CN115636811A - Method for synthesizing isoindoline benzylamine derivative - Google Patents
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Abstract
The invention relates to a synthesis method of isoindoline benzylamine derivatives, which overcomes the defects of expensive raw materials, long reaction steps, complicated experimental operation and post-treatment, difficult industrial production and the like of the series of derivatives. The preparation method comprises the following steps: synthesizing the isoindoline benzylamine derivative through four-step reaction of catalysis, bromination, cyclization and reduction; the synthetic method has the advantages of less side reaction in the whole synthetic route, high conversion rate and yield, wide application substrates, mild operation conditions and high safety, and is favorable for large-scale production and industrialized popularization and application.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a synthesis method of isoindoline benzylamine derivatives.
Background
The isoindoline benzylamine compound is a molecule with a special structure, a key pharmacophore unit can be effectively connected and integrated into a rigid structure of the isoindoline benzylamine compound to form a molecule with a special spatial configuration/conformation, so that the isoindoline benzylamine compound can be matched with the spatial structure of different biological protein macromolecules in an organism to generate corresponding biological activity or effect, a plurality of isoindoline benzylamine compounds with different biological activities have, and the introduction of halogen and other groups effectively regulates or enhances the solubility and the effectiveness of a medicament, so that the isoindoline benzylamine compound has a wide application value, and particularly has application in medicaments for treating or preventing diseases, symptoms or conditions related to abnormal functions, such as GSPT1, IKZF2, IKZF3, CK1 alpha, N-MYC or C-MYC and the like, wherein protein mutation, expression, allosteric and abnormal functions are caused by GSPT1, IKZF2, IKZF3, IK1, N-MYC or C and the like.
The prior literature inquiry shows that the patent WO2022/029138, PCT/EP2021/071694 (shown in the following route) and some documents report the synthesis of isoindoline benzylamine derivatives, but the disclosed synthetic methods have various defects, the whole synthetic route has long steps, a plurality of side reactions, low conversion rate and yield and high preparation cost; each specific compound in the derivative needs to be synthesized from starting raw materials, a common intermediate is not used, the synthesis is simplified, the applicability is low, and the amplification and industrial production application are not facilitated.
Therefore, those skilled in the art have been devoted to developing a new method for synthesizing isoindoline benzylamine derivatives, which aims to solve the above-mentioned drawbacks of the synthesis methods of such compounds in the prior art.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the synthesis method of the isoindoline benzylamine derivative has the defects of multiple steps, multiple side reactions, low conversion rate and yield, no common intermediate, poor applicability, expensive reagent, high cost, no contribution to industrial production and the like, and simplifies synthesis.
In order to achieve the above objects, the present invention provides a novel method for synthesizing isoindoline benzylamine derivatives having a structure represented by the following formula a,
R 1 、R 2 identical or different, independently of one another, from hydrogen, deuterium, halogen;
m is 1,2 or 3;
R 3 selected from hydrogen, deuterium, halogen, the following groups unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、 -CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H;
wherein R is 4 、R 5 、R 6 、R 7 Any one of them is-CH 2 NH 2 With R 4 is-CH 2 NH 2 For example, the structure of the isoindoline benzylamine derivative is shown as the following formula A-1,
wherein R is 1 、R 2 Identical or different, independently of one another, from hydrogen, deuterium, halogen;
m is 1,2 or 3;
R 3 selected from hydrogen, deuterium, halogen, the following groups unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 is-CH 2 NH 2 ，R 5 、R 6 、R 7 Identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl;
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H;
the synthesis route of the isoindoline benzylamine derivative is shown as the following scheme I:
route I:
wherein X is Cl, br, I; r 1 ～R 13 、m、Q 1a 、Q 1b As defined above;
the specific operation steps are as follows:
step 1, compound A-1-0, zn (CN) 2 And Pd (PPh) 3 ) 4 Dissolving in dioxane/water (8v);
step 2, dissolving the compound A-1-1 and NBS in carbon tetrachloride, adding a catalytic amount of azodiisobutyronitrile, heating and carrying out reflux reaction until the reaction of the A-1-1 is complete, and carrying out post-treatment to obtain a compound A-1-2;
step 3, dissolving the compound A-1-2, the amino substrate and DIPEA in DMF, heating the reaction solution to 80 ℃ for reaction until the reaction of the A-1-2 is complete, and performing post-treatment to obtain a compound A-1-3;
step 4, dissolving the compound A-1-3 in THF, adding 10% Raney Ni catalyst, heating to 40 ℃ in a hydrogen environment for reaction until the reaction of the A-1-3 is complete, and performing post-treatment to obtain a corresponding target compound A-1;
further, said R 1 、R 2 Identical or different, independently of one another, from hydrogen, deuterium, halogen;
further, m is 1,2 or 3;
further, said R 3 Selected from hydrogen, deuterium, halogen, the following groups, unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
further, said Q 1 is-CQ 1a Q 1b -; wherein Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
further, said R 4 Is CH 2 NH 2 ，R 5 、R 6 、R 7 Identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl groups including or excluding heteroatoms or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl;
further, said R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H;
further, in the step 1, the mixed solvent is a mixed solvent of dioxane and water (8 v/1 v), and the volume ratio (v: v) is 5:1-15; preferably the solvent volume ratio (v: v) is 8:1;
further, in the step 1, the weight-to-volume ratio (g: mL) of the compound a-1-0 to the mixed solvent is 1; preferably the weight to volume ratio (g: mL) is 1;
further, in the step 1, the compound A-1-0 is reacted with Zn (CN) 2 The molar weight ratio of 1:1-1:3; preferably the molar weight ratio is 1:2;
further, in the step 1, the compound A-1-0 is reacted with Pd (PPh) 3 ) 4 The molar weight ratio of (1); the preferred molar weight ratio is 1;
further, in the step 1, the reaction temperature of the reaction is preferably 80 ℃;
further, in the step 2, the organic solvent is THF, acetonitrile, CHCl 3 、CCl 4 One or more of (a); preferably, the organic solvent is CCl 4 ；
Further, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-1-1 to the organic solvent is 1; preferably the weight to volume ratio (g: mL) is 1;
further, in the step 2, the molar weight ratio of the compound A-1-1 to NBS is 1:1-1:3; preferably the molar weight ratio is 1:2;
further, in the step 2, the molar weight ratio of the compound A-1-1 to the azobisisobutyronitrile is 1; the preferred molar weight ratio is 1;
further, in the step 2, the reaction temperature of the reaction is preferably 65 ℃;
further, in the step 3, the organic solvent is one or more of acetonitrile, DMF and DMA; preferably the organic solvent is DMF;
further, in the step 3, the weight-to-volume ratio (g: mL) of the compound a-1-2 to the organic solvent is 1; preferably the weight to volume ratio (g: mL) is 1;
further, in the step 3, the molar weight ratio of the compound A-1-2 to the aminolactam substrate is 1:1-1:3; preferably the molar weight ratio is 1:2;
further, in the step 3, the molar weight ratio of the compound A-1-2 to the DIPEA is 1.5-1:3; preferably the molar weight ratio is 1:2;
further, in the step 3, the reaction temperature of the reaction is preferably 80 ℃;
further, in the step 4, the organic solvent is one or more of acetonitrile, THF, etOH, DMF and DMA; preferably the organic solvent is THF;
further, in the step 4, the weight-to-volume ratio (g: mL) of the compound a-1-3 to the organic solvent is 1; preferably the weight to volume ratio (g: mL) is 1;
further, in the step 4, the weight ratio of the compound A-1-3 to Raney Ni is 1; the preferred molar weight ratio is 1;
further, in the step 4, the reaction temperature of the reaction is preferably 40 ℃;
according to the synthesis method of the isoindoline benzylamine derivative, the specific operation of the step 1 is as follows:
dissolving the intermediate A-1-0 and zinc cyanide in dioxane/water, adding palladium tetratriphenylphosphine, heating the reaction solution to 80 ℃ under the protection of nitrogen, reacting for about 2 hours, and detecting by LCMS to show that the raw materials disappear. And (3) cooling the mixed system to room temperature, filtering, adding water into the filtrate for dilution, and adding ethyl acetate for extraction and liquid separation. The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Obtaining A-1-1 through column chromatography;
