Carbamate group substituted chiral bicyclic imidazole catalyst and synthesis method thereof

Abstract

The invention relates to the technical field of chiral organic small molecule catalysts, in particular to a carbamate group substituted chiral bicyclic imidazole catalyst and a synthesis method thereof. The structure of the chiral bicyclic imidazole catalyst is shown as a chemical formula (I), and the chiral bicyclic imidazole catalyst can be synthesized by one step through esterification reaction of isocyanate or an acyl chloride compound (II) and a chiral alcohol compound (III). The chiral bicyclic imidazole catalyst disclosed by the invention can efficiently catalyze reactions such as asymmetric phosphorylation and the like to construct a chiral phosphine oxide compound serving as an important module, is successfully applied to efficient synthesis of a precursor substance of a Utrophin regulator (-)-SMT022332 for treating Duchenne muscular dystrophy, and shows excellent catalytic efficiency and practical value. The chiral bicyclic imidazole catalyst provided by the invention is simple and convenient to synthesize and high in catalytic efficiency, and has a wide application prospect in synthesis of chiral phosphine oxide compounds.

Description

Technical Field

[0001] This invention relates to the field of chiral organic small molecule catalyst technology, specifically to chiral bicyclic imidazole catalysts substituted with carbamate groups and their synthesis methods. Background Technology

[0002] Chiral organic small molecule asymmetric catalysis, along with metal catalysis and enzyme catalysis, constitutes the three pillars of modern asymmetric synthesis. Among them, chiral tertiary amines, as Lewis base organic catalysts, with core skeletons including quinine rings, dimethylaminopyridine (DMAP), N-methylimidazole (NMI), and amidine, have become important tools for driving various chemical transformations. Despite their diversity, these traditional chiral tertiary amine catalysts still have significant limitations in structure and performance, severely restricting their large-scale industrial application.

[0003] Existing chiral tertiary amine catalysts face bottlenecks in both structure and catalytic activity. Structurally, their synthesis is generally cumbersome and costly. For example, the preparation of chiral DMAPs is difficult to scale up; chiral NMIs, due to the distance of the chiral center from the active site, often require the introduction of additional functional groups (such as hydrogen bonding units) to assist in chiral control, which further increases the complexity of the structure and synthesis. In terms of performance, it is difficult to balance the activity and selectivity of the catalyst. In the DMAP framework, ortho-substitution stifles activity due to steric hindrance, while meta-substitution leads to poor chiral control due to excessive distance. Although NMIs retain some activity at ortho-substitution due to larger bond angles, the space for adjusting the bond angles of the traditional catalyst framework is limited, failing to fundamentally resolve this contradiction.

[0004] To overcome the aforementioned bottlenecks, Zhang Wanbin's research group proposed a "bond angle regulation" strategy, which involves designing novel chiral bicyclic imidazole frameworks to balance catalytic activity and enantioselectivity. J. Am. Chem. Soc. 2010, 132 , 15939-15941; Angew. Chem. Int. Ed. 2020, 59 , 20814-20819; Angew. Chem. Int. Ed. 2021, 60 , 1641-1645; CCS Chem 2023, 5 , 361-371; ACS Catal 2023, 13, 16300-16306; CN118027038A; CN113754693A; CN113754694A; CN104557876A; CN104557827A; CN103288876A; CN102863447A; CN102329281A; CN101676288). Among these, the DPI skeleton boasts a bond angle as high as 137°, effectively mitigating steric hindrance from adjacent chiral groups and achieving precise chiral control while maintaining high activity. Based on this skeleton, multiple catalyst series have been developed, including alkoxy-DPI, acyloxy-DPI, and alkyl-DPI, exhibiting excellent performance in various asymmetric reactions, such as Steglich rearrangement and dynamic kinetic resolution. In particular, it has achieved a key breakthrough in the asymmetric phosphorylation synthesis of the antiviral drug remdesivir, demonstrating significant application value. Angew. Chem. Int. Ed. 2020, 59 , 20814-20819;CN113754692A).

[0005] Based on this, the present invention provides a series of novel chiral bicyclic imidazole catalysts substituted with carbamate groups. This design introduces groups with both hydrogen bond donor and stereocontrol functions at key positions in formula (I), thereby synergistically improving catalytic activity and enantioselectivity, and enriching the structural system of this type of catalyst. Summary of the Invention

[0006] The purpose of this invention is to provide a chiral bicyclic imidazole catalyst substituted with a carbamate group and its synthesis method, so as to further synergistically enhance the catalytic activity and enantioselectivity of the chiral bicyclic imidazole skeleton.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: a class of chiral bicyclic imidazole compounds substituted with carbamate groups, the structural formula of which is shown in (I): , Among them, the chiral configuration of carbon marked with * is R or S R 1 and R 2 The group is an H atom or one of alkyl or aryl substituents, R 1 and R 2 The functional groups can be the same or different; R 4 and R 5 It can be an H atom or a methyl group, R 4 and R 5 The functional groups can be the same or different.

