the reaction in the step C is finished, concentrating to remove tetrahydrofuran, and adding acid to adjust the pH value to 2-3, wherein the acid reagent is hydrochloric acid, hydrobromic acid or citric acid aqueous solution, and preferably hydrochloric acid aqueous solution.
4. And D, optimizing.
Preferably, in the reaction step D, compound IV is deacidified in an organic solvent by adding a base to obtain compound V.
Wherein, the alkali is selected from any one of potassium carbonate, sodium carbonate and cesium carbonate, and is preferably cesium carbonate.
Wherein, the organic solvent is selected from any one of N, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and dimethyl sulfoxide is preferred.
In step D, the molar ratio of compound IV to base is preferably 1:3.
The reaction temperature in step D is preferably 80 ℃ to 120 ℃, more preferably 110 ℃, and the reaction time is preferably 10 to 24 hours, more preferably 12 hours.
And D, after the reaction in the step D is finished, cooling to room temperature, adding water into the reaction solution, stirring for 2-3 hours, performing suction filtration, and drying to obtain a compound V.
5. And E, optimizing.
Preferably, in the reaction step E, the compound V is substituted with DMF under the action of a base to obtain a compound VI.
The alkali is selected from one of n-butyl lithium, isopropyl magnesium chloride and isopropyl magnesium chloride lithium chloride solution, and n-butyl lithium is preferable.
Preferably, the organic solvent is one or more selected from tetrahydrofuran, diethyl ether and methyl tert-butyl ether, and tetrahydrofuran is preferably used as the reaction solvent.
The reaction temperature in step E is preferably in the range of-90 ℃ to-70 ℃, more preferably in the range of-78 ℃ to-75 ℃.
Preferably, in step E, the molar ratio of compound V to DMF is 1.5, and the molar ratio of compound V to base is 1.
The step E can adopt the following raw material adding sequence and reaction mode:
dissolving the compound V in tetrahydrofuran, cooling to-78 ℃, dropwise adding n-butyl lithium, keeping the temperature at-78 ℃ for reacting for 1 hour, adding DMF, keeping the temperature at-78 ℃ for reacting for 1-2 hours.
And E, after the reaction in the step E is finished, adding a saturated ammonium chloride solvent for quenching, adding ethyl acetate for extraction, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound VI, wherein the preferred temperature for quenching is-50 ℃.
6. And F, optimizing.
Preferably, in the reaction step F, the compound VI is subjected to reductive amination by using a reducing agent and tert-butyl carbamate in an organic solvent under acidic conditions to obtain a compound VII.
Among them, the acidic reagent is preferably an organic acid selected from trifluoroacetic acid and acetic acid, preferably trifluoroacetic acid.
The reductive amination reducing agent is preferably one of triethylsilane and chlorosilane, and is more preferably triethylsilane.
Preferably, the organic solvent is selected from one of dichloromethane, acetonitrile and tetrahydrofuran, and dichloromethane is preferred.
During the reductive amination reaction, the molar ratio of the compound VI to the acidic reagent is preferably 1:3, and the molar ratio of the compound VI to the reducing agent is preferably 1:5.
And D, after the reaction step F is finished, evaporating the organic solvent, dissolving the organic solvent in ethyl acetate, adding sodium bicarbonate for washing, drying the mixture by anhydrous sodium sulfate, and concentrating the dried mixture to obtain a compound VII.
7. And G, optimizing.
Preferably, in the step G, the compound VII is subjected to catalytic hydrogenation in a catalyst and an organic solvent to obtain the compound VII.
Among these, the catalytic hydrogenation may be carried out under normal pressure and under pressure, and normal pressure hydrogenation is preferred.
The hydrogenation catalyst is preferably palladium on carbon or palladium hydroxide on carbon, and more preferably palladium on carbon. Among them, the supported palladium content in the palladium on carbon and the palladium hydroxide on carbon may be 5 to 10%, preferably 10%.