according to the synthesis method of the isoindoline benzylamine derivative, the step 2 comprises the following specific operations:
dissolving the intermediate A-1-1 and N-bromosuccinimide in carbon tetrachloride, heating to 65 ℃, adding a catalytic amount of azobisisobutyronitrile, and continuously stirring for reacting for about 4 hours at the temperature, wherein LCMS detection shows that the raw material A-1-1 is completely reacted. Cooling to room temperature, suction filtering, washing the filter cake with dichloromethane, adding water into the filtrate for dilution, adding dichloromethane for extraction and liquid separation. Combining organic phases, backwashing by using saturated sodium sulfite solution and saturated salt water in sequence, drying the organic phases by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain A-1-2;
according to the synthesis method of the isoindoline benzylamine derivative, the specific operation of the step 3 is as follows:
intermediate A-1-2 and the aminolactam substrate were dissolved in N, N-dimethylformamide and diisopropylethylamine was added at room temperature. The mixed system was warmed to 80 ℃ and the reaction stirred at this temperature for about 4 hours and LCMS detection indicated that the a-1-2 reaction was complete. Cooling to room temperature, slowly adding water into the reaction solution to precipitate a white solid, performing suction filtration, pulping and washing the solid with petroleum ether/ethyl acetate (5/1) to remove impurities, performing suction filtration, and drying a filter cake to obtain A-1-3;
according to the synthesis method of the isoindoline benzylamine derivative, the specific operation of the step 4 is as follows:
dissolving A-1-3 in tetrahydrofuran, and adding Raney nickel at room temperature. The mixed system is replaced by hydrogen three times, a certain hydrogen pressure system is kept, the temperature is increased to 40 ℃, the reaction is stirred for about 4 hours at the temperature, and LCMS detection shows that the A-1-3 reaction is complete. The reaction solution is filtered after cooling, the filter cake is washed three times with tetrahydrofuran, and the filtrates are combined and concentrated under reduced pressure. To obtain the isoindoline benzylamine derivative A-1 (shown as a formula A-1).
The technical parameter characteristics in the above methods of the present invention can be combined at will.
In the above-mentioned operations, the post-treatment includes, but is not limited to, quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or more of water quenching, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the present invention, the quenching with a quencher refers to a process in which a quencher is added to a reaction solution to stop the reaction from proceeding to the right;
the quenching agent is one or more of water, ice water and hydrochloric acid aqueous solution;
in a preferred embodiment of the present invention, the extraction solvent is dichloromethane or ethyl acetate;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solids and liquids in a reaction solution, or a process of separating solids and liquids in a post-treatment operation; the filtration comprises common filtration and separation and centrifugal separation; wherein, the common filtration separation includes but is not limited to filtration using filter cloth, membrane filtration, and diatomite filtration;
in a preferred embodiment of the present invention, the water washing, alkali washing and acid washing include, but are not limited to, the use of saturated sodium bicarbonate solution, 5% potassium carbonate aqueous solution, saturated brine;
in a preferred embodiment of the present invention, the drying comprises anhydrous sodium sulfate drying of the filtrate, vacuum drying;
in a preferred embodiment of the present invention, the concentration refers to a process of removing a liquid solvent, including concentration under reduced pressure, concentration under normal pressure, low-temperature spin-drying, and the like;
the steps, solvents, reagents, filtration, drying, concentration, extraction, separation and the like in the synthesis method of the isoindoline benzylamine derivative can be combined or separated at will, and the purpose of the invention can be achieved.
