A kind of synthetic method of benzisoquinoline compound

Abstract

The invention discloses a method for synthesizing a benzisoquinoline compound, and belongs to the technical field of compound synthesis. The method comprises the following steps: compound S4 reacts with alcohol under alkaline conditions to obtain compound S5; compound S5 is hydrolyzed under acidic conditions to obtain compound S6; compound S6 is subjected to a reduction amination reaction with aldehyde or ketone and a borohydride reagent under alkaline or acidic conditions to obtain a benzisoquinoline compound. The synthetic route of the invention has the characteristics of mild reaction conditions, short circuit, high yield, easy to scale up for batch production, suitable for industrial production, and simple operation. Experimental results show that the yield of the product synthesized by the synthetic method of the invention can reach 52.15%, which solves the problems that the synthetic method of benzisoquinoline compounds is relatively scarce, the synthetic conditions are harsh, and it is difficult to carry out large-scale synthesis above the gram level.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing a benzisoquinoline compound. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] ZO080 disclosed in patent WO2023169371A1 is a highly active small molecule inhibitor for inhibiting PD1-PD-L1 interaction and has clinical application prospects. The structural formula of compound ZO080 is as follows:

[0004]

[0005] From the structural formula, we can know that ZO080 belongs to the novel benzoisoquinoline compound. However, the synthesis method of this type of structure is relatively scarce, and the synthesis conditions are harsh, making it difficult to carry out large-scale synthesis above the gram level. For example, patent WO2023169371A1 discloses the synthesis of ZO080 compound using the following synthesis route, which is a milligram-level synthesis with harsh synthesis conditions and a total yield of only 5%, which is very low.

[0006]

[0007] In order to meet the requirements of rapid synthesis and large-scale preparation of ZO080-like compounds, it is necessary to develop efficient synthesis methods. Summary of the invention

[0008] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing benzoisoquinoline compounds. The synthesis method provided by the present invention has mild reaction conditions, short circuit, high yield, and is easy to scale up for mass production.

[0009] In order to achieve the above object, the technical solution of the present invention is:

[0010] The first aspect of the present invention provides a method for synthesizing a benzisoquinoline compound, comprising the following steps:

[0011] (1) Compound S4 reacts with alcohol under alkaline conditions to obtain compound S5;

[0012] (2) Compound S5 is hydrolyzed under acidic conditions to obtain compound S6;

[0013] (3) Compound S6 is subjected to a reductive amination reaction with an aldehyde or ketone and a borohydride reagent under alkaline or acidic conditions to obtain a benzisoquinoline compound;

[0014] The structural formulas of the compounds S4, S5 and S6 are as follows, and the structure of the benzisoquinoline compound is shown in S7;

[0015]

[0016] Among them, R3 is selected from halogen, and R4 and R5 are both selected from C1~C4 alkyl.

[0017] In some embodiments of the present invention, step (1) is: dissolving compound S4, triphenylphosphine, a base and an alcohol in an organic solvent, and subjecting the compound S5 to a Mitsunobu reaction at 0°C to 100°C;

[0018] The base includes but is not limited to any one or more of azodicarbonamide (TMAD), diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD);

[0019] The organic solvent is, but is not limited to, any one or more of tetrahydrofuran or benzene;

[0020] The molar ratio of the compound S4, triphenylphosphine, base and alcohol is 1.0: 1.0-5.0: 1.0-5.0: 1.0-5.0. In some embodiments of the present invention, step (2) is: dissolving the compound S5 in an organic solvent, adding an acid, and reacting at -10°C to 50°C to obtain the compound S6;

[0021] The organic solvent is, but is not limited to, any one or more of dichloromethane or methanol;

[0022] The acid includes, but is not limited to, any one or more of trifluoroacetic acid or hydrochloric acid.

[0023] Preferably, the acid is hydrochloric acid and the reaction temperature is 0°C to 25°C.

[0024] In some embodiments of the present invention, step (3) is: dissolving compound S6 and ketone in an organic solvent, adding an acid or a base and stirring, and then adding a borohydride reagent to carry out a reduction amination reaction to obtain a benzisoquinoline compound.