Preferably, the reaction temperature in step G is preferably from 25 ℃ to 80 ℃, more preferably 35 ℃, and the reaction time is preferably from 10 to 24 hours, more preferably 16 hours.
Preferably, the organic solvent is selected from one of methanol and ethanol, more preferably methanol.
Preferably, the amount of catalyst is 5-10%, preferably 10%, of the mass of the starting material.
After reaction step G was complete, the mixture was filtered through celite, and the organic solvent was removed by concentration under reduced pressure to give compound VIII.
8. And H, optimizing.
Preferably, in the reaction step H, the compound VIII is deprotected by adding an acid to an organic solvent to obtain a compound 8.
The reaction temperature in step H is preferably 0 ℃ to 30 ℃, more preferably 20 ℃ to 30 ℃, and the reaction time is preferably 10 to 24 hours, more preferably 12 hours.
Among them, the acidic reagent is preferably an organic acid selected from trifluoroacetic acid and an organic solvent solution of hydrochloric acid, preferably an organic solvent solution of hydrochloric acid.
Wherein, the organic solvent is selected from one or more of methanol, ethanol, isopropanol and dioxane, and is preferably isopropanol.
In step H, the molar ratio of compound VIII and acidic reagent is preferably 1:5.
And H, after the reaction in the step H is finished, evaporating the organic solvent, adding methyl tert-butyl ether, stirring at room temperature for 2-3 hours, and performing suction filtration to obtain a compound 8.
Compared with the prior art, the invention has the following beneficial effects:
(1) The reaction in each step is mild, the operation is simple and convenient, and dangerous highly toxic substances are avoided.
(2) The crude product obtained by the reaction in each step can be directly reacted or subjected to simple post-treatment for the next step, the production efficiency is high, and the method is favorable for industrial production.
(3) High selectivity, less side reaction, no isomer, and no time and labor consuming separation and purification operation.
(4) The invention has greatly improved overall yield and reduced cost.
Drawings
FIG. 1 is the structural formula of the compound MAK 683.
FIG. 2 is a scheme showing the synthesis of the compound MAK683 of the prior art.
Figure 3 is a synthetic scheme of an intermediate of an EED inhibitor.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to specific examples, which are intended to be illustrative and not limiting. Those skilled in the art will appreciate that the embodiments described below are illustrative of some, but not all embodiments of the invention and that those skilled in the art will be able to practice the embodiments without inventive faculty within the scope of the invention. Laboratory methods in which specific conditions are not specified in the following examples are in accordance with conventional methods and conventional conditions.
In the embodiment of the invention, all nuclear magnetic detection results are obtained by detecting with a Bruker AV400 MHz nuclear magnetic resonance instrument, and TMS is an internal standard. All mass spectrometric measurements were performed by LCMS 2020.
Example 1
Step A: preparation of Compound II
Anhydrous tetrahydrofuran (1200 ml) was added to the flask under nitrogen, stirring was started and Compound I (120g, 0.63mol) was added. The temperature is controlled to be reduced to minus 78 ℃, tetrahydrofuran solution (380ml, 0.76mol, 2.0M) of lithium diisopropylamide is dripped, the temperature is controlled to be minus 78 ℃ after the dripping is finished, the mixture is stirred for one hour, N-dimethylformamide (69.35g, 0.95mol) is dripped, and the reaction is kept at the temperature of minus 78 ℃ for 1 hour after the dripping is finished.
