Preparation method of CXCR4 antagonist drug Mavorixfor and isoquinoline derivative of CXCR4 antagonist drug Mavorixfor

Abstract

The invention discloses a preparation method of a CXCR4 antagonist drug Mavorixfor and an isoquinoline derivative thereof, which comprises the following specific operation procedures: dissolving isoquinoline or benzimidazole in acetonitrile, adding methanol, a multi-bipyridine cobalt catalyst, electrolyte and a proton source, reacting under the conditions of visible light irradiation and constant voltage, and separating and purifying to obtain the CXCR4 antagonist drug Mavorixfor and the isoquinoline derivative thereof. And carrying out C-N coupling on the obtained hydroxymethylation product and a drug intermediate through a Mitsunobu reaction, so as to prepare the CXCR4 antagonist drug Mavorixfor and the isoquinoline derivative thereof. The method has the advantages of easily available and cheap raw materials, simple steps, high atom utilization rate, no need of additional addition of a stoichiometric oxidant, and good application prospects.

Description

Technical Field

[0001] This invention relates to a method for preparing a CXCR4 antagonist drug, Mavorixafor, and its isoquinoline derivatives. Background Technology

[0002] Nitrogen-containing aromatic heterocycles, such as isoquinolines, quinolines, phthalazines, and benzothiazoles, and their derivatives, are an important class of heterocyclic compounds that play a significant role in the pharmaceutical field, exhibiting a variety of biological activities, including antibacterial, antimalarial, antitumor, anti-AIDS, anti-inflammatory, antidepressant, antiarrhythmic, anticancer, anticonvulsant, antiviral, and antihypertensive effects. For example, AMD11070 (Mavorixafor), a benzimidazole analog, has been clinically evaluated as an antiretroviral drug and is currently used to treat WHIM syndrome. WimDehaen et al. designed a series of novel CXCR4 antagonists based on isoquinoline structures and investigated their anti-HIV activity (Molecules 2021, 26(20), 6297). To achieve the coupling of nitrogen-containing aromatic heterocycle fragments in the CXCR4 antagonist structure, it is often necessary to prepare 1-hydroxymethyl isoquinoline analogs and hydroxymethyl-substituted benzimidazole analogs.

[0003] Currently, complex synthetic routes are often used for hydroxymethyl-substituted isoquinolines and benzimidazole derivatives. For example, the synthetic route for hydroxymethylated isoquinolines involves: first, acetophenone derivative, 2,2-dimethoxyethylamine, and 4-nitrophenyl azide are dissolved in toluene and reacted in a multi-component reaction at 100°C to generate a dimethyl acetal-substituted triazole derivative. Then, a modified Pomeranz-Fritsch reaction is used to convert the intermediate to triazolo[5,1-a]isoquinoline under concentrated sulfuric acid. Next, the triazole group is ring-opened using water as a nucleophile via acid catalysis to obtain 1-hydroxymethylisoquinoline compounds. This route is cumbersome and uses large amounts of strong acid reagents, posing safety risks and failing to meet the requirements of industrial scale-up and green chemistry. Therefore, a simple, efficient, and environmentally friendly synthetic route is needed. In the subsequent synthetic route, treatment with thionyl chloride (SOCl2) at room temperature is required to obtain the 1-chloromethylisoquinoline derivative, as shown below:

[0004]

[0005] Therefore, in recent years, a large amount of research has been conducted on how to efficiently prepare hydroxymethylated products in one step. In 2019, Lei Aiwen's research group achieved hydroxymethylation of nitrogen-containing heteroaryl hydrocarbons under visible light irradiation using Selectfluor (Nat. Commun. 2019, 10, 1-7.). In 2021, Joyram Guin's team achieved the heteroarylation reaction of ethers, alcohols, and amides under photocatalysis without the need for additional photocatalysts and stoichiometric amounts of oxidants (Org. Lett. 2021, 23, 6886-6890.). In 2022, Zhang Pengfei's research group used methanol as a reagent to promote the hydroxymethylation of heteroaryl hydrocarbons through the synergistic effect of PhIFA and visible light under conditions without exogenous acids and transition metals (Mol. Catal. 2022, 530, 112594.). In 2024, Jose C. Gonzalez-Gomez et al. successfully achieved the hydroxymethylation reaction of nitrogen-containing aromatic hydrocarbons with methanol by combining electrochemistry and photocatalysis, including the efficient conversion of bioactive substrates (Org. Lett. 2024, 26, 7447-7451.). Summary of the Invention