Compared with the prior art, the method for synthesizing the isoindoline benzylamine derivative only needs four steps of reaction to obtain a target product, has short steps, less side reactions, high conversion rate and yield, single step yield of more than 80 percent and total yield of more than 40 percent, and is far higher than the total yield of the prior disclosed method; the synthesis method can be applied to synthesis of different derivative structures and has good applicability; the whole method has the advantages of simple and easily obtained reagent raw materials, no use of expensive reagents, reduced cost, mild reaction conditions, good operability and high safety; the operation repeatability is good, and the method is suitable for production in an enlarged workshop; the post-treatment energy consumption is low, a large amount of toxic wastewater is not generated, the environment is protected, the environment is not polluted, the safety level and the production cost of production are reduced, the application of green and environment-friendly industrial production is facilitated, and the method has a wide application prospect.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Example 1 Synthesis of 3- (4- (aminomethyl) -6-chloro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (formula A-1)
Step 1, dissolving the intermediate A-1-0 (9.8g, 39.8mmol) and zinc cyanide (9.328 g, 79.7mmol) in dioxane/water (160 ml/20 ml), adding a reaction solution of tetratriphenylphosphine palladium (2.3g, 2mmol), heating to 80 ℃ under the protection of nitrogen, reacting for about 2 hours, and detecting by LCMS to show that the raw material A-1-0 is completely reacted. After the mixed system was cooled to room temperature, the mixture was filtered, 100 ml of water was added to the filtrate to dilute the mixture, and ethyl acetate (2 × 100 ml) was added to extract the separated liquid. The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography (ethyl acetate/petroleum ether = 1/20-1/10) gave off-white solid a-1-17.1g, in 92% yield.
Step 2, dissolving intermediate A-1-1 (7.1g, 3.68mmol) and N-bromosuccinimide (13.1 g,73.6 mmol) in 98 ml of carbon tetrachloride and heating to 65 ℃, then adding a catalytic amount of azobisisobutyronitrile (0.12 g) and continuing stirring at the temperature for about 4 hours, and LCMS detection shows that the raw material disappears. Cooled to room temperature, filtered with suction, the filter cake was washed with 30 ml of dichloromethane, and 100 ml of water was added to the filtrate to dilute and dichloromethane (2 × 30 ml) was added to extract the layers. The combined organic phase was backwashed with a saturated sodium sulfite solution and a saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow liquid A-1 to 29.5g, with a yield of 95%.
Step 3, intermediate A-1-2 (5.4g, 19.9mmol) and 3-aminopiperidine-2,6-dione hydrochloride (6.6g, 39.8mmol) were dissolved in 108 ml of N, N-dimethylformamide and diisopropylethylamine (5.1g, 39.8mmol) was added at room temperature. The mixed system was warmed to 80 ℃ and the reaction was stirred at this temperature for about 4 hours and LCMS showed completion of the a-1-2 reaction. 300 ml of water was slowly added to the reaction solution, suction filtration was performed, the solid was washed with 100 ml of petroleum ether/ethyl acetate (5/1) to remove impurities, and the solid was dried to obtain an off-white solid A-1 to 3.9 g with a yield of 85%.
Step 4, dissolve A-1-3 (1g, 3.5 mmol) in 20 mL tetrahydrofuran and add Raney nickel (0.1 g) at room temperature. The mixed system is replaced by hydrogen three times, a certain hydrogen pressure system is kept, the temperature is increased to 40 ℃, the reaction is stirred for about 4 hours at the temperature, and LCMS detection shows that the A-1-3 reaction is complete. The reaction solution is cooled and filtered with suction, the filter cake is washed three times with 50 ml of dichloromethane/methanol (10/1), and the filtrates are combined and concentrated under reduced pressure. White solid A-10.96g was obtained in a yield of 95%.
The 3- (4- (aminomethyl) -6-chloro-1-oxoisoquinolin-2-yl) piperidine-2,6-dione (formula A-1) obtained above was subjected to structural NMR detection, and the detection results were as follows:
1 HNMR(400MHz,DMSO-d 6 )δ11.04(s,1H),8.62(s,2H),7.72-7.68 (m,1H),7.61-7.56(m,1H),5.18(dd,J＝13.2,5.1Hz,1H),4.65(d, J＝17.4Hz,1H),4.46(d,J＝17.3Hz,1H),4.12(s,2H),2.97-2.89 (m,1H),2.68-2.60(m,1H),2.42-2.35(m,1H),2.08-1.95(m,1H).
the detection result shows that the synthesized compound 3- (4- (aminomethyl) -6-chloro-1-oxoisoquinolin-2-yl) piperidine-2,6-diketone (A-1) has a correct structure.
