High-throughput screening synthesis method of oxoisoindoline-carboxylic acid compound

Abstract

The invention discloses a high-throughput screening synthesis method of an oxoisoindoline-carboxylic acid compound, which comprises the following steps: in a polar solvent, carrying out carbonyl insertion reaction on a compound as shown in a formula I in the presence of a Pd catalyst and alkali under a heating condition to obtain an oxoisoindoline-carboxylic acid compound as shown in a formula II, in the formula, X is CH2 or C = O, and Y is CH3 or H. The oxo-isoindoline-carboxylic acid compound is synthesized and constructed through high-throughput screening, a series of oxo-isoindoline-carboxylic acid compounds are obtained, and optimal reaction conditions are obtained in an extremely short time through proper high-throughput screening, so that the reaction conditions of high yield and high compatibility are quickly locked, and the yield of the oxo-isoindoline-carboxylic acid compound is greatly improved. The innovative breakthrough of the method in the aspect of reaction mechanism is more highlighted, and a solution capable of being popularized is provided for efficient synthesis of similar carboxylic acid derivatives.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of synthesis of oxygen-containing isoindoline-carboxylic acid compounds, in particular, a high-throughput screening and synthesis method of oxygen isoindoline-carboxylic acid compounds. BACKGROUND

[0002] Oxygen isoindoline-carboxylic acid compounds have been used as molecular building blocks for the synthesis of T-type calcium channel antagonists, CDK inhibitors and antidepressant candidates due to their modular derivatization of "carboxylic acid + lactam" bifunctional groups. Their carboxamide derivatives exhibit significant low-density lipoprotein oxidation inhibition and free radical scavenging activity, which can be used for the prevention and treatment of atherosclerosis. In addition, the skeleton can also be used as a photosensitive linker, a polymer monomer and an isotopic labeling internal standard, and is widely used in the fields of cardiovascular drug research and development, functional materials and clinical analysis.

[0003] In the existing synthesis route of oxygen isoindoline-carboxylic acid compounds, the preparation of oxygen isoindoline-5-carboxylic acid often needs to rely on a roundabout oxidation reaction sequence due to the difficulty in realizing the key hydrolysis step, resulting in a long synthesis path and a low overall yield, which seriously restricts the large-scale preparation and application of the compounds. SUMMARY

[0004] In view of the long-standing synthesis bottleneck of synthesizing oxygen isoindoline-5-carboxylic acid compounds which are prone to hydrolysis by Pd-catalyzed CO insertion carbonylation reaction in the prior art, the present application successfully constructs a library of oxygen isoindoline-carboxylic acid compounds with diverse structures through a systematic high-throughput synthesis and screening strategy. In particular, the present application reveals the synergistic mechanism and screening specificity of each element in the insertion carbonylation reaction: by systematically investigating the precise matching relationship between the catalyst type and its ligand structure, the appropriate basic conditions, the polarity and hydrolysis ability of the solvent, and the applicable range of the substrate, the optimization process not only quickly locks the reaction conditions with high yield and high compatibility, but also highlights the innovative breakthrough of the present application at the level of reaction mechanism, thereby providing a general solution for the efficient synthesis of similar carboxylic acid derivatives.

[0005] To achieve the above object, the present application provides a high-throughput screening and synthesis method of oxygen isoindoline-carboxylic acid compounds, which adopts the following technical scheme: A high-throughput screening and synthesis method of oxygen isoindoline-carboxylic acid compounds, comprising the following steps:

[0006] In a polar solvent, the compound shown in formula I undergoes an insertion carbonylation reaction in the presence of a Pd catalyst and a base and under heating conditions to obtain an oxygen isoindoline-carboxylic acid compound shown in formula II. In the formula, X is CH2 or C=O, and Y is CH3 or H.

[0007] In some embodiments, the method comprises: (a) providing a compound of Formula I, a base, a solvent, and a catalyst to each of a plurality of reaction chambers; (b) maintaining the plurality of reaction chambers under conditions suitable for forming a compound of Formula II; (c) simultaneously purifying the plurality of compounds of Formula II; and (d) evaluating one or more physicochemical properties of the purified compounds of Formula II.