[0006] The purpose of this invention is to provide a simple, high-purity, and green method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives. Specifically, it provides a green synthetic method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives by reacting isoquinoline and benzimidazole compounds with methanol under the action of a visible light source and a constant voltage power supply, using a cobalt pyridine complex as a photocatalyst. The hydroxymethylated isoquinoline or benzimidazole derivatives are then prepared by C-N coupling.

[0007] The technical solution adopted in this invention is as follows:

[0008] This invention defines a method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives, comprising the following steps:

[0009] S1: Under inert gas protection, isoquinoline or benzimidazole compounds represented by general formula (I) are dissolved in an organic solvent, methanol, cobalt polypyridine catalyst, electrolyte and proton source are added, and the mixture is mixed to form a reaction solution. A cathode and anode are inserted into the reaction solution and an electric current is applied. The reaction is carried out under visible light irradiation and constant voltage conditions. After the reaction is completed, post-processing is performed to obtain the hydroxymethylated isoquinoline or benzimidazole derivative intermediate represented by formula (II).

[0010] S2: The intermediate of formula (II) is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinolin-8-yl]amino})butyl]carbamate via C–N coupling to obtain the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives as shown in formula (III), and the reaction equation is as follows:

[0011]

[0012] Furthermore, the cobalt polypyridine catalyst described in this invention is Co(4,4′-R2bpy)3(PF6). n Or Co(phen)3(PF6) n etc., wherein R is methyl, bromine, tert-butyl, methoxy or hydrogen, and n = 2 or 3, and the amount used is 1 to 10 mol% of substrate I, preferably 4 to 6 mol%.

[0013] Furthermore, the polypyridine cobalt catalyst is preferably at least one of the following compounds:

[0014]

[0015] Furthermore, the polypyridine cobalt catalyst is preferably Co(4,4'-Me2bpy)3(PF6)2 or Co(4,4'-Br2bpy)3(PF6)2.

[0016] Furthermore, the electrolyte of the present invention is at least one of lithium perchlorate (LiClO4), tetrabutylammonium perchlorate (n-Bu4NClO4), tetrabutylammonium hexafluorophosphonate (n-Bu4NPF6), and tetrabutylammonium tetrafluoroborate (n-Bu4NBF4), and its amount is 0.5 to 10 equivalents of the molar amount of substrate I, preferably 1 to 6 equivalents of lithium perchlorate.

[0017] Furthermore, the proton source described in this invention is trifluoroacetic acid (TFA) or acetic acid, and the amount used is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents of trifluoroacetic acid.

[0018] Further, in step S1, the organic solvent is methanol, acetonitrile, dichloromethane, hexafluoroisopropanol, dichloroethane, acetone, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture of at least two of these, preferably acetonitrile or a mixture of acetonitrile and methanol in a volume ratio of 0.8-2:1. Since the cobalt polypyridine catalyst is insoluble in methanol, the reaction solvent in step S1 cannot be entirely methanol; otherwise, the reaction yield will be low.

[0019] Further, in step S1, the molar ratio of isoquinoline or benzimidazole derivative represented by formula (Ⅰ) of the present invention to methanol is 1:2 to 1:100, preferably 1:10 to 1:50.

[0020] Furthermore, the light source described in this invention is visible light with a wavelength of 360–460 nm, preferably a visible light source with a wavelength of 390–460 nm.

[0021] Furthermore, the power supply described in this invention is a constant voltage DC power supply of 0.5 to 2V or a constant current DC power supply of 1 to 3mA, preferably a constant voltage DC power supply of 1 to 1.5V, with carbon felt as the anode and platinum sheet as the cathode.

