Preparation method of novel chiral tetrahydroisoquinoline imidazoline compound

Abstract

The invention discloses a preparation method of a novel chiral tetrahydroisoquinoline imidazoline compound, and relates to the technical field of medical chemical synthesis, and the technical key points are as follows: through a transition metal salt / chiral ligand catalytic system, an asymmetric [3 + 2] cycloaddition reaction with isocyano acetate is carried out to obtain the chiral tetrahydroisoquinoline imidazoline compound. The simple and convenient synthesis of the chiral tetrahydroisoquinoline imidazoline compound is further realized; the method is simple in step, simple and convenient to operate, mild in condition, rapid in reaction, small in pollution and high in efficiency, provides important methodological support for later modification of functional molecules in the fields of medicines, materials and the like, and has huge industrial application value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing a novel chiral tetrahydroisoquinolinimidazole compound. Background Art

[0002] Tetrahydroisoquinoline and imidazoline are common structural units in natural products and drug molecules. Structural molecules with such skeletons often have excellent biological and pharmaceutical activities and have important research value in the history of drug development and human disease treatment. Therefore, exploring and developing effective strategies for their efficient construction has always been one of the hot topics in the field of organic synthetic chemistry research.

[0003] Natural products with an isoquinoline core structure are numerous and widely found in nature, including neferine, safracin B, solifenacin, tetrabenazine, praziquantel, and elacridar. In addition to their excellent biological activity, tetrahydroisoquinoline and imidazoline derivatives serve as important organic synthesis intermediates for the synthesis of complex natural products and bioactive molecules. Furthermore, drug molecules containing a benzodiazepine ring structure often possess high structural rigidity, which can reduce conformational freedom and facilitate precise alignment with the active site of the target protein, thereby improving binding affinity, enhancing the binding specificity of the drug molecule to the target, and reducing off-target effects. For example, the benzodiazepine ring structure of diazepam enhances its binding to GABA receptors. These molecules are generally more stable than linear or monocyclic molecules, reducing their metabolism by hepatic cytochrome P450 enzymes (CYP450) and prolonging their half-life. They also offer moderate lipid solubility and a high number of hydrogen bond donors / acceptors, supporting intestinal absorption and making them suitable for oral administration. However, there have been no systematic reports of chiral tetrahydroisoquinolinimidazole compounds.

[0004] To this end, the present invention aims to provide a novel method for preparing a chiral tetrahydroisoquinolinimidazoline compound to solve the above problems. Summary of the Invention

[0005] The present invention aims to solve the above-mentioned problems and provides a novel method for preparing a chiral tetrahydroisoquinolin-imidazoline compound. The method further realizes the simple synthesis of the chiral tetrahydroisoquinolin-imidazoline compound through an asymmetric [3+2] cycloaddition reaction with isocyanate using a transition metal salt / chiral ligand catalytic system. The method has simple steps, simple operation, mild conditions, rapid reaction, low pollution, and high efficiency. The method provides important methodological support for the later modification of functional molecules in the fields of medicine, materials, etc. and has great industrial application value.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

[0007] The present invention provides a method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound, which comprises:

[0008] S1. introducing an inert gas into a solvent, adding a chiral phosphine ligand and a transition metal salt into the solvent, and obtaining a catalyst through a complex reaction;

[0009] S2. Add 3,4-dihydroisoquinoline and isocyanate to the catalyst to undergo an asymmetric [3+2] cycloaddition reaction to obtain a chiral tetrahydroisoquinolinimidazole compound.

[0010] The chiral phosphine ligands include but are not limited to the following ligands L1-L6:

[0011]

[0012] In the above structural formula, R represents an alkyl group such as methyl, ethyl, isopropyl, tert-butyl, and a halogen, as well as any other heterocyclic ring or aromatic ring with a substituent; Ar represents a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 3,5-dimethylphenyl group, a 3,5-dimethyl-4-methoxyphenyl group, a 3,4,5-trimethylphenyl group, a 3,5-di-tert-butylphenyl group, a 3,5-di-tert-butyl-4-methoxy group, a 3,5-di-tert-butyl-4-methyl group, and any other aromatic ring.

[0013] The solvent is one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, toluene, 1,2-dichloroethane, n-hexane, and 1,4-dioxane, and isopropyl acetate is more preferred.

[0014] The reaction temperature of the asymmetric [3+2] cycloaddition reaction is -40 to 120° C., and the reaction time is 1 to 120 hours.

[0015] The molar ratio of the transition metal salt to the chiral phosphine ligand is 1.0:1.0-1.2, the reaction temperature of the complex reaction is room temperature, and the complex reaction time is 1-3 hours.