[0008] In some embodiments, the catalyst comprises a transition metal and a ligand, and the catalyst is selected from the group consisting of Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(PPh3)4; or the catalyst is selected from any combination of a transition metal Pd(OAc)2, Pd2(dba)3, [Pd(ally)Cl]2 and a ligand PPh3, PCy3.

[0009] In some embodiments, the base is selected from the group consisting of sodium carbonate, potassium phosphate.

[0010] In some embodiments, the solvent is a mixture of DMF and H2O.

[0011] In some embodiments, the plurality of reaction chambers are a plurality of reaction vials independently arranged in metal holes of a parallel reactor, and rubber pads are arranged above the reaction vials, and metal needles for gas exchange are inserted into the rubber pads, so as to ensure gas exchange while avoiding cross-contamination of solvents.

[0012] In some embodiments, the inorganic base is added to the reaction vials first, followed by the magnetic stirrer and the substrate and the catalyst; if the catalyst is a combination of a transition metal and a ligand, the ligand is added first, and the transition metal is added last; if the catalyst is a metal with a ligand, the catalyst is directly added; and each material is added to all reaction vials at the same time through an auxiliary liquid storage tank.

[0013] In some embodiments, the heating stirrer supports the reaction vials through a metal tray, and the rotation speed of the reaction is controlled to be 800-1000 revolutions.

[0014] In some embodiments, the catalyst is Pd(dppf)Cl2, the solvent is a mixture of DMF and H2O, and the base is Na2CO3.

[0015] In some embodiments, the ratio of the compound of Formula I to the catalyst to the base is 1: (0.05-0.1): 2.

[0016] In some embodiments, the reaction temperature of the insertion carbonylation reaction is 98-102°C, and the reaction time is 15-17h.

[0017] While screening reaction conditions and synthesizing related compounds can be achieved through conventional chemical methods, these methods are time-consuming, costly, and typically only provide specific solutions, not solutions for multiple compounds simultaneously. Current synthetic methods involve a slow process of changing and attempting to optimize each reaction parameter sequentially. This may include the type and concentration of the substrate, reaction time, base and catalyst, as well as the type and stoichiometry of the catalyst, the type of solvent, temperature, and purification steps. Such gradual changes in reaction parameters lead to long periods of comprehensive experimentation and errors, making condition optimization even more laborious. Compared to conventional techniques, the advantages of this invention are: 1) This invention provides a complex high-throughput screening scheme for various compounds. Based on appropriate solvents, transition metals, types and equivalences of bases and substrates, it screens reaction materials, suppresses hydrolysis side reactions in the reaction system, achieves efficient carbonylation, and fully utilizes the best catalytic reaction performance to synthesize target compounds.

[0018] 2) This invention, through a high-throughput system based on a parallel reactor and a heating stirrer, enables rapid feeding and modification of reaction conditions, providing a solution for high-throughput screening and synthesis of compounds. It is used to rapidly screen reaction conditions and synthesize target compounds. Utilizing this high-throughput system, the catalyst of this invention optimizes the reaction pathway through a combination of transition metals and multiple ligands. The Pd catalyst is reduced under heating and appropriate alkaline conditions, subsequently undergoing oxidative addition with the reaction substrate. CO coordinates and is appropriately hydrolyzed and reduced in a polar solvent, completing a continuous catalytic cycle. Throughout the catalytic cycle, based on appropriate reaction conditions, a multi-factor synergistic mechanism and a high-efficiency carbonylation reaction of palladium-catalyzed CO insertion are achieved, representing an innovative breakthrough.