[0008] The synthetic route for the carbamate-substituted chiral bicyclic imidazole compound (Ⅰ) of the present invention is shown below: .

[0009] This invention also relates to key intermediates of carbamate-substituted chiral bicyclic imidazole compounds, the structural formula of which is shown in (IV): , Among them, the chiral configuration of carbon marked with * is R or S R 6 The group is an alkyl group such as methyl or ethyl, R 7 The group represents one or more substitution sites on the naphthalene ring; these substituents can be hydrogen atoms, any hydrocarbon groups or halogen atoms, and their type, number and connection position are not limited.

[0010] The synthetic route for the key intermediate (IV) of the carbamate-substituted chiral bicyclic imidazole compound of the present invention is shown below: .

[0011] The beneficial effects of this invention are: The carbamate-substituted chiral bicyclic imidazole catalyst developed in this invention can efficiently construct pentavalent phosphine chiral centers through a synergistic catalytic mechanism of Lewis base and hydrogen bonding. In the synthesis of the key precursor of the Utrophin regulator SMT022332, compared to Babbs et al. (…), Tetrahedron 2020, 76 The catalyst (130819) achieved an 83% enantioselectivity in the synthesis of SMT022332 analogues using a chiral auxiliary agent strategy. This catalyst can efficiently obtain the target product with 89% stereoselectivity, demonstrating a clear advantage. Attached Figure Description

[0012] Figure 1 This is a synthetic route diagram of the chiral bicyclic imidazole catalyst of the present invention; Figure 2 This is a synthetic route diagram of the isocyanate involved in this invention; Figure 3 This is the NMR spectrum of compound 9 in Example 25 of the present invention. 1 [H NMR (400MHz, CDCl3)]; Figure 4 This is the NMR spectrum of compound 9 in Example 25 of the present invention. 31 [P NMR (162MHz, CDCl3)]; Figure 5 This is the NMR spectrum of compound 9 in Example 25 of the present invention. 19[F NMR (376MHz, CDCl3)]; Figure 6 This is the racemic chromatogram of compound 9 in Example 25 of the present invention; Figure 7 This is the enantiomeric chromatogram of compound 9 in Example 25 of the present invention. Detailed Implementation

[0013] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention.

[0014] Example 1 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2] -α Imidazole-7-carbamate (C1) Method 1: Under the protection of an inert gas, ( R or S 124.1 mg, 1.0 mmol, 1.0 eq) of OH-DPI was dissolved in anhydrous THF (10 mL) and stirred at 0 °C for 15 minutes. Trichloroacetyl isocyanate (2.0 mmol, 2.0 eq) was slowly added dropwise, and the reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete, methanol (5 mL), water (5 mL), and K₂CO₃ (276 mg, 2.0 mmol) were added, and the mixture was stirred at room temperature until TLC showed complete conversion of the starting material. The solvent was removed by vacuum distillation, and the residue was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a yellow solid. The crude product was recrystallized from the mixture of isopropyl ether and dichloromethane at -50 °C to finally give the title compound as a white solid (86 mg, 51% yield).

[0015] Method 2: Under the protection of an inert gas, ( R or S An acetonitrile solution of 124.1 mg (1.0 mmol, 1.0 eq) of OH-DPI was cooled to 0 °C and stirred at 0 °C for 15 minutes. Chlorosulfonyl isocyanate (2.0 eq) was added, and the mixture was stirred for 2 hours. Concentrated hydrochloric acid (1 mL) was slowly added, and the reaction was continued with stirring for 4 hours. The reaction mixture was quenched with sodium bicarbonate, diluted with water, and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a yellow solid. The crude product was recrystallized from the crude product using a mixed solvent of isopropyl ether and dichloromethane at low temperature to finally give the title compound as a white solid (56 mg, 33% yield).

[0016] Method 3: Under the protection of an inert gas, ( R orS A mixture of 124.1 mg (1.0 mmol, 1.0 eq) of OH-DPI, sodium isocyanate (186.1 mg, 3 mmol, 3.0 eq) and trifluoroperacetic acid (3 mmol) in dichloromethane (25 mL) was stirred at room temperature for 3 hours. The reaction was monitored by TLC, with repeated additions of the sodium isocyanate and trifluoroperacetic acid mixture over 24 hours. The reaction solution was diluted with water (30 mL) and dichloromethane (20 mL), and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane (30 mL × 2). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The crude product was recrystallized from the crude product using a mixture of isopropyl ether and dichloromethane at low temperature to finally obtain the title compound as a white solid (30 mg, 18% yield).