[0022] Further, the post-processing steps after the reaction in step S1 are as follows: After the reaction is completed, the reaction solution is quenched in a saturated sodium bicarbonate solution, the anode is ultrasonically washed with ethyl acetate, the combined treatment solutions are extracted with ethyl acetate, the combined organic phases are dried with anhydrous sodium sulfate, and the crude product is concentrated under reduced pressure. The crude product is purified on a silica gel column with a volume ratio of n-hexane / ethyl acetate of 5:1 to 1:1 to obtain the hydroxymethylated isoquinoline or benzimidazole derivative of the target compound (II).

[0023] Furthermore, in step S2, C–N coupling is achieved through one of the following three methods:

[0024] 1. In the presence of azodicarboxylic acid ester reagent and phosphorus reagent, the hydroxyl group of intermediate of formula (II) is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate via photo-stretching reaction;

[0025] 2. After oxidizing the hydroxyl group of the intermediate of formula (II) to an aldehyde group, it is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate via carbonyl reduction in the presence of NaBH(OAc)3 and acetic acid;

[0026] 3. After converting the hydroxyl group of the intermediate of formula (II) into a halogen through a substitution reaction, it is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate in the presence of KI and DIPEA;

[0027] The product after the coupling reaction is subjected to Boc removal under acidic conditions to obtain the target product;

[0028] Taking the isoquinoline derivative as an example, the reaction formulas for the C–N coupling of the above three methods are as follows:

[0029]

[0030] Furthermore, the C–N coupling in step S2 is preferably photoelongation reaction coupling.

[0031] Furthermore, the azodicarboxylic acid ester reagent used in the photoelongation reaction of the present invention is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), or di-tert-butyl azodicarboxylate (DBAD), and its amount is 0.5 to 6 equivalents of the molar amount of tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate, preferably 1 to 3 equivalents of diisopropyl azodicarboxylate.

[0032] Furthermore, the phosphine reagent used in the photoelongation reaction of the present invention is triphenylphosphine or tributylphosphine, and its amount is 0.5 to 6 equivalents of the molar amount of tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate, preferably 1 to 3 equivalents of triphenylphosphine.

[0033] By employing the above-described technology, compared with the prior art, the present invention has the following significant advantages:

[0034] (1) The synthesis method of hydroxymethylated isoquinoline or benzimidazole derivatives does not require the addition of chemical equivalent oxidant, and uses electric current as oxidant, which is green and clean and in line with the concept of green chemistry.

[0035] (2) There is no need to further derivatize the hydroxymethylated isoquinoline or benzimidazole derivatives into halogens or aldehydes. The hydroxyl group and the tertiary amine can be coupled directly in one step by photo-extending reaction. The steps are simple, the atom utilization rate is high, the reaction conditions are mild, and the post-processing operation is simple. Detailed Implementation

[0036] In this invention, all eight catalysts are known compounds. The CAS number of catalyst PC1 is 79151-82-9, the CAS number of catalyst PC2 is 1480716-55-9, the CAS number of catalyst PC3 is 1174892-12-6, the CAS number of catalyst PC4 is 28392-61-2, the CAS number of catalyst PC5 is 79151-77-2, the CAS number of catalyst PC6 is 630392-02-8, the CAS number of catalyst PC7 is 79151-78-3, and the CAS number of catalyst PC8 is 31876-74-1.

[0037] The tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate in this invention is a known compound with CAS number 558446-23-4.

[0038] Example 1(±)-Mavorixafor

[0039]

[0040] 1) Add benzimidazole (591 mg, 5 mmol), methanol (2 mL), Co(4,4′-Me2bpy)3(PF6)2 (270 mg, 0.3 mmol), trifluoroacetic acid (TFA, 1.15 mL, 15 mmol), lithium perchlorate (LiClO4, 531 mg, 5 mmol), and acetonitrile (50 mL) to a pre-dried 250 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W 390–400 nm LED lamps and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 50 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 1:1 to obtain hydroxymethylated benzimidazole (0.368 g, yield 50%).