[0019] In summary, this invention presents a high-throughput screening scheme specifically designed for this sensitive system. Through multi-parameter synergistic optimization, the unique stability of the Pd catalyst in the cyclic catalytic reaction was systematically investigated and screened. The base-promoted reduction of the Pd catalyst and the precisely controlled polar solvent for hydrolysis without causing the decomposition of other sensitive groups, combined with the control of CO pressure and reaction temperature, ultimately yielded unexpectedly high yield and high selectivity reaction conditions. This combination of conditions is highly specific, resolving the core contradiction of "inhibiting hydrolysis and promoting carbonylation." Attached Figure Description

[0020] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0021] Figure 1 The illustration shows the screening process and results of the first round of catalysts in Example 1.

[0022] Figure 2 The illustration shows the second round of screening process and results for alkali and solvent in Example 2.

[0023] Figure 3 The figure illustrates the results of the screening synthesis of catalyst equivalents in Example 3. Detailed Implementation

[0024] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0025] All solvents used in this invention are of analytical grade. All substances used as raw materials in the examples were obtained through commercial purchase.

[0026] According to a preferred embodiment of the present invention, a high-throughput screening synthesis method for oxoisoindoline-carboxylic acid compounds is provided, comprising the following steps:

[0027] In a solvent, the compound shown in Formula I undergoes an intercalation reaction in the presence of a catalyst and a base, and under heating conditions, to give the oxoisoindoline-carboxylic acid compound shown in Formula II.

[0028] In the formula, X is CH2 or C=O, and Y is CH3 or H.

[0029] Specifically, the method includes (a) supplying each of a plurality of reaction chambers with a compound of formula I (i.e., compound I), a base, a solvent, and a catalyst; (b) maintaining the plurality of reaction chambers under conditions suitable for forming a compound of formula II (i.e., compound II); (c) simultaneously purifying the plurality of compounds of formula II; and (d) evaluating one or more physicochemical properties of the purified compound II.

[0030] In some embodiments, the method disclosed herein may further include mixing the formula I with the base, catalyst, and solvent in at least one of the plurality of reaction chambers to form a homogeneous mixture.

[0031] This invention systematically analyzes the precise matching relationships between catalyst type and its ligand structure, base type and dosage, solvent polarity and coordination ability, and substrate applicability. The catalyst of this invention optimizes the reaction pathway through a combination of transition metals and multiple ligands. Under heating and CO and alkaline conditions, it is reduced to the Pd(0)-dppf complex. Pd(0) undergoes oxidative addition to the C–Br bond of the bromide to generate the Ar–Pd(II)–Br complex. CO coordinates to Pd and subsequently inserts into the Ar–Pd bond to form the aryl-palladium species Ar–C(O)–Pd–Br. Water ( Ar–C(O)–Pd–Br is attacked by the nucleophile on the carbonyl carbon of the acyl-palladium intermediate to form a carboxylic acid, which then reduces and eliminates Pd(O), completing the catalytic cycle. Water acts as the nucleophile for the hydrolysis of Ar–C(O)–Pd–Br; insufficient water content will affect the entire catalytic cycle, while excessive water content may lead to side reactions in some cases. This invention further optimizes and controls the appropriate amount of water (20 μL). Adding 200 μL of DMF resulted in complete hydrolysis without causing decomposition of other sensitive groups. This revealed the synergistic mechanism and screening specificity of various elements in the carbonylation reaction, achieving a multi-element synergistic mechanism and innovative breakthrough in palladium-catalyzed CO carbonylation reaction.

[0032] In some embodiments, the molar ratio of the compound shown in Formula I to the catalyst and base is 1:(0.05~0.1):2. Furthermore, the reaction temperature for the carbonylation reaction is controlled at 98-102℃, and the reaction time is 15-17 h. Carbonylation reactions typically require high temperature and high pressure, but theoretically, low-temperature equilibrium is needed to suppress unnecessary hydrolysis. However, this invention, through the synergistic effect of its components, still controls unnecessary hydrolysis even at high temperatures of around 100℃. Thus, the combination of conditions in this invention is highly specific, resolving the core contradiction of "inhibiting hydrolysis and promoting carbonylation."