TLC detection until compound I completely disappeared, quenched the reaction with saturated ammonium chloride (300 ml), extracted twice with ethyl acetate (300 ml), combined organic phases, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 125g of a yellow solid, compound II, yield: 91.2 percent. The characterization data for this compound are as follows: 1 HNMR(400MHz, CDCl 3 ), δ: 10.20（dd,J=14.8,2.8Hz,1H）, 7.57-7.34(m, 2H) . ESI-MS, m/z(%):220.82 (M + H ) + 。
and B: preparation of Compound III
Compound II (100g, 0.45mol) and methyl glycolate (207g, 2.3mol), tetrahydrofuran (1500 ml) were added to a dry reaction flask under nitrogen, maintained at 20 ℃ to 30 ℃, sodium hydride (35.26g, 0.92mol) was added in portions, heated to 70 ℃ and reacted for 10 hours. After the TLC reaction was completed, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride (400 ml)Reaction, extraction twice with ethyl acetate (400 ml), combining the organic phases, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentration to give 280g of crude product as compound III, which was used directly in the next reaction. The characterization data for this compound are as follows: ESI-MS, M/z (%): 272.88 (M + H) + 。
And C: preparation of Compound IV
Tetrahydrofuran (900 ml), water (300 ml) were added to a reaction flask, the crude compound III obtained in the above step was added, and lithium hydroxide (54.80g, 1.38mol) was added in portions and stirred at room temperature for 12 hours. After TLC detection raw material disappears, concentrating to remove tetrahydrofuran, adding hydrochloric acid aqueous solution to adjust pH value to 2-3, gradually precipitating solid, stirring for 2-3 hours, performing suction filtration, washing and drying the solid to obtain 95g of compound IV, wherein the yield of the two steps is as follows: 81.1 percent. The characterization data for this compound are as follows: 1 HNMR(400MHz, DMSO-d6),δ: 12.50(br,1H), 7.85-7.81(m, 1H), 7.58-7.53(m, 2H). ESI-MS, m/z(%):258.90 (M + H ) + 。
step D: preparation of Compound V
Adding DMSO (1000 ml) and a compound IV (200g, 0.78mol) into a reaction flask, stirring, adding cesium carbonate (760g, 2.34mol) in batches, heating the system to 110 ℃ for reaction for 12 hours, cooling to room temperature after TLC (thin layer chromatography) till the raw materials disappear, adding the reaction system into water, gradually precipitating a solid, stirring for 2-3 hours, carrying out suction filtration, washing with water, and drying to obtain a compound V140g, wherein the yield is as follows: 84.3 percent. The characterization data for this compound are as follows: 1 HNMR(400MHz, DMSO-d6), δ:8.20(d,J=4.0HZ,1H),7.71-7.68(m, 1H), 7.34（t，J=12.0HZ, 1H）, 6.99(s,1H). ESI-MS, m/z(%):214.98 (M + H ) + 。
step E: preparation of Compound VI
Adding 1000ml of tetrahydrofuran into a dry three-neck flask under the protection of nitrogen, adding a compound V (100g, 0.47mol), cooling the system to-78 ℃, controlling the temperature to-78 ℃, pumping N-butyllithium (225ml, 0.56mol, 2.5M), maintaining the temperature at-78 ℃, stirring for 1 hour, dropwise adding N, N-dimethylformamide (51.46g, 0.70mol), and keeping the temperature at-78 ℃ for reacting for 1 hour after the dropwise adding is finished.