[0025] The ketone includes but is not limited to any one or more of 4-cyclohexanonecarboxylic acid methyl ester, 4-cyclohexanonecarboxylic acid ethyl ester, 4-cyclohexanonecarboxylic acid isopropyl ester, 4-cyclohexanonecarboxylic acid benzyl ester, and 4-cyclohexanonecarboxylic acid tert-butyl ester.

[0026] The organic solvent includes, but is not limited to, any one or more of dichloromethane, tetrahydrofuran, methanol or 1,2-dichloroethane.

[0027] The acid includes, but is not limited to, any one or more of acetic acid, butyric acid, propionic acid, oxalic acid, malonic acid, citric acid, glycolic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and pyrophosphoric acid.

[0028] The base includes, but is not limited to, any one or more of triethylamine, N,N-diisopropylethylamine, piperidine, pyridine, potassium carbonate, cesium carbonate, and sodium hydride.

[0029] The borohydride reagent includes, but is not limited to, any one or more of sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride.

[0030] The molar ratio of the compound S6, the acid or base, the aldehyde or ketone and the borohydride reagent is 1.0:1.0-20.0:1.0-20.0:1.0-20.0.

[0031] In some embodiments of the present invention, step (3) is: dissolving compound S6 and methyl 4-cyclohexanonecarboxylate in dichloromethane, adding acetic acid and stirring, and then adding sodium cyanoborohydride to carry out a reduction amination reaction to obtain a benzisoquinoline compound;

[0032] The molar ratio of the compound S6, acetic acid, methyl 4-cyclohexanonecarboxylate and sodium cyanoborohydride is 1.0:1.0-6.0:1.0-6.0:1.0-6.0.

[0033] In some embodiments of the present invention, the preparation method of compound S4 comprises the following steps:

[0034] (i) Using compound S1 as a raw material, converting the bromine substituent on the benzene ring into a methoxy group through reaction to obtain compound S2;

[0035] (ii) Compound S2 is subjected to debenzylation of the amino group and then protected with Boc to obtain compound S3;

[0036] (iii) Compound S3 reacts with a Lewis acid in an organic solvent at -78°C to 80°C to obtain Compound S4;

[0037] The structural formula of the compound S1 is shown below:

[0038]

[0039] Wherein, R1 is selected from C6-C8 alkyl, and R2 is selected from halogen.

[0040] In some embodiments of the present invention, step (i) in the method for preparing compound S4 is: dissolving compound S1 in an organic solvent, adding a base and a catalyst, and reacting at 50° C. to 120° C. to obtain compound S2;

[0041] The molar ratio of the compound S1, the base and the catalyst is 1.0:1.0-20.0:0-0.5;

[0042] The base includes but is not limited to any one or more of sodium methoxide, cesium carbonate or magnesium carbonate, preferably sodium methoxide;

[0043] The catalyst includes but is not limited to any one or more of cuprous bromide and cuprous chloride;

[0044] The organic solvent includes, but is not limited to, any one or more of methanol, acetonitrile, diethyl ether, N,N-dimethylformamide or toluene.

[0045] In some embodiments of the present invention, step (ii) in the method for preparing compound S4 is: dissolving compound S2 in an organic solvent, adding a palladium catalyst, reacting under a hydrogen atmosphere, and then protecting the amino group with a protecting group to obtain compound S3;

[0046] The organic solvent is, but is not limited to, any one or more of methanol, acetonitrile, diethyl ether, N,N-dimethylformamide or toluene;

[0047] Protecting group reagents include, but are not limited to, any one or more of di-tert-butyl dicarbonate, diisobutyl dicarbonate, di-n-butyl dicarbonate, dibenzyl dicarbonate, diethyl dicarbonate, dimethyl dicarbonate, di-n-propyl dicarbonate or diisopropyl dicarbonate, preferably di-tert-butyl dicarbonate;

[0048] The molar ratio of the compound S2, the palladium catalyst and the protecting group reagent is 1.0:0.01-0.1:1.0-3.0.