[0033] This optimization process not only quickly locks in high-yield and highly compatible reaction conditions, but also highlights the innovative breakthrough of this invention at the reaction mechanism level, providing a generalizable solution for the efficient synthesis of a series of oxoisoindoline-carboxylic acid compounds.

[0034] The catalyst comprises a transition metal and a ligand. The catalyst in this invention is selected from Pd(dppf)Cl2, Pd(PPh3)2Cl2, and Pd(PPh3)4; or the catalyst is selected from any combination of transition metals Pd(OAc)2, Pd2(dba)3, and [Pd(ally)Cl]2 with ligands PPh3 and PCy3.

[0035] The alkali is selected from sodium carbonate and potassium phosphate.

[0036] The solvent used is a mixed solution of DMF and H2O.

[0037] To obtain high-throughput reaction conditions quickly and accurately, this invention utilizes a high-throughput system for the aforementioned high-throughput reaction. The high-throughput system includes a parallel reactor and a heating stirrer. The multiple reaction chambers consist of independent reaction flasks located within metal orifices in a parallel reactor. Each reaction flask is topped with a rubber pad to ensure the independence of the reaction. Metal needles for gas exchange are embedded in the rubber pads. This ensures gas exchange while preventing cross-contamination of the solvent. In some embodiments, a single reactor may optionally include at least four or at least ten reaction chambers.

[0038] Furthermore, the heating stirrer supports the reaction flask via a metal tray, which better ensures the heat transfer efficiency between the heater and the reactor, guaranteeing a stable reaction temperature. The reaction flask is located within the metal orifice of the parallel reactor, and the reaction liquid is encased in heated metal, preventing temperature differences between the upper and lower parts of the reaction liquid.

[0039] In some embodiments, an inorganic base is added to the reaction flask first, followed by a magnetic stir bar, substrate, and catalyst. If the catalyst is a ligand-containing metal, such as Pd(dppf)Cl2, Pd(PPh3)2Cl2, or Pd(PPh3)4, it can be added directly. If the catalyst is selected from any combination of transition metals such as Pd(OAc)2, Pd2(dba)3, or [Pd(ally)Cl]2 with ligands such as PPh3 or PCy3, the catalyst ligands are added first, followed by the transition metal. Each material is added simultaneously to all reaction flasks via an auxiliary storage tank. This prevents the magnetic stir bar from sticking to the bottom of the reaction flask during rotary evaporation of the solvent. Furthermore, the simultaneous addition of each material to all reaction flasks via an auxiliary storage tank ensures timely and uniform feeding.

[0040] In practical applications, auxiliary storage tanks are made of polymer plastic materials to accommodate various solvents. Since the storage tank has multiple slots, it can simultaneously hold multiple different reaction liquid systems, ensuring the synchronicity and timeliness of the reaction.

[0041] The method also includes simultaneously heating and stirring multiple reaction flasks using a heated stirrer after the reactants are added to the reaction flasks, and separating the products from the multiple reaction flasks after the reaction is complete.

[0042] The polymer materials used in the parallel reactors are all high-temperature resistant, and the reaction flasks are made of special glass material with a certain pressure resistance of 5mL, 10mL, or 20mL. These materials are all designed to prevent air contamination of the transition metals during the reaction, which could lead to their deactivation, and to ensure the independence of the reactors and avoid cross-contamination. In some implementation schemes, each reaction chamber uses less than 1mL of solvent.

[0043] In some implementations, the reaction speed is controlled at 800-1000 rpm during high-throughput screening. 880 rpm is preferred; too low a speed may result in insufficient stirring, while too high a speed may lead to excessively vigorous stirring.