[0017]

[0018] 1 H NMR (400 MHz, Methanol- d 4) δ 7.11 (d, J = 1.4 Hz, 1H), 7.07 (d, J = 1.3Hz, 1H), 5.86 (dd, J = 7.3, 2.7 Hz, 1H), 4.20 – 4.13 (m, 1H), 4.07 – 4.01 (m,1H), 3.09 – 3.00 (m, 1H), 2.60 – 2.52 (m, 1H). 13 C NMR (101 MHz, Methanol- d 4) δ158.55, 152.62, 133.99, 117.00, 68.40, 44.00, 35.93. Example 2 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Preparation of imidazole-7-methylcarbamate (C2) Under inert gas protection, cooled to below 0°C ( R or STriethylamine (1.20 equivalents) was added to an anhydrous DCE (10 mL) solution of 124.1 mg (1.0 mmol, 1.0 equivalent) of DPI and DMAP (0.20 mmol). The mixture was stirred for 10 minutes, and then methylcarbamoyl chloride (1.20 equivalents) was slowly added dropwise. The reaction was stirred at room temperature until TLC monitoring showed complete conversion of the starting material. The solvent was removed by vacuum distillation, and the residue was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow solid (90 mg, 50% yield).

[0019]

[0020] 1 H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.95 (s, 1H), 5.92 (dd, J = 7.1,2.7 Hz, 1H), 4.75 (s, 1H), 4.17 – 4.11 (m, 1H), 4.00 – 3.95 (m, 1H), 3.12 –3.03 (m, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.64 – 2.58 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 156.42, 151.63, 134.97, 115.55, 67.93, 43.06, 35.43, 27.72. Example 3 ( R or S )-6,7-dihydro-5 H -pyrrolo[1,2- α Preparation of imidazole-7-dimethylcarbamate (C3) At 0℃, towards ( R or S Triethylamine (0.21 mL, 1.50 equivalent) was added to a solution of 10 mL of anhydrous toluene containing 124.1 mg (1.0 mmol, 1.0 equivalent) of OH-DPI and 0.2 mmol (DMAP). After stirring the mixture for 10 minutes, dimethylcarbamoyl chloride (0.19 mL, 2.0 equivalent) was slowly added dropwise. The reaction mixture was stirred under reflux (120 °C) for 48 hours, with dimethylcarbamoyl chloride added in batches during this period. After the reaction was complete, the residue was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil (21 mg, 11% yield).

[0021]

[0022] 1 H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.95 (s, 1H), 5.92 (dd, J = 7.1,2.7 Hz, 1H), 4.19 – 4.13 (m, 1H), 4.00– 3.94 (m, 1H), 3.12 – 3.03 (m, 1H), 2.93 (s, 3H), 2.87 (s, 3H), 2.64 – 2.57 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ155.95, 151.80, 134.81, 115.42, 68.29, 43.00, 36.64, 36.18, 35.52. Example 4 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Preparation of imidazole-7-ethylcarbamate (C4) Will( R or S )-OH-DPI (62 mg, 0.50 mmol, 1.0 equivalent) was dissolved in anhydrous toluene (10 mL), and ethyl isocyanate (0.50 mmol, 1.0 equivalent) was added. The reaction mixture was heated under reflux (120 °C) for 24 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate = 1:1) to give the target product (67 mg, 69% yield).

[0023]

[0024] 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 6.94 (s, 1H), 5.90 (dd, J = 7.2,2.7 Hz, 1H), 5.12 (s, 1H), 4.22 – 4.08 (m, 1H), 4.00 – 3.94 (m, 1H), 3.31 –3.15 (m, 2H), 3.12 – 2.97 (m, 1H), 2.73 – 2.47 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.62, 151.57, 134.64, 115.45, 67.53, 42.96,35.91, 35.29, 15.16. Example 5 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Preparation of imidazole-7-propylcarbamate (C5) The experimental procedure was the same as in Example 4, with a yield of 51%.

[0025]

[0026] 1 H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 6.95 (s, 1H), 5.90 (dd, J = 7.2,2.7 Hz, 1H), 4.94 (s, 1H), 4.17 – 4.10 (m, 1H), 4.00 – 3.94 (m, 1H), 3.27 –3.00 (m, 3H), 2.64 – 2.56 (m, 1H), 1.52 (q, J = 7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.78, 151.62, 134.84, 115.51, 67.73, 43.02,42.88, 35.41, 23.20, 11.30. Example 6 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Preparation of imidazole-7-cyclopentylcarbamate (C6) The experimental procedure was the same as in Example 4, with a yield of 66%.