[0049] In some embodiments of the present invention, step (ii) in the method for preparing compound S4 is: reacting compound S2, 1-chloroethyl chloroformate, and a base in an organic solvent, hydrolyzing to obtain an intermediate, and then protecting the amino group with a protecting group to obtain compound S3;

[0050] The base includes but is not limited to any one or more of N,N-diisopropylethylamine, triethylamine N-methylmorpholine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate;

[0051] The organic solvent is, but is not limited to, any one or more of methanol, acetonitrile, diethyl ether, N,N-dimethylformamide or toluene;

[0052] Protecting group reagents include, but are not limited to, any one or more of di-tert-butyl dicarbonate, diisobutyl dicarbonate, di-n-butyl dicarbonate, dibenzyl dicarbonate, diethyl dicarbonate, dimethyl dicarbonate, di-n-propyl dicarbonate or diisopropyl dicarbonate, preferably di-tert-butyl dicarbonate;

[0053] The molar ratio of the compound S2, 1-chloroethyl chloroformate, base and protecting group reagent is 1.0:1.0-5.0:1.0-10.0:0-5.0, preferably 1.0:1.0-3.0:1.0-4.0:1.0-3.0.

[0054] In some embodiments of the present invention, in step (iii) of the method for preparing compound S4, the organic solvent is, but is not limited to, any one or more of dichloromethane, tetrahydrofuran or acetonitrile, preferably dichloromethane;

[0055] The Lewis acid includes but is not limited to any one or more of boron tribromide, aluminum chloride or aluminum bromide, preferably boron tribromide;

[0056] The molar ratio of the compound S3 to the Lewis acid is 1.0:1.0-10.0;

[0057] The reaction temperature is preferably -78°C to 25°C.

[0058] The beneficial effects of the present invention are:

[0059] Compared with the prior art, the present invention provides a method for synthesizing a benzisoquinoline compound, comprising the following steps: compound S4 reacts with an alcohol under alkaline conditions to obtain compound S5; compound S5 is hydrolyzed under acidic conditions to obtain compound S6; compound S6 is subjected to a reductive amination reaction with an aldehyde or ketone and a borohydride reagent under alkaline or acidic conditions to obtain a benzisoquinoline compound. The benzisoquinoline compound disclosed in the present invention is a core structural fragment of a D-L1 small molecule inhibitor, and can also be used as an important synthetic block for the synthesis of other drugs. The synthetic route of the present invention has the characteristics of mild reaction conditions, short circuit, high yield, easy to scale up batch production, suitable for industrial production, and simple operation. The experimental results show that the yield of the product synthesized by the synthetic method of the present invention can reach 52.15%, which is much greater than the total yield (5%) in patent WO2023169371A1. DETAILED DESCRIPTION

[0060] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0061] Example 1

[0062] A method for synthesizing a benzisoquinoline compound comprises the following steps:

[0063] The synthesis reaction equation is as follows:

[0064]

[0065] Step 1: Synthesis of 2-benzyl-6-methoxy-2,3-dihydro-1H-benzo[de]isoquinoline (S2)

[0066] Compound S1 (500 g, 1.48 mol) was dissolved in methanol (1.5 L). Sodium methoxide solution (2.96 L, 14.8 mol, 5 mol / L) was added under nitrogen atmosphere. The mixture was heated to reflux for 5 hours. After the reaction, the temperature was restored to room temperature. The solvent was dried by spin drying. The organic phase was dissolved in dichloromethane and washed with water. The organic phase was dried and spin dried and used directly in the next step to obtain target compound S2: 394 g. The yield was 92%.

[0067] 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J=8.7Hz,1H),7.44-7.37(m,3H),7.36-7.29(m,3H),7.20(d, J=7.1Hz,1H),7.08(d,J=7.8Hz,1H),6.75(d,J=7.7Hz,1H),4.02(s,2H),3.98(s,3H),3.80(s,2H).

[0068] Step 2: Synthesis of tert-butyl 6-methoxy-1H-benzo[de]isoquinoline-2(3H)-carboxylate (S3)

[0069] Compound S2 (390 g, 1.3 mol) was dissolved in methanol (1.5 L), and Pd / C (7.84 g, 74 mmol) was added under nitrogen atmosphere. Hydrogen was passed through the mixture and the reaction was carried out at room temperature overnight. After the reaction, Pd / C was filtered out, and the solvent was spin-dried and used directly in the next step.

[0070] The above compound (1.3 mol) was dissolved in dichloromethane (2 L), and then Et3N (394.3 g, 3.9 mol) was added and stirred at room temperature for 15 minutes. Finally, Boc2O (566.6 g, 2.6 mol) was added and monitored by spot plate. After the reaction was complete, the reaction was stopped, the solvent was dried and separated and purified by silica gel column to obtain the target compound S3: 351 g, and the total yield of two steps was 90%.