[0044] Based on the above embodiments, the present invention selected the following substrates for the following specific experiments: Compound I is selected from any one of the following compounds:

[0045] Compound II is selected from any one of the following compounds:

[0046] Example 1 The high-pressure parallel reactor (containing reaction flasks with independent metal orifice plates A1-A9) was transferred to a glove box. Inorganic base was added to the reaction flasks first, followed by a magnetic stir bar, substrate, and catalyst ligand. Finally, a transition metal was added. Each material was added simultaneously to all reaction flasks at once via an auxiliary storage tank. The specific materials are: Substrate: Add 0.1 mmol I-1 to each of A1-A9; Catalyst ligands and transition metals: 0.005 mmol Pd(dppf)Cl2 (0.05 eq) was added to A1; 0.005 mmol Pd(PPh3)2Cl2 (0.05 eq) was added to A2; 0.005 mmol Pd(PPh3)4 (0.05 eq) was added to A3; 0.01 mmol PCy3 was added to A4, A6, and A8 respectively; 0.01 mmol PPh3 was added to A5, A7, and A9 respectively; 0.005 mmol Pd(OAc)2 was added to A4 and A5 respectively; 0.0025 mmol Pd2(dba)3 was added to A6 and A7 respectively; and 0.0025 mmol [Pd(ally)Cl]2 was added to A8 and A9 respectively. Alkali: Add 0.2 mmol of Na2CO3 to each of A1-A9; Solvent: Add 200 μL of DMF to each of A1-A9 and 20 μL of H2O to each of A1-A9.

[0047] After feeding is completed, seal the reactor, transfer the reactor out of the glove box, pressurize with CO to 1.5 MPa, and place the reaction at 100 °C for 16 hours.

[0048] Table 1. High-throughput screening experiment in Example 1

[0049] Combination Figure 1 As shown, after screening in Example 1, the A1 plate yielded a better catalyst, Pd(dppf)Cl2.

[0050] Example 2 Based on the results of Example 1, further high-throughput screening was performed.

[0051] Transfer the reactor to the glove box; Add 0.1 mmol of I-1 to each of A1-A5, and add 0.005 mmol of Pd(dppf)Cl2 (0.05 eq) to each of A1-A5. Add 0.2 mmol Na2CO3 to A1, 0.2 mmol K3PO4 to A2, 0.1 mmol Na2CO3 to A3, 0.15 mmol Na2CO3 to A4, and 0.2 mmol Na2CO3 to A5. Add 200 μL of DMF to A1-A4 respectively, and add 20 μL of H2O to A1-A4 respectively; add 200 μL of DMF to A5, and add 40 μL of H2O to A5. After feeding is completed, the reactor is sealed and transferred out of the glove box. The CO pressure is 1.5 MPa and the reaction is carried out at 100°C for 16 hours.

[0052] The specific reaction results are as follows: Figure 2 As shown, this indicates that, through screening in Example 2, a better alkali, Na2CO3, and a better solvent, namely a mixed solvent of 200 μL DMF and 20 μL H2O, were obtained.

[0053] Example 3 Based on the results of Examples 1 and 2, the optimal combination of transition metal catalyst, base and solvent was selected. Example 3 mainly screened the equivalent amount of catalyst.

[0054] Transfer the reactor to the glove box; Add 0.1 mmol of I-1, 0.005 mmol of Pd(dppf)Cl2 (0.05 eq), and 0.2 mmol of Na2CO3 to A1; Add 0.1 mmol of I-1, 0.004 mmol of Pd(dppf)Cl2 (0.04 eq), and 0.2 mmol of Na2CO3 to A2; Add 0.1 mmol of I-1, 0.003 mmol of Pd(dppf)Cl2 (0.03 eq), and 0.2 mmol of Na2CO3 to A3; Add 0.1 mmol of I-1, 0.002 mmol of Pd(dppf)Cl2 (0.02 eq), and 0.2 mmol of Na2CO3 to A4; Add 0.1 mmol of I-1, 0.01 mmol of Pd(dppf)Cl2 (0.1 eq), and 0.2 mmol of Na2CO3 to A5; After feeding is complete, seal the reactor, transfer it out of the glove box, pressurize it with CO to 1.5 MPa, and place the reaction at 100°C. o The reaction was carried out at C for 16 hours.

[0055] The specific reaction results are as follows: Figure 3 As shown, this indicates that a better catalyst equivalent, 0.05 eq Pd(dppf)Cl2, was obtained through screening in Example 3.