[0027]

[0028] 1 H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 6.95 (s, 1H), 5.90 (dd, J =7.2, 2.6 Hz, 1H), 4.80 (d, J= 7.5 Hz, 1H), 4.16 – 4.10 (m, 1H), 4.08 – 3.94(m, 2H), 3.11 – 3.02 (m, 1H), 2.64 – 2.57 (m, 1H), 1.98 – 1.92 (m, 2H), 1.69– 1.53 (m, 4H), 1.44 – 1.35 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 155.19, 151.66,134.92, 115.51, 67.66, 52.90, 43.04, 35.45, 33.31, 33.23, 23.58, 23.54. Example 7 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Preparation of imidazole-7-benzylcarbamate (C7) The experimental procedure was the same as in Example 4, with a yield of 67%.

[0029]

[0030] 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.25 (m, 5H), 7.18 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 0.9 Hz, 1H), 5.96 (dd, J = 7.2, 2.7 Hz, 1H), 5.16 (s, 1H), 4.39 (d, J = 6.0 Hz, 2H), 4.18 – 4.11 (m, 1H), 4.00 – 3.95 (m, 1H), 3.16 – 3.02 (m, 1H), 2.66 – 2.60 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 155.81, 151.50, 138.25, 134.96,128.83, 127.70, 127.64, 115.58, 68.09, 45.28, 43.06, 35.42. Example 8 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- αImidazole-7-(2-methylbenzyl)carbamate (C8) The experimental procedure was the same as in Example 4, and the yield was 83%.

[0031]

[0032] 1 H NMR (400 MHz, CDCl3): δ 7.29 – 7.12 (m, 5H), 6.94 (s, 1H), 5.95(dd, J = 7.4, 2.7 Hz, 1H), 5.05 (s, 1H), 4.38 (d, J = 5.7 Hz, 2H), 4.23 – 4.07(m, 1H), 4.00 – 3.95 (m, 1H), 3.13 – 3.03 (m, 1H), 2.66– 2.60 (m, 1H), 2.33(s, 3H). 13 C NMR (101 MHz, CDCl3): δ 155.64, 151.50, 136.26, 135.89, 134.96, 130.62, 128.19, 127.88, 126.36, 115.57, 68.07, 43.29, 43.06, 35.44, 19.10. Example 9 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(3-methylbenzyl)carbamate (C9) The experimental procedure was the same as in Example 4, with a yield of 78%.

[0033]

[0034] 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.06 (m, 5H), 6.92 (d, J = 1.3 Hz, 1H), 5.91 (dd, J = 7.3, 2.7 Hz, 1H), 5.45 (s, 1H), 4.39 – 4.26 (m, 2H), 4.17 – 4.06(m, 1H), 4.04 – 3.90 (m, 1H), 3.12 – 2.97 (m, 1H), 2.63 – 2.57 (m, 1H), 2.33 (s, 3H).13 C NMR (101 MHz, CDCl3) δ 155.81, 151.45, 138.39, 138.26, 138.23,134.74, 128.59, 128.27, 124.56, 115.49, 67.91, 45.07, 42.97, 35.33, 21.42. Example 10 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(4-methylbenzyl)carbamate (C10) The experimental procedure was the same as in Example 4, with a yield of 52%.

[0035]

[0036] 1 H NMR (400 MHz, CDCl3) δ 7.18-7.10 (m, 5H), 6.94 (s, 1H), 5.95 (dd, J =7.2, 2.6 Hz, 1H), 5.12 (s, 1H), 4.33 (d, J = 5.8 Hz, 2H), 4.17-4.10 (m, 1H), 4.00-3.94 (m, 1H), 3.12-3.03 (m, 1H), 2.66-2.59 (m, 1H), 2.33 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.76, 151.51, 137.37, 135.19, 134.91, 129.47, 127.64,115.57, 68.02, 45.02, 43.06, 35.42, 21.22. Example 11 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(4-trifluoromethylbenzyl)carbamate (C11) The experimental procedure was the same as in Example 4, with a yield of 69%.

[0037]

[0038] 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J= 7.9 Hz, 2H), 7.41 (d, J = 7.9 Hz,2H), 7.18 (s, 1H), 6.94 (s, 1H), 5.94 (dd, J = 7.6, 2.7 Hz, 1H), 5.69 (s, 1H), 4.42 (d, J = 6.2 Hz, 2H), 4.21 – 4.10 (m, 1H), 4.05 – 3.94 (m, 1H), 3.11 – 3.04(m, 1H), 2.67 – 2.60 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 155.82, 151.31,142.45, 134.50, 129.71 (q, J = 33.4 Hz), 127.61, 125.61 (q, J = 3.6 Hz), 124.1(apparent br. d, J = 272.7 Hz; assigned as q), 115.6, 68.0, 44.5, 43.12,35.21. 19 F NMR (376 MHz, CDCl3) δ -62.50. Example 12 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(2-phenylprop-2-yl)carbamate (C12) The experimental procedure was the same as in Example 4, with a yield of 51%.