Example 2 Synthesis of 3- (5- (aminomethyl) -6-fluoro-1-oxoisoindolin-2-yl) pyrrolidine-2,5-dione (formula A-2)
Step 1, dissolving the intermediate A-2-0 (9.8g, 39.8mmol) and zinc cyanide (9.328 g, 79.7mmol) in dioxane/water (160 ml/20 ml), adding a reaction solution of tetratriphenylphosphine palladium (2.3g, 2mmol) and heating to 80 ℃ under the protection of nitrogen for reacting for about 2 hours, and detecting by LCMS to show that the raw materials disappear. After the mixed system is cooled to room temperature, the mixed system is filtered, 100 ml of water is added into the filtrate for dilution, and ethyl acetate (2x 100 ml) is added for extraction and liquid separation. The organic phases were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography (ethyl acetate/petroleum ether = 1/20-1/10) gave off-white solid a-2-16.9g with a yield of 90%.
Step 2, dissolving intermediate A-2-1 (7.1g, 3.68mmol) and N-bromosuccinimide (13.1 g,73.6 mmol) in 98 ml of carbon tetrachloride, heating to 65 ℃, adding a catalytic amount of azobisisobutyronitrile (0.12 g) and continuing to stir at the temperature for about 4 hours, and LCMS detection shows that the raw material disappears. Cooled to room temperature, filtered with suction, the filter cake was washed with 30 ml of dichloromethane, diluted by adding 100 ml of water to the filtrate and extracted with dichloromethane (2 × 30 ml). The combined organic phase was backwashed with a saturated sodium sulfite solution and a saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow liquid A-2-29.3g, with a yield of 93%.
Step 3, intermediate A-2-2 (5.4g, 19.9mmol) and 3-methylpyrrolidine-2,5-dione hydrochloride (6.0g, 39.8mmol) were dissolved in 108 ml of N, N-dimethylformamide, and diisopropylethylamine (5.1g, 39.8mmol) was added at room temperature. The mixed system was warmed to 80 ℃ and the reaction stirred at this temperature for about 4 hours and LCMS showed completion of the a-2-2 reaction. To the reaction solution was added 200 ml of water for dilution and a mixture (3 × 100 ml) of methanol/dichloromethane =1 was added for extraction and liquid separation. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Column chromatography (methanol/dichloromethane = 1/100-1/30) afforded a-2-33.8g as an off-white solid in 70% yield.
Step 4, dissolve A-2-3 (1g, 3.7 mmol) in 20 ml tetrahydrofuran and add Raney nickel (0.1 g) at room temperature. The mixed system is replaced by hydrogen three times and a certain hydrogen pressure system is kept, the temperature is increased to 40 ℃, the reaction is stirred at the temperature for about 4 hours, the detection of LCMS shows that the reaction of the FDAB-1 is complete, the reaction solution is filtered by suction after being cooled, the filter cake is washed by 50 ml of dichloromethane/methanol (10/1) three times, and the filtrates are combined and concentrated under reduced pressure. White solid A-20.94g was obtained in 93% yield.
The 3- (5- (aminomethyl) -6-fluoro-1-oxoisoindolin-2-yl) pyrrolidine-2,5-dione (formula A-2) obtained above was subjected to structural NMR detection, and the detection results were as follows:
1 HNMR(400MHz,DMSO-d 6 )δ10.03(s,1H),8.51(s,2H),7.71(d, J＝6.2Hz,1H),7.55(d,J＝8.7Hz,1H),5.24(dd,J＝13.3,5.0Hz, 1H),4.48(d,J＝17.4Hz,1H),4.34(d,J＝17.4Hz,1H),4.17(s,2H), 3.13-2.99(m,1H),2.93-2.85(m,1H).
the detection result shows that the synthesized compound 3- (5- (aminomethyl) -6-fluoro-1-oxoisoindoline-2-yl) pyrrolidine-2,5-diketone (A-2) has a correct structure.