TLC detection till complete disappearance of compound V and saturationThe reaction was quenched with ammonium chloride (400 ml), extracted twice with ethyl acetate (350 ml), and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 62g of a yellow solid as compound VI in yield: 81.2 percent. The characterization data for this compound are as follows: 1 HNMR(400MHz, CDCl 3 ),δ: 10.18（s，1H）,8.15(m, 1H)，7.85-7.76(m, 1H),7.28（t，J=12.0HZ, 1H）, 6.85(s，1H). ESI-MS, m/z(%):165.08 (M + H ) + 。
step F: preparation of Compound VII
Adding 1000ml of dichloromethane into a dry reaction bottle, adding a compound VI (120g, 0.56mol), adding trifluoroacetic acid (182.4 g, 1.60mol), adding tert-butyl carbamate (78.6 g, 0.67mol), dropwise adding triethylsilane (325.58g, 2.80mol), stirring at room temperature for 12 hours after the addition is finished, after TLC detection of disappearance of raw materials, concentrating a reaction system to remove a solvent, dissolving a residue in ethyl acetate (1000 ml), washing with saturated sodium bicarbonate (500 ml), washing with saturated sodium chloride, drying with anhydrous sodium sulfate, performing suction filtration and concentration to obtain a residue, adding 500ml of petroleum ether, stirring at room temperature, gradually precipitating a solid, and performing suction filtration to obtain 151g of a white solid, namely a compound VII, wherein the yield is as follows: 77.6 percent. The characterization data for this compound are as follows: 1 HNMR(400MHz, DMSO-d6),δ: 8.08 (d,J=4.2HZ, 1H), 7.52-4.42 (m, 1H), 7.25（t，J=10.0HZ, 1H）,7.15（br s，1H）, 6.68(s，1H)，1.38（s, 9H）. ESI-MS, m/z(%):266.12 (M + H ) + 。
step G: preparation of Compound VIII
Compound VII (100g, 0.38mol) was dissolved in methanol (1000 ml), 10g of 10% palladium carbon was added, the reaction system was subjected to hydrogenation reaction at room temperature under normal pressure, and after stirring at room temperature for 16 hours, compound VII was eliminated by TLC detection. The reaction system was filtered through celite, and the filtrate was concentrated to give 95g of a yellow solid, i.e., compound VIII in 94.3% yield. The characterization data for this compound are as follows: 1 HNMR(400MHz, DMSO-d6),δ: 7.25 (br s, 1H), 6.86 (m, 1H), 6.63（m, 1H）,4.12（d，J=1.2 HZ，2H）, 3.21(t，J=8.6 HZ，1H)，1.38（s, 9H）. ESI-MS, m/z(%):268.25 (M + H ) + 。
step H: preparation of Compound 8
Compound VIII (150g, 0.56mol) was added to methanol (1000 ml), a 4M methanol solution of hydrochloric acid (700 ml) was added, stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and the residue was added with methyl t-butyl ether to precipitate a solid, stirred for 2 to 3 hours, and suction filtered to give compound 8 102g as a white solid in 89.2% yield. The characterization data for this compound are as follows: 1 HNMR(400MHz, DMSO-d6),δ: 8.95-8.27(br s, 2 H), 7.0-6.95（m, 1H）, 6.79（m，1H）, 4.05-3.91(m，2H)，3.42（t, J=8.4 HZ，2H）. ESI-MS, m/z(%):168.25 (M + H ) + 。
the above embodiments are exemplary only, and are intended to illustrate the technical concept and features of the present invention so that those skilled in the art can understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A method for preparing an intermediate of an EED inhibitor, comprising:
the following synthetic route was used:
the method comprises the following steps:
step A: the compound I and N, N-dimethylformamide are substituted to generate a compound II;
and B, step B: the compound II and ethyl glycolate undergo cyclization to obtain a compound III;
and C: hydrolyzing the compound III under the alkaline condition to obtain a compound IV;
step D: decarboxylating the compound IV to obtain a compound V;
and E, step E: the compound V and N, N-dimethylformamide are substituted to obtain a compound VI;
step F: carrying out reductive amination on the compound VI and tert-butyl carbamate under the action of a reducing agent to obtain a compound VII;
step G: catalytically hydrogenating the compound VII to obtain a compound VIII;
step H: and removing the protecting group of the compound VIII under an acidic condition to obtain a compound 8.
2. The process for preparing an intermediate of an EED inhibitor according to claim 1, characterized in that: in the step A, the compound I and N, N-dimethylformamide have substitution reaction under the action of organic base, wherein the organic base is any one of lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and 2,2,6,6-tetramethyllithium piperidine.
3. The process for preparing an intermediate of an EED inhibitor according to claim 2, characterized in that: in step a, the molar ratio of compound I, N, N-dimethylformamide to organic base is 1.5.