[0039]

[0040] 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 6.94 (s, 1H), 5.83 (dd, J = 7.3, 2.7Hz, 1H), 5.27 (s, 1H), 4.11 (d, J= 10.5 Hz, 1H), 3.95 (s, 1H), 3.03 (q, J = 8.2,7.1 Hz, 1H), 2.57 (s, 1H), 1.67 (d, J = 5.9 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ153.84, 151.59, 146.87, 134.92, 128.52, 126.91, 124.93, 115.54, 67.54, 55.51, 43.04, 35.55, 29.26. Example 13 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(1,1-diphenylethyl)carbamate (C13) The experimental procedure was the same as in Example 4, with a yield of 50%.

[0041]

[0042] 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.22 (m, 10H), 7.21 – 7.16 (m, 1H), 6.93 (s, 1H), 5.85 (dd, J = 7.1, 2.6 Hz, 1H), 5.64 (s, 1H), 4.31 – 4.08 (m,1H), 3.99 – 3.87 (s, 1H), 3.12 – 2.92 (m, 1H), 2.69 – 2.47 (m, 1H), 2.17 (s,3H). 13 C NMR (101 MHz, CDCl3): δ 153.82, 151.46, 146.07, 134.90, 128.50,127.26, 126.62, 126.53, 115.58, 67.76, 61.99, 43.06, 35.60, 27.73. Example 14 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-triphenylmethylcarbamate (C14) The experimental procedure was the same as in Example 4, with a yield of 65%.

[0043]

[0044] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.16 (m, 16 H), 6.94 (s, 1H), 6.13(s, 1H), 5.79 (d, J = 7.0 Hz, 1H), 4.13 – 4.09 (m, 1H), 4.00 – 3.85 (m, 1H), 3.02 – 2.97 (m, 1H), 2.58 –2.41 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 154.15,151.35, 144.65, 134.98, 128.73, 128.07, 127.25, 115.65, 70.11, 68.02, 43.04,35.71. Example 15 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-phenylethylcarbamate (C15) The experimental procedure was the same as in Example 4, with a yield of 68%.

[0045]

[0046] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H), 7.25 – 7.16 (m, 4H), 6.94 (s, 1H), 5.90 (dd, J = 7.3, 2.7 Hz, 1H), 4.83 (s, 1H), 4.18 – 4.06 (m,1H), 4.02 – 3.89 (m, 1H), 3.55 – 3.38 (m, 2H), 3.13– 2.98 (m, 1H), 2.89 –2.71 (m, 2H), 2.65 – 2.48 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 155.68, 151.52,138.66, 134.94, 128.89, 128.79, 126.69, 115.56, 67.90, 43.04, 42.29, 36.11,35.40. Example 16 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(( S 1-Phenylacetyl)carbamate (C16) The experimental procedure was the same as in Example 4, with a yield of 70%.

[0047]

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.23 (m, 5H), 7.18 (s, 1H), 6.93 (s, 1H), 5.92 (dd, J = 7.2, 2.7 Hz, 1H), 5.12 (s, 1H), 4.99 – 4.74 (m, 1H), 4.11 –4.08 (m,1H), 3.99 – 3.93 (m, 1H), 3.16 – 2.98 (m, 1H), 2.61 – 2.53 (m, 1H),1.48 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.89, 151.56, 143.50,134.94, 128.82, 127.51, 126.05, 115.56,67.87, 50.94, 43.06, 35.41, 22.68. Example 17 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(( R 1-Phenylacetyl)carbamate (C17) The experimental procedure was the same as in Example 4, with a yield of 61%.

[0049]

[0050] 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.22 (m, 5H), 7.18 (s, 1H), 6.93 (s,1H), 5.92 (dd, J= 7.1, 2.7 Hz, 1H), 5.29 (s, 1H), 4.89 – 4.82 (m, 1H), 4.17 –4.05 (m, 1H), 4.00 – 3.89 (m, 1H), 3.20 – 2.91 (m, 1H), 2.81 – 2.42 (m, 1H),1.47 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.87, 151.53, 143.54,134.86, 128.74, 127.43, 126.02, 115.53, 67.79, 50.89, 43.03, 35.37, 22.65. Example 18 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazol-7-yl(( R or S 1-Phenylacetyl)carbamate (C18), (C19) The experimental procedure was the same as in Example 4, with a yield of 40%.