[0041] 2) Hydroxymethylated benzimidazole was dissolved in dichloromethane (25 mL), and excess thionyl chloride (SOCl2) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted multiple times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography with a 1:1 volume ratio of n-hexane / ethyl acetate to give 2-chloromethylbenzimidazole (0.380 g, yield 92%).

[0042] 3) 2-Chloromethylbenzimidazole (0.380 g, 2.3 mmol, 1 equivalent) and di-tert-butyl dicarbonate (0.645 g, 3 mmol, 1.3 equivalent) were suspended in DMF (50 mL), and N,N-diisopropylethylamine (90 mg, 0.7 mmol, 0.3 equivalent) was added. The mixture was stirred at 40 °C for 10 hours. The reaction solution was quenched with water (50 mL), extracted, dried and concentrated to obtain the product 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole (0.559 g, yield 91%).

[0043] 4) Tert-butyl (4-((5,6,7,8-tetrahydroquinoline-8-yl)amino)butyl)carbamate (0.568 g, 1.78 mmol, 1 equivalent) was dissolved in acetonitrile (36 mL), and 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole (0.537 g, 2 mmol, 1.12 equivalent), DIPEA (0.461 mL, 2.67 mmol, 1.5 equivalent) and potassium iodide (18 mg, 0.18 mmol, 0.1 equivalent) were added. The mixture was stirred at 60 °C for 18 hours. After quenching the reaction solution, it was extracted, dried and concentrated, and purified by column chromatography with dichloromethane / methanol eluent at a volume ratio of 10:1 to obtain a yellow liquid (0.665 g, yield 68%).

[0044] 5) The target product precursor (0.665 g, 1.21 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added under ice bath conditions. After stirring at 0 °C for 2 hours, the mixture was concentrated. The crude product was dissolved in 4 M sodium hydroxide solution, extracted with chloroform, dried, and concentrated to obtain the brown liquid final product (±)-Mavorixafor (0.402 g, yield 95%). Using benzimidazole as the starting material, the overall yield of the target compound was calculated to be 27%. The specific synthetic route is as follows:

[0045]

[0046] The final product NMR data are as follows:

[0047] 1 H NMR(600MHz, DMSO-d6+D2O)δ8.78(d,J=4.1Hz,1H),8.24(d,J=7.9Hz,1H),7.85–7.7 3(m,3H),7.51(dd,J=6.2,3.2Hz,2H),4.53(dd,J=11.0,5.7Hz,1H),4.44(s,2H),2.9 5–2.89(m,2H),2.79–2.72(m,1H),2.72–2.66(m,2H),2.57–2.52(m,1H),2.32–2.24 (m,1H),2.09–2.02(m,1H),1.95–1.88(m,1H),1.80–1.72(m,1H),1.66–1.43(m,4H).

[0048] 13 C NMR (151MHz, DMSO-d6+D2O) δ152.5,152.0,145.0,141.1,138.3,132.2,125.2,124.9,114.2,59.4,50.7,47.2,38.3,27.3,24.6,24.3,20.9,20.2.

[0049] Example 2(±)-Mavorixafor

[0050]

[0051] 1) Add benzimidazole (473 mg, 4 mmol), methanol (2 mL), Co(4,4′-Me2bpy)3(PF6)2 (216 mg, 0.24 mmol), trifluoroacetic acid (TFA, 0.92 mL, 12 mmol), lithium perchlorate (LiClO4, 425 mg, 4 mmol), and acetonitrile (50 mL) to a pre-dried 250 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W 390–400 nm LED lamps and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 50 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 1:1 to obtain hydroxymethylated benzimidazole (0.295 g, yield 50%).

[0052] 2) In a 40 mL solution of tetrahydrofuran containing tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate (0.568 g, 1.78 mmol, 1 equivalent), triphenylphosphine (0.700 g, 2.67 mmol, 1.5 equivalent), and hydroxymethylated benzimidazole (0.295 g, 1.99 mmol, 1.12 equivalent), diisopropyl azodicarbonate (0.540 g, 2.67 mmol, 1.5 equivalent) was added dropwise. The addition was completed within 10 minutes, and the mixture was stirred at 0 °C for 6 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the resulting yellow liquid was purified by rapid column chromatography with dichloromethane / methanol at a volume ratio of 10:1 to give a yellow oily product (0.472 g, yield 59%).