[0071] 1 H NMR(400MHz,Chloroform-d)δ8.11(dd,J=8.6,1.1Hz,1H),7.72(d,J=7.6Hz,1H),7.55(dd,J=8.6,7.0Hz ,1H),7.34(d,J=7.0Hz,1H),7.14(d,J=7.6Hz,1H),4.90(s,2H),4.85(s,2H),3.88(s,3H),1.48(s,9H).

[0072] Step 3: Synthesis of tert-butyl 6-hydroxy-1H-benzo[de]isoquinoline-2(3H)-carboxylate (S4)

[0073] Compound S3 (350 g, 1.17 mol) was dissolved in dichloromethane (1.5 L), cooled to -40 °C, and boron tribromide (2.34 L, 2.34 mol, 1 mol / L) was added dropwise under a nitrogen atmosphere. The temperature was slowly raised to room temperature and the mixture was reacted overnight. After the reaction, the reaction solution was poured into a saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was collected, dried, and then spin-dried to obtain the target compound S4: 317 g, yield: 95%.

[0074] 1 H NMR(400MHz,Chloroform-d)δ8.06(d,J=8.6Hz,1H),7.44(t,J=7.5Hz,1H),7.30( s,1H),7.06(d,J=7.6Hz,1H),6.76(s,1H),4.88(s,2H),4.82(s,2H),1.48(s,9H).

[0075] Step 4: Synthesis of tert-butyl 6-((3-bromo-2-methylbenzyl)oxy)-1H-benzo[de]isoquinoline-2(3H)-carboxylate (S5)

[0076] Compound S4 (315 g, 1.1 mol) and 3-bromo-2-methylbenzyl alcohol (243.3 g, 1.21 mol) were dissolved in tetrahydrofuran (3 L), and then triphenylphosphine (577 g, 2.2 mol) was added and cooled in an ice-water bath, and finally diisopropyl azodicarboxylate (267 g, 1.32 mol) was added and slowly heated to room temperature to react overnight. After the reaction, the solvent was dried and purified to obtain the target compound S5: 438 g, with a yield of 85%.

[0077] 1 H NMR (400MHz, Chloroform-d) δ8.15(d,J=8.5Hz,1H),7.58(d,J=8.0Hz,1H),7.44(q,J=7.9Hz,2H),7.31(d,J=7.1Hz,1H),7.18(d,J= 7.8Hz,1H),7.10(t,J=7.9Hz,1H),6.85(d,J=7.8Hz,1H),5.21(s,2H),4.88(s,2H),4.84(s,2H),2.48(d,J=2.2Hz,3H),1.48(s,9H).

[0078] Step 5: Synthesis of 6-((3-bromo-2-methylbenzyl)oxy)-2,3-dihydro-1H-benzo[de]isoquinoline (S6)

[0079] Compound S5 (435.6 g, 0.93 mol) was dissolved in dichloromethane (1.5 L), and then 4N hydrochloric acid 1,4-dioxane solution (400 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was directly used in the next step after being spin-dried.

[0080] 1 H NMR(400MHz,Chloroform-d)δ8.26(d,J=9.2Hz,1H),7.60(d,J=7.9Hz,1H),7.51-7.45(m,2H),7.43(d,J=7.3Hz,1H),7.34 (d,J=6.9Hz,1H),7.11(t,J=7.8Hz,1H),6.90(dd,J=11.8,7.7Hz,1H),5.21(s,2H),4.59(s,2H),4.55(s,2H),2.48(s,3H).

[0081] Step 6: Synthesis of methyl 4-(6-((3-bromo-2-methylbenzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)cyclohexane-1-carboxylate (S7)

[0082] Compound S6 (0.9 mol) and methyl 4-cyclohexanonecarboxylate (292 g, 1.5 mol) were dissolved in tetrahydrofuran (2 L), acetic acid (304 g, 3.00 mol) was added and stirred for 30 minutes, and then sodium cyanoborohydride (94.3 g, 1.50 mol) was added and reacted at room temperature for 12 hours. After the reaction was completed, water was added, and dichloromethane was extracted. The organic phase was collected and dried, and the target compound S7 was obtained after separation and purification by chromatography column: 357 g, and the total yield of two steps was 78%.