[0056] Example 4 Based on the results of Examples 1 and 2, the optimal combination of transition metal catalyst, base and solvent was selected for the preparation of related compounds. Example 3 mainly shows the preparation of some compounds (the specific reaction steps for each compound will be listed in detail below).

[0057] Transfer the reactor to the glove box; Add 0.1 mmol of I-1 to A1, 0.1 mmol of I-2 to A2, and 0.1 mmol of I-3 to A3; Add 0.005 mmol Pd(dppf)Cl2 (0.05 eq) and 0.2 mmol Na2CO3 to A1-A3 respectively; Add 200 μL of DMF and 20 μL of H2O to A1-A3 respectively; After feeding is complete, seal the reactor and transfer it out of the glove box. Pressurize the CO at 1.5 MPa and place the reaction at 100°C. o The reaction was carried out at C for 16 hours.

[0058] After the reaction was complete, some compounds were obtained through high-throughput preparation. Specific reaction information is as follows: Reaction 1:

[0059] 0.1 mmol I-1 was dissolved in a reactor containing 200 μL DMF and 20 μL H2O, using 0.005 mmol Pd(dppf)Cl2 as a transition metal catalyst and 0.2 mmol Na2CO3 as a base, at 100 o The mixture was stirred at C for 16 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellowish-white solid as product compound II-1, with a yield of 88% and m / Z 192 [M+H]. + .

[0060] NMR characterization of compound II-1 (white solid): 1 H NMR (400 MHz, DMSO) δ 13.78 (s, 1H), 11.58 (s, 1H), 8.35 (d, J =7.2 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J = 7.3 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 167.88 (s), 135.37 (s), 132.57 (s), 122.82 (s). Reaction 2:

[0061] 0.1 mmol I-2 was dissolved in a reactor containing 200 μL DMF and 20 μL H2O, using 0.005 mmol Pd(dppf)Cl2 as a transition metal catalyst and 0.2 mmol Na2CO3 as a base, at 100 o The mixture was stirred at C for 16 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a yellowish-white solid as product compound II-2, with a yield of 95% and m / Z 178 [M+H]. + .

[0062] NMR characterization of compound II-2 (white solid): 1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.75 (s, 1H), 8.16 (dd, J =5.6, 1.6 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 4.47 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 169.55 (s), 167.29 (s), 149.07 (s), 133.54 (s), 132.57 (s), 131.10 (s), 124.62 (s), 124.00 (s), 45.65 (s). Reaction 3:

[0063] 0.1 mmol of I-3 was dissolved in a reactor containing 200 μL of DMF and 20 μL of H2O, using 0.005 mmol of Pd(dppf)Cl2 as a transition metal catalyst and 0.2 mmol of Na2CO3 as a base, at 100 o The mixture was stirred at C for 16 h, and the reaction was monitored by TLC. Separation by column chromatography yielded a white solid as product compound II-3, with a yield of 90% and m / Z 206 [M+H]. + .

[0064] NMR characterization of compound II-3 (white solid): 1 H NMR (400 MHz, DMSO) δ 13.65 (s, 1H), 8.29 (dd, J = 7.7, 1.4 Hz,1H), 8.13 (d, J = 0.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 3.06 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 166.60 (d, J = 3.8 Hz), 165.19 (s), 135.45(s), 134.50 (s), 131.62 (s), 122.61 (s), 122.24 (s), 23.33 (s). In summary, this invention, supported by a high-throughput system, successfully screened for optimal compound conditions and prepared related compounds, significantly reducing screening time and trial-and-error costs. This provides substantial support for screening reaction conditions and preparing target compounds. The following multi-dimensional comparative experiments further validate the aforementioned high-throughput results:

[0065] Comparative Example 1

[0066] A high-throughput screening synthesis method for oxoisoindoline-carboxylic acid compounds is basically the same as the method described in specific reaction 1 above, except that the feed ratio of the reaction raw materials is different.

[0067] The yields under different conditions in the above reaction examples and comparative examples are compared as follows: 1. Different compounds II were synthesized with different feed ratios, as shown in Table 2.