[0053] 3) The product from the previous step (0.472 g, 1.05 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added under ice bath (0 °C). The mixture was stirred at 0 °C for 2 hours. The reaction solution was concentrated under vacuum, and the crude product was dissolved in 4 M sodium hydroxide solution, extracted with chloroform, dried, and concentrated to obtain the brown liquid final product (±)-Mavorixafor (0.345 g, yield 95%). Using benzimidazole as the starting material, the overall yield of the target compound was calculated to be 28%. The specific synthetic route is as follows:

[0054]

[0055] Example 3 (±) - Mavorixafor

[0056]

[0057] 1) Add benzimidazole (473 mg, 4 mmol), methanol (2 mL), Co(4,4′-Me2bpy)3(PF6)2 (216 mg, 0.24 mmol), trifluoroacetic acid (TFA, 0.92 mL, 12 mmol), lithium perchlorate (LiClO4, 425 mg, 4 mmol), and acetonitrile (50 mL) to a pre-dried 250 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W 390–400 nm LED lamps and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 50 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 1:1 to obtain hydroxymethylated benzimidazole (0.295 g, yield 50%).

[0058] 2) Under an oxygen atmosphere, hydroxymethylated benzimidazole (0.295 g, 1.99 mmol), ferric nitrate nonahydrate (0.040 g, 0.1 mmol, 0.05 equivalent), TEMPO (0.016 g, 0.1 mmol, 0.05 equivalent), sodium chloride (0.012 g, 0.2 mmol, 0.1 equivalent), and 1,2-dichloroethane (5 mL) were added to a 25 mL round-bottom flask, and the mixture was stirred at room temperature for 24 hours. The crude product was filtered through a short silica gel column, the filtrate was concentrated, and then purified by silica gel column chromatography in a 1:1 (v / v) hexane / ethyl acetate solvent to obtain aldehyde-modified benzimidazole (0.273 g, yield 94%).

[0059] 3) Aldehyde-modified benzimidazole (0.273 g, 1.87 mmol, 1 equivalent) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate (0.597 g, 1.87 mmol, 1 equivalent), acetic acid (0.107 mL, 1.87 mmol, 1 equivalent), and sodium triacetoxyborohydride (1.19 g, 5.61 mmol, 3 equivalents). The mixture was stirred at room temperature for 3 hours until the reaction was complete. The solvent was removed under reduced pressure, and the resulting yellow liquid was purified by rapid column chromatography in a 10:1 (v / v) dichloromethane / methanol solvent to give a yellow oily product (0.462 g, 55% yield).

[0060] 4) The product from the previous step (0.462 g, 1.03 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added under ice bath (0 °C). The mixture was stirred at 0 °C for 2 hours. The reaction solution was concentrated under vacuum, and the crude product was dissolved in 4 M sodium hydroxide solution, extracted with chloroform, dried, and concentrated to give the brown liquid final product (±)-Mavorixafor (0.341 g, yield 95%). Using benzimidazole as the starting material, the overall yield of the target compound was calculated to be 25%. The specific synthetic route is as follows:

[0061]

[0062] Example 4: CXCR4 antagonist isoquinoline derivative

[0063]

[0064] 1) Isoquinoline (413 mg, 3.2 mmol), Co(4,4′-Br2bpy)3(PF6)2 (247 mg, 0.192 mmol), trifluoroacetic acid (TFA, 738 μL, 9.6 mmol), lithium perchlorate (LiClO4, 680 mg, 6.4 mmol), and acetonitrile / methanol (15 / 15 mL) were added to a pre-dried 100 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, argon gas was purged for 5 minutes. The reaction system was then irradiated with two 25 W 390–400 nm LED lamps at room temperature, and a constant voltage of 1 V was applied for the reaction to continue for 30 hours. After the reaction was completed, the reaction solution was quenched in 30 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 5:1 to obtain hydroxymethylated isoquinoline (0.340 g, yield 67%).