[0016] Transition metal salts include: Rh, Ru, Ir, Au, Ag, Cu, Fe, Co, Ni, Ti, V, Re, and Mn. Suitable transition metal complexes include: (Rh(NBD)2) + BF4 -; [Rh(NBD)Cl]2; [Rh(COD)Cl]2; [Rh(COD)2]X; Rh(acac)(CO)2; Rh(ethylene)2(acac); (Rh(ethylene)2Cl)2; RhCl(PPh3)3; Rh(CO)2Cl2; ne); Ru(arene)X2(diphosphine); Ru(aryl)X2; Ru(RCOO)2(diphosphine); Ru(methallyl)2(diphosphine); Ru(aryl)X2(PPh3)3; n ; Ru(aryl)X2(diphosphine); RuCl2(COD); (Ru(COD)2)X; RuX2(diphosphine); RuCl2(=CHR)(PR'3)2; )2)X; (Ir(COD)Cl)2; Ir(COD))X; AuX; AgX; CuX; Cu2X; In the above transition metal complexes, R and R' can be alkyl, alkoxy or substituted alkyl, aryl is aryl, Ar can be 3,5-ditrifluoromethylbenzene or fluorobenzene. X is a counter anion, such as BF4 - , ClO4 - , SbF6 - , PF6 - , CF3SO3 - ,RCOO - ,B(C6H3(CF3)2)4 - , Cl - , Br - , I - ,OAc - etc. L is a solvent, such as methanol, tetrahydrofuran, n-hexane, etc. Further, the transition metal salt is Ag2O, AgOAc, and more preferably AgOAc.

[0017] The reaction temperature of the asymmetric cycloaddition reaction is -40 to 120° C., more preferably -20 to 50° C., and even more preferably -20 to 0° C. The reaction time is 1 to 120 hours, preferably 12 to 60 hours, and even more preferably 24 to 48 hours.

[0018] The catalyst obtained by the complexation is not separated and is directly used to catalyze the asymmetric cycloaddition reaction.

[0019] Compared with the existing technology, this solution has the following beneficial effects:

[0020] The present invention further realizes the simple synthesis of chiral tetrahydroisoquinolinoimidazolinyl compounds through an asymmetric [3+2] cycloaddition reaction with isocyanate using a transition metal salt / chiral ligand catalytic system. The technical solution is simple to operate, has a rapid reaction, is low in cost, and has extremely high conversion rate and selectivity, as well as atom economy and environmental friendliness, and has extremely high industrial value. The catalyst system using a transition metal salt / chiral phosphine ligand has high stability and reactivity, and can improve or overcome the occurrence of catalyst deactivation caused by the coordination of the product to the catalyst metal center. Compared with other current technologies, the process is more advanced, the synthesis route is short, the generation of intermediate products and waste materials is significantly reduced, the process is efficient and green, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of the synthesis route of chiral tetrahydroisoquinolinimidazole compounds in an embodiment of the present invention;

[0022] Figure 2 is the molecular structural formula of dimethyl (1S,5S,10bS)-9-fluoro-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in an embodiment of the present invention;

[0023] Figure 3 In the embodiment of the present invention 1 H NMR (400 MHz, Methanol-d4) spectrum;

[0024] Figure 4 In the embodiment of the present invention 13 C NMR (101 MHz, Methanol-d4) spectrum;

[0025] Figure 5 In the embodiment of the present invention 19 F NMR (376 MHz, Methanol-d4) spectrum;

[0026] Figure 6 Schematic diagram of HPLC in an embodiment of the present invention;

[0027] Figure 7 Schematic diagram of the synthesis route of dimethyl (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in an embodiment of the present invention;

[0028] Figure 8 is the molecular structural formula of dimethyl (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in the embodiment of the present invention;

[0029] Figure 9 is the H NMR (400 MHz, Methanol-d4) spectrum in the examples of the present invention;

[0030] Figure 10 In the embodiment of the present invention 13 C NMR (101 MHz, Methanol-d4) spectrum;

[0031] Figure 11 Schematic diagram of HPLC in an embodiment of the present invention;

[0032] Figure 12 This is an X-ray diffraction single crystal pattern of dimethyl (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in an embodiment of the present invention. DETAILED DESCRIPTION

[0033] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention will be further described in detail below in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0034] It should be noted that, in the absence of conflict, the embodiments and features of the embodiments of the present invention can be combined with each other. The present invention will be described in detail below with reference to the embodiments.

[0035] Example 1: Preparation of metal catalyst complex:

[0036] Take AgOAc (0.01 mmol, 1.0 equiv) and DTB-L1 (0.011 mmol, 1.1 equiv), add 0.5 mL of ultra-dry isopropyl acetate, and stir at room temperature for 1 hour.

[0037] Take 0.1mmol substrate as an example:

[0038] Methyl 7-fluoro-1-methyl-3,4-dihydroisoquinoline-3-carboxylate (0.1 mmol) was weighed and added to the above catalyst solution. The reaction apparatus was placed in a low-temperature bath at -20°C. After 15 minutes, isopropyl isocyanate (0.11 mmol) was added dropwise, and 0.5 mL of ultra-dry isopropyl acetate was added. The mixture was stirred at -20°C for 24 hours.

[0039] After the reaction, conventional purification methods were used to obtain dimethyl (1S,5S,10bS)-9-fluoro-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in an 80% yield. High-performance liquid chromatography confirmed an ee value of 99%, and H-NMR spectroscopy confirmed a dr value >20:1.