[0068] Table 2. Raw materials and products of the above reaction examples

[0069] As can be seen from the results in Table 2, the reaction exhibits the highest catalytic activity and the lowest cost when the catalyst equivalent is 0.05 eq.

[0070] Comparative Example 2 A high-throughput screening synthesis method for oxoisoindoline-carboxylic acid compounds is basically the same as the method described in specific reaction 1 above, except that the reaction temperature and time are different.

[0071] The reaction conditions at different reaction temperatures and times are shown in Table 3.

[0072] Table 3. Reaction conditions at different reaction temperatures

[0073] As can be seen from the results in Table 3, when the temperature is 100 o The reaction is most effective at temperature C. When the temperature is too high, the formation of hydrolysis byproducts will be accelerated, and when the temperature is too low, the reaction rate will be significantly reduced.

[0074] In summary, the reaction conditions determined by high-throughput screening in this invention are as follows: the catalyst is Pd(dppf)Cl2, the solvent is a mixed solution of DMF and H2O, and the base is Na2CO3. The ratio of the compound shown in Formula I to the catalyst and base is 1:(0.05~0.1):2. The reaction temperature for the carbonylation reaction is 98-102℃, and the reaction time is 15-17h. Based on these conditions, a relatively high product yield is obtained.

[0075] Based on the above-described preferred embodiments of the present invention, those skilled in the art can make various changes and modifications without departing from the inventive concept, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A high-throughput screening synthesis method for oxoisoindoline-carboxylic acid compounds, characterized in that, Includes the following steps: ； In a polar solvent, the compound shown in Formula I undergoes an intercalation reaction in the presence of a Pd catalyst and a base, and under heating conditions, to give the oxoisoindoline-carboxylic acid compound shown in Formula II. In the formula, X is CH2 or C=O, and Y is CH3 or H.

2. The high-throughput screening synthesis method according to claim 1, characterized in that, The method includes: (a) supplying each of a plurality of reaction chambers with a compound of formula I, a base, a solvent, and a catalyst; (b) maintaining the plurality of reaction chambers under conditions suitable for the formation of a compound of formula II; (c) simultaneously purifying the plurality of compounds of formula II; and (d) evaluating one or more physicochemical properties of the purified compound of formula II.

3. The high-throughput screening synthesis method according to claim 1, characterized in that, The catalyst comprises a transition metal and a ligand, wherein the catalyst is selected from Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(PPh3)4; or the catalyst is selected from any combination of transition metals Pd(OAc)2, Pd2(dba)3, [Pd(ally)Cl]2 and ligands PPh3, PCy3.

4. The high-throughput screening synthesis method according to claim 3, characterized in that, The alkali is selected from sodium carbonate, potassium phosphate, or a combination thereof.

5. The high-throughput screening synthesis method according to claim 3, characterized in that, The solvent used is a mixed solution of DMF and H2O.

6. The high-throughput screening synthesis method according to claim 2, characterized in that, The multiple reaction chambers are independent of each other and are set in metal holes in a parallel reactor. Each reaction flask has a rubber pad on top and metal needles for gas exchange are inserted into the rubber pad.

7. The high-throughput screening synthesis method according to claim 6, characterized in that, Inorganic base is added to the reaction flask first, followed by magnetic stir bar, substrate and catalyst. If the catalyst is a combination of transition metal and ligand, the catalyst ligand is added first and the transition metal is added last. Each material is added to all reaction flasks at once through an auxiliary storage tank.

8. The high-throughput screening synthesis method according to claim 1, characterized in that, The catalyst used is Pd(dppf)Cl2, the solvent is a mixed solution of DMF and H2O, and the alkali is Na2CO3.

9. The high-throughput screening synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the catalyst and base is 1: (0.05~0.1):

2.

10. The high-throughput screening synthesis method according to claim 1, characterized in that, The reaction temperature for the carbonyl insertion reaction is 98-102℃, and the reaction time is 15-17h.

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