[0065] 2) A solution containing tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate (0.568 g, 1.78 mmol, 1 equivalent), triphenylphosphine (0.700 g, 2.67 mmol, 1.5 equivalent), and hydroxymethylated isoquinoline (0.340 g, 2.14 mmol, 1.2 equivalent) was dissolved in tetrahydrofuran (40 mL) and stirred in an ice bath. Diisopropyl azodicarbonate (0.540 g, 2.67 mmol, 1.5 equivalent) was added dropwise. The addition was completed within 10 minutes, and the mixture was stirred at 0 °C for 6 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the resulting yellow liquid was purified by rapid column chromatography in a 10:1 (v / v) dichloromethane / methanol solvent to give a yellow oily product (0.681 g, yield 83%).

[0066] 3) The product from the previous step (0.681 g, 1.48 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added under ice bath (0 °C). The mixture was stirred at 0 °C for 2 hours. The reaction solution was concentrated under vacuum, and the crude product was dissolved in 4 M sodium hydroxide solution and extracted with chloroform (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the CXCR4 antagonist isoquinoline derivative (0.432 g, yield 81%). Using isoquinoline as the starting material, the overall yield of the target compound was calculated to be 45%. The specific synthetic route is shown in the figure.

[0067]

[0068] The final product NMR data are as follows:

[0069] 1 H NMR (400MHz, DMSO-d6) δ8.53–8.32(m,3H),7.86(d,J=8.2Hz,1H),7.73–7.61(m,2H),7 .58(t,J=7.8Hz,1H),7.41(d,J=7.6Hz,1H),7.13–7.01(m,1H),4.36(d,J=14.5Hz,1H) ,4.22–4.07(m,2H),2.79–2.67(m,1H),2.65–2.56(m,1H),2.54–2.40(m,4H),2.11–2. 01(m,1H),1.95–1.85(m,2H),1.75–1.68(m,1H),1.56–1.46(m,1H),1.36–1.21(m,3H).

[0070] 13C NMR(101MHz,DMSO-d6)δ159.2,157.5,147.2,141.7,137.3,136.1,134.6,130.6,127.5, 127.4,127.1,125.7,122.0,120.3,61.3,55.1,51.5,40.2,28.9,28.4,25.2,23.6,21.5.

[0071] Example 5: CXCR4 antagonist isoquinoline derivative

[0072]

[0073] 1) Isoquinoline (413 mg, 3.2 mmol), Co(4,4′-Br2bpy)3(PF6)2 (247 mg, 0.192 mmol), trifluoroacetic acid (TFA, 738 μL, 9.6 mmol), lithium perchlorate (LiClO4, 680 mg, 6.4 mmol), and acetonitrile / methanol (15 / 15 mL) were added to a pre-dried 100 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, argon gas was purged for 5 minutes. The reaction system was then irradiated with two 25 W 390–400 nm LED lamps at room temperature, and a constant voltage of 1 V was applied for the reaction to continue for 30 hours. After the reaction was completed, the reaction solution was quenched in 30 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 5:1 to obtain hydroxymethylated isoquinoline (0.340 g, yield 67%).

[0074] 2) Under an oxygen atmosphere, hydroxymethylated isoquinoline (0.340 g, 2.13 mmol), ferric nitrate nonahydrate (0.040 g, 0.1 mmol, 0.05 equivalent), TEMPO (0.016 g, 0.1 mmol, 0.05 equivalent), sodium chloride (0.012 g, 0.2 mmol, 0.1 equivalent), and 1,2-dichloroethane (5 mL) were added to a 25 mL round-bottom flask, and the mixture was stirred at room temperature for 24 hours. The crude product was filtered through a short silica gel column, the filtrate was concentrated, and then purified by silica gel column chromatography using a 5:1 (v / v) hexane / ethyl acetate solvent to obtain aldehyde-modified isoquinoline (0.321 g, yield 96%).