Example 3 Synthesis of 3- (6- (aminomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (formula A-3)
The target product compound 3- (6- (aminomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (formula a-3) was synthesized by a procedure similar to that of example 1.
Example 4 Synthesis of 3- (7- (aminomethyl) -4-fluoro-1-oxoisoindolin-2-yl) pyrrolidine-2,5-dione (formula A-4)
The target product compound 3- (7- (aminomethyl) -4-fluoro-1-oxoisoindolin-2-yl) pyrrolidine-2,5-dione (formula a-4) was synthesized by the procedure similar to that of example 2.
Purity detection is carried out on the isoindoline benzylamine derivative (shown as a formula A) obtained in the product obtained in the embodiment 1-4, and the detection result shows that the purity of the compound A-1-A-4 obtained in the embodiment 1-4 is more than 95%;
in conclusion, the isoindoline benzylamine derivative (formula A) obtained by the embodiment of the invention has the advantages of correct structure, high purity, low impurity content and excellent quality, and can be directly used for further development of medicines.
The isoindoline benzylamine derivative (formula A) obtained by the method of other embodiments and technical schemes of the invention has similar beneficial effects as described above.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (7)
1. The synthesis method of the isoindoline benzylamine derivative is characterized in that the structure of the isoindoline benzylamine derivative is shown as the following formula A,
R 1 、R 2 identical or different, independently of one another, from hydrogen, deuterium, halogen;
m is 1,2 or 3;
R 3 selected from hydrogen, deuterium, halogen, the following groups unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H;
the synthesis method of the isoindoline benzylamine derivative is characterized in that R is used 4 is-CH 2 NH 2 For example, the synthetic route is shown in scheme I:
route I:
wherein X is Cl, br, I;
R 1 、R 2 identical or different, independently of one another, from hydrogen, deuterium, halogen;
m is 1,2 or 3;
R 3 selected from hydrogen, deuterium, halogen, the following groups, unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 is-CH 2 NH 2 ，R 5 、R 6 、R 7 Identical or different and independently of one another are selected from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl;
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H;
the method for synthesizing the isoindoline benzylamine derivative is characterized by comprising the following steps of:
step 1, compound A-x-0, zn (CN) 2 And Pd (PPh) 3 ) 4 Dissolving in dioxane/water (8v);
step 2, dissolving the compound A-x-1 and NBS in carbon tetrachloride, adding a catalytic amount of azodiisobutyronitrile, heating and carrying out reflux reaction until the A-x-1 is completely reacted, and carrying out post-treatment to obtain a compound A-x-2;
step 3, dissolving the compound A-x-2, the amino substrate and DIPEA in DMF, heating the reaction solution to 80 ℃ for reaction until the reaction of the A-x-2 is complete, and carrying out post-treatment to obtain a compound A-x-3;
and 4, dissolving the compound A-x-3 in THF, adding 10% Raney Ni catalyst, heating to 40 ℃ in a hydrogen environment for reaction until the A-x-3 completely reacts, and performing post-treatment to obtain the corresponding compound A-x (x =1,2,3,4).
2. Isoindoline benzylamine derivative according to claim 1, wherein R is 1 、R 2 Selected from hydrogen or deuterium;
m is 1,2 or 3;
R 3 selected from hydrogen, deuterium, halogen, the following groups, unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5-C10 aryl including or not including hetero atoms or one or more selected fromSubstituted with substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 And cannot be H.
3. Isoindoline benzylamine derivative according to claim 1 or 2, wherein R is 1 、R 2 Selected from hydrogen or deuterium;
m is 1 or 2;
R 3 selected from hydrogen, deuterium, halogen, the following groups, unsubstituted or optionally substituted by one, two or more: c 1-12 Alkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 And cannot be H.