[0051] 1 H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 8.5, 6.3 Hz, 2H), 7.27 – 7.23(m, 3H), 7.19 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 5.91 (dd, J = 7.2, 2.6Hz, 1H), 5.16 (d, J = 6.5 Hz, 1H), 4.60 (q, J = 7.5 Hz, 1H), 4.06 – 4.13 (m, 1H), 3.95 (ddd, J = 10.7, 8.6, 3.7 Hz, 1H), 3.14 – 2.92 (m, 1H), 2.65 – 2.49 (m,1H), 1.86 – 1.72 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ155.09, 151.54, 142.39, 134.94, 128.75, 127.47, 126.53, 115.58, 67.96, 57.09,43.05, 35.47, 29.89, 10.73. Example 19 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-(naphth-2-ylmethyl)carbamate (C20) The experimental procedure was the same as in Example 4, with a yield of 63%.

[0052] 1 H NMR (400 MHz, CDCl3) δ 7.85 – 7.67 (m, 4H), 7.50 – 7.36 (m, 3H), 7.19 (s, 1H), 6.94 (s, 1H), 5.98 (dd, J = 7.3, 2.8 Hz, 1H), 5.28 (s, 1H), 4.67– 4.48 (m, 2H), 4.23 – 4.08 (m, 1H), 4.06 – 3.85 (m, 1H), 3.12 – 3.06 (m,1H), 2.74 – 2.55 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 155.87, 151.47, 135.71,134.93, 133.49, 132.94, 128.67, 127.92, 127.82, 126.41, 126.18, 126.08,125.76, 115.60, 68.17, 45.43, 43.09, 35.43. Example 20 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-( R or S )-(naphthalene-2-ethyl)carbamate carbamate (C21), (C22) Will(( R or S))-OH-DPI (1.0 mmol, 1.0 eq) was dissolved in anhydrous toluene (10 mL), and (IV)-1 (0.9 eq) was added. The reaction mixture was heated under reflux (110 °C) for 24 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate = 1:1) to give the target product (77% yield).

[0053]

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.87 – 7.73 (m, 4H), 7.52 – 7.39 (m, 3H), 7.18 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 5.87 (dd, J = 7.1, 2.7 Hz, 1H), 5.24 –5.23 (m, 1H), 5.14 – 4.95 (m, 1H), 4.18 – 4.13 (m, 1H), 3.99 – 3.93 (m, 1H),3.22 – 2.99 (m, 1H), 2.70 – 2.61 (m, 1H), 1.57 (d, J = 6.6 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 154.99, 151.40, 140.68, 134.88, 133.41, 132.84, 128.59, 128.04,127.72, 126.28, 125.91, 124.49, 124.42, 115.55, 68.07, 50.99, 43.02, 35.46,22.55. Example 21 ( R or S )-6,7-dihydro-5H-pyrrolo[1,2- α Imidazole-7-( R or S )-(naphthalene-1-ethyl)carbamate carbamate (C23), (C24) The experimental procedure was the same as in Example 4, with a yield of 73%.

[0055]

[0056] 1H NMR (400 MHz, CDCl3) δ 8.13 – 7.99 (m, 1H), 7.86 – 7.61 (m, 2H), 7.49 – 7.36 (m, 4H), 7.05 – 6.95 (m, 1H), 6.80 – 6.67 (m, 1H), 5.94 – 5.74(m, 2H), 5.70 – 5.49 (m, 1H), 3.99 – 3.80 (m, 1H), 3.78 – 3.63 (m, 1H), 2.90 – 2.73 (m, 1H), 2.46 – 2.27(m, 1H), 1.49 (d, J = 5.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.83, 151.31, 139.13, 134.46, 133.82, 130.67, 128.76, 127.93,126.26, 125.62, 125.29, 123.15, 122.26, 115.31, 67.51, 46.74, 42.74, 35.16,21.83. Example 22 ( R or S )-2-(1-isocyanate ethyl)naphthalene(IV)-1 Under inert gas protection, 10.0 mmol ( R or S 1-(2-naphthyl)ethylamine was dissolved in 10 mL of anhydrous dichloromethane and cooled to 0°C in an ice-water bath. While stirring, a solution of 21 mmol triethylamine dissolved in 5 mL of anhydrous dichloromethane was slowly added dropwise. Subsequently, a solution of 4.0 mmol triphosgene (equivalent to 1.2 phosgene units) dissolved in 10 mL of anhydrous dichloromethane was slowly added dropwise over 5 minutes. After the addition was complete, the reaction mixture was stirred at 0°C for 30 minutes. The ice-water bath was then removed, and the reaction system was allowed to slowly warm to room temperature naturally over 3 hours. The resulting crude reaction solution was concentrated under vacuum to remove the solvent. The residue was dissolved in 15 mL of anhydrous diethyl ether and quickly filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to obtain crude isocyanate, which could be used directly in subsequent reactions.