[0075] 3) Aldehyde-modified isoquinoline (0.321 g, 2.04 mmol, 1 equivalent) was dissolved in 1,2-dichloroethane (10 mL), and then tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate (0.651 g, 2.04 mmol, 1 equivalent), acetic acid (0.117 mL, 2.04 mmol, 1 equivalent), and sodium triacetoxyborohydride (1.30 g, 6.12 mmol, 3 equivalent) were added sequentially. The mixture was stirred at room temperature for 3 hours until the reaction was complete. The solvent was removed by vacuum distillation, and the resulting yellow liquid was purified by rapid column chromatography in a 10:1 (v / v) dichloromethane / methanol solvent to give a yellow oily product (0.629 g, 67% yield).

[0076] 4) The product from the previous step (0.629 g, 1.37 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added under ice bath (0 °C). The mixture was stirred at 0 °C for 2 hours. The reaction solution was concentrated under vacuum, and the crude product was dissolved in 4M sodium hydroxide solution, extracted with chloroform, dried, and concentrated to obtain the CXCR4 antagonist isoquinoline derivative (0.469 g, yield 95%). Using isoquinoline as the starting material, the overall yield of the target compound was calculated to be 41%. The specific synthetic route is as follows:

[0077]

[0078] Experimental data for other reaction conditions in Example 6

[0079] Experiment 1: The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, except that the only difference was that the type and amount of catalyst were changed. The experimental results are listed in Table 1 below.

[0080] The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, with the only differences being the following two points: ① the type and stoichiometry of the catalyst were changed; ② the substrate was replaced by an equimolar amount of isoquinoline instead of benzimidazole. The experimental results are listed in Table 1 below.

[0081] In Table 1, the equivalent of the catalyst refers to the percentage of the molar equivalent of the amount of catalyst used relative to the "isoquinoline or benzimidazole substrate".

[0082] Table 1

[0083]

[0084] Experiment 2: The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, except that the type and ratio of the reaction solvent were changed. The volume of the reaction solvent was kept constant at 50 mL. The experimental results are listed in Table 2 below.

[0085] The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, with the only differences being the following two points: ① the type and ratio of the reaction solvent were changed; ② the reaction substrate was replaced by an equimolar amount of isoquinoline instead of benzimidazole. The experimental results are listed in Table 2 below.

[0086] Table 2. Screening of solvent types and ratios

[0087]

[0088] Experiment 3: The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, except that the only difference was that the wavelength of the light source was changed. The experimental results are listed in Table 3 below.

[0089] The experimental procedure for the hydroxymethylation reaction was the same as step 1) of Example 1, with the only differences being the following two points: ① the wavelength of the light source was changed; ② the reaction substrate was replaced by an equimolar amount of isoquinoline instead of benzimidazole. The experimental results are listed in Table 3 below.

[0090] Table 3 Selection of light source wavelengths

[0091]

[0092] Experiment 4: The experimental steps of the photo-extending reaction were repeated from step 2) of Example 2, with the only differences being the following two points: ① the type of azodicarboxylic acid ester reagent was changed, while its molar amount remained unchanged; ② the reactants of the C–N coupling reaction were replaced with hydroxymethylated isoquinoline or hydroxymethylated benzimidazole, while their amount remained unchanged at 1.99 mmol.

[0093] The yields of C–N coupling products under different reaction conditions are shown in Table 4.

[0094] Table 4 Screening of Azodicarboxylic Acid Ester Reagents

[0095]

[0096] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing a CXCR4 antagonist drug, Mavorixafor, and its isoquinoline derivatives, characterized in that... Includes the following steps: S1: Under inert gas protection, the isoquinoline or benzimidazole compound represented by general formula (I) is dissolved in an organic solvent, methanol, cobalt polypyridine catalyst, electrolyte and proton source are added, and the mixture is mixed to form a reaction solution. The cathode and anode are inserted into the reaction solution and an electric current is applied. The reaction is carried out under visible light irradiation and constant voltage conditions. After the reaction is completed, the hydroxymethylated isoquinoline or benzimidazole derivative intermediate represented by formula (II) is obtained. S2: The intermediate of formula (II) is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinolin-8-yl]amino})butyl]carbamate via C–N coupling to obtain the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives as shown in formula (III), and the reaction equation is as follows:

2. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... In step S1, the polypyridine cobalt catalyst is Co(4,4′-R2bpy)3(PF6). n Or Co(phen)3(PF6) n R is methyl, bromine, tert-butyl, methoxy or hydrogen, and n = 2 or 3, and its amount is 1 to 10 mol% of the molar amount of substrate I, preferably 4 to 6 mol%. The polypyridine cobalt catalyst is preferably at least one of the following compounds:

3. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... The electrolyte is at least one of lithium perchlorate (LiClO4), tetrabutylammonium perchlorate (n-Bu4NClO4), tetrabutylammonium hexafluorophosphonate (n-Bu4NPF6), or tetrabutylammonium tetrafluoroborate (n-Bu4NBF4), and its amount is 0.5 to 10 equivalents of the molar amount of substrate I, preferably 1 to 6 equivalents of lithium perchlorate.

4. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivative according to claim 1, characterized in that... The proton source is trifluoroacetic acid (TFA) or acetic acid, and its amount is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents of trifluoroacetic acid.

5. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... In step S1, the organic solvent is methanol, acetonitrile, dichloromethane, hexafluoroisopropanol, dichloroethane, acetone, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture of at least two of these, preferably acetonitrile or a mixture of acetonitrile and methanol in a volume ratio of 0.8-2:

1.

6. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivative according to claim 1, characterized in that... In step S1, the molar ratio of isoquinoline or benzimidazole derivative shown in formula (Ⅰ) to methanol is 1:2 to 1:100, preferably 1:10 to 1:

50.

7. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivative according to claim 1, characterized in that... In step S1, the reaction conditions are: the light source is visible light with a wavelength of 360-460 nm, the power supply is a constant voltage DC power supply of 0.5-2V, preferably a visible light source of 390-460 nm and a constant voltage DC power supply of 1-1.5V, the anode is carbon felt, and the cathode is platinum sheet.

8. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... The post-processing steps after the reaction in step S1 are as follows: After the reaction is completed, the reaction solution is quenched in a saturated sodium bicarbonate solution, the anode is ultrasonically washed with ethyl acetate, the combined treatment solutions are extracted with ethyl acetate, the combined organic phases are dried with anhydrous sodium sulfate, and the crude product is concentrated under reduced pressure. The crude product is purified on a silica gel column with a volume ratio of n-hexane / ethyl acetate of 5:1 to 1:1 to obtain the hydroxymethylated isoquinoline or benzimidazole derivative of the target compound (II).

9. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... In step S2, C–N coupling occurs through one of the following three methods:

1. In the presence of azodicarboxylic acid ester reagent and phosphorus reagent, the hydroxyl group of intermediate of formula (II) is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate via photo-stretching reaction; 2. After oxidizing the hydroxyl group of the intermediate of formula (II) to an aldehyde group, it is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate via carbonyl reduction in the presence of NaBH(OAc)3 and acetic acid; 3. After converting the hydroxyl group of the intermediate of formula (II) into a halogen through a substitution reaction, it is coupled with tert-butyl[4-({[5,6,7,8-tetrahydroquinoline-8-yl]amino})butyl]carbamate in the presence of KI and DIPEA; The C–N coupling in step S2 is preferably photoelastography coupling; The product after the coupling reaction is subjected to Boc removal under acidic conditions to obtain the target product.

10. The method for preparing the CXCR4 antagonist drug Mavorixafor and its isoquinoline derivatives according to claim 1, characterized in that... The azodicarboxylic acid ester reagent used in the photoelongation reaction is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), or di-tert-butyl azodicarboxylate (DBAD), and its amount is 0.5 to 6 equivalents. The phosphine reagent used is triphenylphosphine or tributylphosphine, and its amount is 0.5 to 6 equivalents, preferably 1 to 3 equivalents of diisopropyl azodicarboxylate and 1 to 3 equivalents of triphenylphosphine.

Images