4. Isoindoline derivative according to claim 1,2 or 3, wherein R is 1 、R 2 Selected from hydrogen or deuterium;
m is 1 or 2;
R 3 selected from hydrogen;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium, C 1-12 Alkyl radical, C 3-20 Cycloalkyl or branched alkyl, alkoxy;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl groups including or excluding heteroatoms or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Not both can be H.
5. Isoindoline derivative according to claim 1,2,3, or 4, wherein R is 1 、R 2 Selected from hydrogen or deuterium;
m is 1 or 2;
R 3 selected from hydrogen;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b Identical or different, independently of one another, from hydrogen, deuterium;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Cannot be H.
6. Isoindoline derivative according to claim 1,2,3,4, or 5, wherein R is 1 、R 2 Selected from hydrogen or deuterium;
m is 1 or 2;
R 3 selected from hydrogen;
Q 1 is-CQ 1a Q 1b -；
Q 1a 、Q 1b The same are selected from hydrogen;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, from hydrogen, halogen, deuterium, cyano, -CR 8 R 9 R 10 、-CONR 11 R 12 、-OR 13 C5 to C10 aryl including or not including a heteroatom or substituted with one or more substituents selected from: halogen, cyano, ester group, aliphatic hydrocarbon group, aryl, heterocyclic aryl; wherein R is 4 、R 5 、R 6 、R 7 At least one is-CH 2 NH 2 ；
R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Identical or different, independently of one another, from the following groups, unsubstituted or optionally substituted by one, two or more: H. c 1-12 Alkyl radical, C 3-20 Cycloalkyl radical, C 1-12 Alkoxy or branched alkyl, alkoxy, C 6-20 Aryl, 5-20 membered heteroaryl; wherein R is 8 、R 9 、R 10 Not both can be H.
7. Isoindoline benzylamine derivative synthesized according to any of claims 1 to 6, wherein the isoindoline benzylamine derivative has a purity of greater than 95% and is useful as an intermediate or a moiety in drug synthesis.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021069705A1 (en) * | 2019-10-09 | 2021-04-15 | Monte Rosa Therapeutics | Isoindolinone compounds |
| WO2021198965A1 (en) * | 2020-03-31 | 2021-10-07 | Orum Therapeutics, Inc. | Neodegrader conjugates |
| WO2022029138A1 (en) * | 2020-08-03 | 2022-02-10 | Captor Therapeutics S.A. | Low molecular weight protein degraders and their applications |
| WO2022073469A1 (en) * | 2020-10-07 | 2022-04-14 | Cullgen (Shanghai) , Inc. | Compounds and methods of treating cancers |
| CN114502543A (en) * | 2019-05-24 | 2022-05-13 | 拜欧斯瑞克斯公司 | Targeted protein compounds, pharmaceutical compositions and therapeutic applications thereof |
| CN114835680A (en) * | 2022-04-29 | 2022-08-02 | 成都分迪药业有限公司 | Halogen substituted isoindoline compound and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114502543A (en) * | 2019-05-24 | 2022-05-13 | 拜欧斯瑞克斯公司 | Targeted protein compounds, pharmaceutical compositions and therapeutic applications thereof |
| WO2021069705A1 (en) * | 2019-10-09 | 2021-04-15 | Monte Rosa Therapeutics | Isoindolinone compounds |
| WO2021198965A1 (en) * | 2020-03-31 | 2021-10-07 | Orum Therapeutics, Inc. | Neodegrader conjugates |
| WO2022029138A1 (en) * | 2020-08-03 | 2022-02-10 | Captor Therapeutics S.A. | Low molecular weight protein degraders and their applications |
| WO2022073469A1 (en) * | 2020-10-07 | 2022-04-14 | Cullgen (Shanghai) , Inc. | Compounds and methods of treating cancers |
| CN114835680A (en) * | 2022-04-29 | 2022-08-02 | 成都分迪药业有限公司 | Halogen substituted isoindoline compound and application thereof |
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