[0083] 1H NMR(500MHz,Chloroform-d)δ8.17(d,J=8.5Hz,1H),7.59(dd,J=8.1,1.2Hz,1H),7.45(dt,J=8.8, 1.7Hz,2H),7.29(dd,J=6.3,2.8Hz,1H),7.18(d,J=7.6Hz,1H),7.11(t,J=7.8Hz,1H),6.87(d,J=7 .8Hz,1H),5.22(s,2H),4.35(d,J=20.5Hz,4H),3.72(s,3H),2.77(s,2H),2.62-2.55(m,2H),2.48 (s,3H),2.30-2.24(m,2H),1.92(d,J=15.7Hz,2H),1.83(dd,J=9.5,4.8Hz,2H),1.52-1.48(m,1H).

[0084] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a benzisoquinoline compound, characterized in that: The steps include: (1) Compound S4, triphenylphosphine, a base, and an alcohol are dissolved in an organic solvent, and subjected to Mitsunobu reaction at 0°C to 100°C to obtain compound S5; the molar ratio of compound S4, triphenylphosphine, a base, and an alcohol is 1.0:2.0:1.2:1.1; the base is DIAD; and the organic solvent is tetrahydrofuran; (2) dissolving compound S5 in an organic solvent, adding an acid, and reacting at 0°C to 25°C to obtain compound S6; the acid is hydrochloric acid; (3) Compound S6 and methyl 4-cyclohexanonecarboxylate are dissolved in tetrahydrofuran, acetic acid is added and stirred, and then sodium cyanoborohydride is added to carry out a reduction amination reaction to obtain a benzisoquinoline compound; the molar ratio of compound S6, acetic acid, methyl 4-cyclohexanonecarboxylate and sodium cyanoborohydride is 3:10:5:5; The structural formulas of the compounds S4, S5 and S6 are as follows, and the structure of the benzisoquinoline compound is shown in S7; Wherein, R3 is selected from halogen, R4 is selected from C1-C4 alkyl, and R5 is methyl; The preparation method of the compound S4 comprises the following steps: (4) dissolving compound S1 in an organic solvent, adding a base, and reacting at 50° C. to 120° C. to obtain compound S2; The base is sodium methoxide; the organic solvent is methanol; (5) Compound S2 is debenzylated at the amino group and then protected with Boc to obtain compound S3; (6) Compound S3 reacts with a Lewis acid in an organic solvent at -78°C to 80°C to obtain compound S4; the organic solvent is dichloromethane; the Lewis acid is boron tribromide; the molar ratio of compound S3 to boron tribromide is 1.0:2.0; The structural formula of the compound S1 is shown below: Among them, R1 is benzyl and R2 is bromine.

2. The synthesis method according to claim 1, characterized in that The organic solvent in step (2) is any one or more of dichloromethane or methanol.

3. The synthesis method according to claim 1, characterized in that Step (5) is: dissolving compound S2 in an organic solvent, adding a palladium catalyst, reacting under a hydrogen atmosphere, and then protecting the amino group with a protecting group to obtain compound S3; The organic solvent is any one or more of methanol, acetonitrile, diethyl ether, N,N-dimethylformamide or toluene; The protecting group is Boc; The molar ratio of the compound S2, the palladium catalyst and the protecting group reagent is 1.0:0.01-0.1:1.0-3.

0.

4. The synthesis method according to claim 1, characterized in that Step (5) is: reacting compound S2, 1-chloroethyl chloroformate and a base in an organic solvent, hydrolyzing to obtain an intermediate, and then protecting the amino group with a protecting group to obtain compound S3; The base is any one or more of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate; The organic solvent is any one or more of methanol, acetonitrile, diethyl ether, N,N-dimethylformamide or toluene; The protecting group is Boc; The molar ratio of the compound S2, 1-chloroethyl chloroformate, base and protecting group reagent is 1.0:1.0-5.0:1.0-10.0:0-5.

0.

5. The synthesis method according to claim 4, characterized in that The molar ratio of the compound S2, 1-chloroethyl chloroformate, base and protecting group reagent is 1.0:1.0-3.0:1.0-4.0:1.0-3.0.

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