4. The process for preparing an intermediate of an EED inhibitor according to claim 1, characterized in that: in the step B, the raw materials are subjected to a ring combination reaction under the action of alkali, and the alkali is one of sodium hydride, potassium hydride and potassium carbonate; the reaction solvent is one of tetrahydrofuran, diethyl ether and methyl tert-butyl ether; the molar ratio of the compound II to the base is 1:2, and the molar ratio of the compound II to the methyl glycolate is 1:5; the reaction temperature is 50-70 ℃ and the reaction time is 6-10 hours.
5. The method of preparing an EED inhibitor intermediate according to claim 1, wherein: in the step C, one of sodium hydroxide, potassium hydroxide and lithium hydroxide is used as the alkali, the reaction is carried out in one or a mixture of several of tetrahydrofuran, methanol, ethanol and water, the molar ratio of the compound III to the alkali is 1:3, the reaction temperature is 10-50 ℃, and the reaction time is 12 hours.
6. The process for preparing an intermediate of an EED inhibitor according to claim 1, characterized in that: in the step D, the compound IV is decarboxylated in an organic solvent under the action of a base; the solvent is one of N, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, the alkali is one of potassium carbonate, sodium carbonate and cesium carbonate, the molar ratio of the compound IV to the alkali is 1:3, the reaction temperature is 80-120 ℃, and the reaction time is 12-24 hours.
7. The process for preparing an intermediate of an EED inhibitor according to claim 1, characterized in that: in step E, the substitution reaction is carried out under the action of a base, the base is one of n-butyllithium, isopropyl magnesium chloride and isopropyl magnesium chloride lithium chloride solution, the solvent is one of tetrahydrofuran, dioxane and dimethyl sulfoxide, the molar ratio of the compound V to the base is 1.2, the reaction temperature is in the range of-90 ℃ to-70 ℃, and the reaction time is 2-4 hours.
8. The method of preparing an EED inhibitor intermediate according to claim 1, wherein: in the step F, the reaction solvent is one of dichloromethane, acetonitrile and tetrahydrofuran, the molar ratio of the compound VI to the reducing agent triethylsilane is 1:5, the reaction temperature is 20-30 ℃, and the reaction time is 12 hours.
9. The process for preparing an intermediate of an EED inhibitor according to claim 1, characterized in that: in step G, the catalyst is palladium carbon catalyst, the palladium content in the catalyst is 10%, the reaction solvent is methanol, the reaction temperature is 25-80 ℃, and the reaction time is 10-24 hours.
10. The method of preparing an EED inhibitor intermediate according to claim 1, wherein: in the step H, the acid used for deprotection is an alcoholic solution of hydrochloric acid, the reaction solvent is one of methanol, ethanol and isopropanol, the reaction temperature is 20-30 ℃, and the reaction time is 12 hours.
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| CN109790166A (en) * | 2016-06-20 | 2019-05-21 | 诺华股份有限公司 | Imidazopyridine is used for treating cancer |
| CN113004233A (en) * | 2019-12-18 | 2021-06-22 | 南京优氟医药科技有限公司 | Compound for preparing PRC2 inhibitor, preparation method and application thereof |
| CN113045523A (en) * | 2019-12-27 | 2021-06-29 | 上海泓博智源医药股份有限公司 | Preparation method of imidazoline pyridine compound intermediate |
| CN113636993A (en) * | 2020-05-11 | 2021-11-12 | 苏州亚盛药业有限公司 | Process for producing (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof, and intermediate therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109790166A (en) * | 2016-06-20 | 2019-05-21 | 诺华股份有限公司 | Imidazopyridine is used for treating cancer |
| CN113004233A (en) * | 2019-12-18 | 2021-06-22 | 南京优氟医药科技有限公司 | Compound for preparing PRC2 inhibitor, preparation method and application thereof |
| CN113045523A (en) * | 2019-12-27 | 2021-06-29 | 上海泓博智源医药股份有限公司 | Preparation method of imidazoline pyridine compound intermediate |
| CN113636993A (en) * | 2020-05-11 | 2021-11-12 | 苏州亚盛药业有限公司 | Process for producing (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof, and intermediate therefor |
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