[0040] The H NMR spectrum, C NMR spectrum, high-resolution mass spectrum and liquid chromatography data of the product (1S,5S,10bS)-9-fluoro-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylic acid dimethyl ester are as follows: Figure 2 shown.

[0041] 80% yield, 99% ee, >20:1dr. 1 H NMR(400MHz, Methanol-d4)δ7.15(dd,J=8.5,5.8Hz,1H),7.02(dd,J=10.1,2.7Hz,1H),6.99–6.91(m,1H),4.95–4 .89(m,2H),4.62(s,1H),3.64(s,3H),3.28–3.22(m,1H),3.21(s,3H),3.00(dd,J=16.0,6.3Hz,1H),1.70(s,3H); 13 C NMR (100MHz, Methanol-d4) δ172.44, 171.37, 162.88 (d, J = 243.5Hz), 138.93 (d, J = 7.1Hz), 131.77 (d, J = 7.8 Hz), 129.46, 115.51 (d, J = 21.3Hz), 114.70 (d, J = 23.1Hz), 81.77, 65.80, 54.67, 52.84, 51.99, 31.96, 30.72; 19 F NMR(376MHz,Methanol-d4)δ-117.17.HRMS(ESI):calculated for C 16 H 18FN2O4 + (M+H + ):321.1245;found:321.1239.

[0042] HPLC:The enantiomeric excess was determined by HPLC on Chiral AS-3column,254nm,25℃,nhexane:iPrOH=75:25; flow 1.0mL / min; t R (major)=7.61min,t R (minor)=14.24min.

[0043] Example 2:

[0044] The catalyst used is the same as in Example 1, taking 0.1 mmol of substrate as an example:

[0045] Methyl 7-hydroxy-1-methyl-3,4-dihydroisoquinoline-3-carboxylate (0.1 mmol) was weighed and added to the above catalyst solution. The reaction apparatus was placed in a low-temperature bath at -20°C. After 15 minutes, methyl isocyanate (0.11 mmol) was added dropwise, and 0.5 mL of ultra-dry isopropyl acetate was added. The mixture was stirred at -20°C for 24 hours.

[0046] After the reaction, conventional purification methods were used to obtain dimethyl (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylate in an 87% yield. High-performance liquid chromatography confirmed an ee value of 81%, and H-NMR spectroscopy confirmed a dr value >20:1.

[0047] The H NMR spectrum, C NMR spectrum, high-resolution mass spectrum and liquid chromatography data of the product (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylic acid dimethyl ester are as follows: Figure 8 shown.

[0048] 87% yield, 81% ee, >20:1dr. 1 H NMR (400MHz, Methanol-d4) δ6.94–6.86(m,1H),6.65–6.60(m,2H),4.88–4.81(m,1H),4.55(s ,1H),3.64(s,3H),3.22(s,3H),3.19–3.12(m,1H),2.95(dd,J=15.4,6.4Hz,1H),1.68(s,3H).13 C NMR(101MHz,Methanol-d4)δ172.76,171.65,157.36,137.69,130.94,123.89,115.8 6,114.45,81.90,65.85,55.02,52.77,51.95,31.89,31.04.HRMS(ESI):calculated for C 16 H 19 N2O5 + (M+H + ):319.1288;found:319.1292.

[0049] HPLC:The enantiomeric excess was determined by HPLC on ChiralAS-3column,254nm,25℃,nhexane:iPrOH=75:25; flow 1.0mL / min; t R (major)=17.57min,t R (minor)=8.85min.

[0050] The X-ray diffraction single crystal of the product (1S,5S,10bS)-9-hydroxy-10b-methyl-1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline-1,5-dicarboxylic acid dimethyl ester is as follows: Figure 12 shown.

[0051] The above specific embodiments are merely explanations of the present invention and are not limitations of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the embodiments as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by patent law.

Claims

1. A method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound, characterized in that: The preparation method is: S1. introducing an inert gas into a solvent, adding a chiral phosphine ligand and a transition metal salt into the solvent, and obtaining a catalyst through a complex reaction; S2. Add 3,4-dihydroisoquinoline and isocyanate to the catalyst to undergo an asymmetric [3+2] cycloaddition reaction to obtain a chiral tetrahydroisoquinolinimidazole compound.

2. The method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound according to claim 1, wherein: The chiral phosphine ligands include the following ligands L1-L6:

3. The method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound according to claim 1, wherein: The solvent is one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, toluene, 1,2-dichloroethane, n-hexane, and 1,4-dioxane.

4. The method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound according to claim 1, wherein: The reaction temperature of the asymmetric [3+2] cycloaddition reaction is -40 to 120° C., and the reaction time is 1 to 120 hours.

5. The method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound according to claim 1, wherein: The molar ratio of the transition metal salt to the chiral phosphine ligand is 1.0:1.0-1.2, the reaction temperature of the complex reaction is room temperature, and the complex reaction time is 1-3 hours.

6. The method for preparing a novel chiral tetrahydroisoquinolin-imidazoline compound according to claim 1, wherein: The transition metals include: Rh, Ru, Ir, Au, Ag, Cu, Fe, Co, Ni, Ti, V, Re and Mn.

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