[0057]

[0058] 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.63 (m, 3H), 7.39 – 7.29 (m,2H),7.25 (dd, J = 8.6, 1.9 Hz, 1H), 4.71 (qd, J = 6.8, 2.0 Hz, 1H), 1.48 (d, J = 6.7Hz, 3H). Example 23 ( R or S )-2-(1-isocyanate ethyl)naphthalene(IV)-1 Under inert gas protection, 10.0 mmol ( R or S 1-(2-naphthyl)ethylamine was dissolved in 10 mL of anhydrous dichloromethane and cooled to -5°C in an ice-water bath. While stirring, a solution of 21 mmol triethylamine dissolved in 5 mL of anhydrous dichloromethane was slowly added dropwise. Subsequently, a solution of 4.0 mmol triphosgene (equivalent to 1.2 phosgene units) dissolved in 10 mL of anhydrous dichloromethane was slowly added dropwise over 5 minutes. After the addition was complete, the reaction mixture was stirred at -5°C for 1 hour. The ice-water bath was then removed, and the reaction system was allowed to slowly warm to room temperature naturally over 5 hours. The resulting crude reaction solution was concentrated under vacuum to remove the solvent. The residue was dissolved in 15 mL of anhydrous diethyl ether and quickly filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to obtain crude isocyanate, which could be used directly in subsequent reactions.

[0059] Example 24 ( R or S )-2-(1-isocyanate ethyl)naphthalene(IV)-1 Under inert gas protection, the carboxylic acid substrate (shown in structural formula (VI)) R or S 10 mmol of 2-(naphthalen-2-yl)propanoic acid was dissolved in 50 mL of anhydrous toluene along with 1.5 equivalents of triethylamine. 1.5 equivalents of diphenylphosphoazide (DPPA) was slowly added dropwise at room temperature. After the addition was complete, the reaction mixture was heated to reflux temperature and stirred at this temperature for 24 hours. The reaction was confirmed to be complete by TLC, and the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. The residue was extracted with ethyl acetate (3 × 50 mL), the combined organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow oily crude product, which was the target isocyanate (compound IV). This crude product did not require further purification and could be used directly in subsequent steps.

[0060] The following are examples of the aforementioned catalyst applications: Example 25: The catalyst developed in this invention achieved an overall yield of 48% and enantioselectivity of 89% in the synthesis of a key precursor for the Utrophin modifier SMT022332. The performance of the carbamate-modified chiral bicyclic imidazole catalyst of Example 20 was significantly superior to the synthetic methods reported in existing patents.

[0061]

[0062] A clean, dry 50 mL Schlenk flask was subjected to three cycles of evacuation followed by inert gas purging. Under continuous inert gas protection, the following were added sequentially: activated molecular sieve (70 mg), catalyst (9.6 mg), dibenzylamine (3.0 equivalent, 115 μL), and anhydrous 1,2-dimethoxyethane (DME, 1 mL). The reaction mixture was stirred vigorously at -50 °C for 20 minutes. Separately, phosphoryl dichloride (66 mg, 0.2 mmol) was dissolved in anhydrous cyclopentyl methyl ether (CPME, 1.5 mL), and this solution was added to the reaction system under inert gas protection. The resulting mixture was stirred vigorously at -50 °C for 60 hours to complete the reaction. A double-necked round-bottom flask equipped with a magnetic stirrer was placed in an oven-dried environment under argon atmosphere, and 4-trifluoromethylphenol (162 mg, 1 mmol) and anhydrous THF (3 mL) were added. After cooling the reaction flask in an ice bath, sodium hydride (41 mg, 1.02 mmol, 5.1 equivalent, 60% mineral oil dispersion) was added in batches. Immediately seal the bottle mouth with a rubber septum and reinforce with sealing film. Stir the mixture at room temperature for 60 minutes. In a separate oven-dried double-necked round-bottom flask, add silver carbonate (12 mg, 22 mol%) and anhydrous THF (1 mL) under an argon atmosphere. Sonicate to disperse until a homogeneous suspension is formed (no macroscopically visible solid particles). Transfer this suspension to the pre-prepared catalytic reaction system in one go, rinsing repeatedly with anhydrous THF (1 mL cumulatively) during the transfer. After 1 minute, add the previously prepared sodium 4-trifluoromethylphenol solution. Stir at -50°C for 24 hours, then filter through a diatomaceous earth mat to remove insoluble salts and molecular sieves. Concentrate the filtrate under reduced pressure, and purify the residue by preparative thin-layer chromatography (PTLC) on silica gel (eluent: hexane / ethyl acetate = 5 / 1 to 3 / 1 gradient elution, 60% yield, 90% ee).

[0063] Compound 8 (68 mg, 0.11 mmol) was reacted with p-toluenesulfonic acid monohydrate ( p-TsOH·H2O (15.0 equivalents) was placed in a single-necked flask and dissolved in methanol (5 mL). The reaction mixture was stirred in an oil bath at 60 °C for 8 hours, then cooled to room temperature and stirred for another 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC), and the reaction was terminated after the reactant 8 was completely converted. After the reaction was complete, the methanol solvent was removed by concentration, and the residue was diluted with ethyl acetate and extracted successively with saturated sodium bicarbonate solution, saturated ammonium chloride solution, and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give an oily crude product. Finally, it was purified by preparative thin-layer chromatography (PTLC) (eluent: petroleum ether / ethyl acetate = 5:1 → 2:1) to give the target product 9 (81% yield, 89% ee). Figure 3-5 The image shows the NMR spectrum of the obtained target product 9.

[0064] 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.09 (m, 1H), 8.08 – 7.99 (m, 2H), 7.54 – 7.48 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 8.4, 4.7 Hz, 1H),7.11 – 7.05 (m, 4H), 3.74 (d, J = 11.5 Hz, 3H). 31 P NMR (162 MHz, CDCl3) δ17.93. 19 F NMR (376 MHz, CDCl3) δ -62.27, -105.82. HPLC conditions: CHIRALPAK ADH,10% iPrOH / hexanes, 0.8 mL / min, 254 nm,t R (minor) = 24.732 min, t R (major) = 37.619 min. The detection results are as follows: Figure 6-7 The figures shown are the chromatograms of the racemic and enantiomers, respectively.

[0065] This invention is not limited to the preferred embodiments described above. Anyone can derive other forms of products under the guidance of this invention. However, regardless of any changes made in their shape or structure, any technical solution that is the same as or similar to this application falls within the protection scope of this invention.

Claims

1. A chiral bicyclic imidazole catalyst substituted with a carbamate group, characterized in that, The structural formula of the chiral bicyclic imidazole catalyst is shown in (Ⅰ): ， Among them, the chiral configuration of carbon marked with * is R or S R 1 and R 2 The groups are respectively one of H atoms, alkyl, and aryl substituents; R 4 and R 5 The groups are either H atoms or methyl groups.

2. The carbamate-substituted chiral bicyclic imidazole catalyst according to claim 1, characterized in that, The structure of the chiral bicyclic imidazole catalyst includes: 。 3. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to any one of claims 1-2, characterized in that: The chiral bicyclic imidazole catalyst is synthesized in one step by esterification reaction of isocyanate or acyl chloride compound and chiral alcohol compound. The structural formula of the acyl chloride compound is shown in (II), and the structural formula of the chiral alcohol compound is shown in (III). ， Among them, the chiral configuration of carbon marked with * is R or S R 1 and R 2 The groups are respectively one of H atoms, alkyl, and aryl substituents; R 3 The functional group includes one of trifluoroformyl, chlorosulfonyl, or sodium ion; R 4 and R 5 The groups are either H atoms or methyl groups.

4. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 3, characterized in that: The molar ratio of the chiral alcohol compound to the isocyanate or acyl chloride compound is 1:(0.9~3.0); the reaction temperature is 0~120℃; and the reaction time is 4~24h.

5. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 3, characterized in that, The structural formula of the isocyanate is shown in (Ⅳ): ， Among them, the chiral configuration of carbon marked with * is R or S R 6 Groups include alkyl groups; R 7 The group represents one or more substitution sites on the naphthalene ring, and the substituents at the substitution sites include one of the following: hydrogen atom, hydrocarbon group, and halogen atom.

6. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 5, characterized in that, The isocyanate is synthesized by reacting a primary amine feedstock and triphosgene in an alkaline organic solvent to obtain compound (IV). The structural formula of the primary amine feedstock is shown in (V): 。 7. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 5, characterized in that, The isocyanate is synthesized by heating a carboxylic acid starting material and a diphenylphosphoazide in an alkaline organic solvent under reflux to obtain compound (IV). The structural formula of the carboxylic acid raw material is shown in (VI): 。 8. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 7 or 8, characterized in that: The base is an organic or inorganic base, including one of triethylamine, 1,8-diazacyclo[5,4,0]undecene-7, diisopropylethylamine, potassium carbonate, and sodium carbonate.

9. The method for synthesizing the carbamate-substituted chiral bicyclic imidazole catalyst according to claim 7 or 8, characterized in that: The molar ratio of the primary amine or carboxylic acid raw material to the alkali is 1:(1.5-2.1).

10. The carbamate-substituted chiral bicyclic imidazole catalyst according to claim 1, characterized in that: The application of the chiral bicyclic imidazole catalyst in the synthesis of a precursor of Utrophin modulator (-)-SMT022332 for the treatment of Duchenne muscular dystrophy.

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