Method for synthesizing chiral phthalate compounds by dynamic kinetic resolution

Abstract

The application discloses a method for synthesizing chiral phthalic ester compounds through dynamic kinetic resolution, and belongs to the technical field of organic synthesis. With racemic 3-hydroxy phthalic compounds 1 and anhydride 2 as raw materials, a dynamic kinetic resolution reaction is carried out under the catalysis of chiral ArPNO to obtain chiral phthalic ester compounds 3, and talosalicylate and talmetacin prodrug are synthesized. In the application, the oxygen atom in the pyridine nitrogen oxide is used as a nucleophilic site to participate in the dynamic kinetic resolution reaction, and the hydrogen in the catalyst molecule also plays a key role. The method has the advantages of mild conditions, no addition of any additive, good yield and high enantioselectivity.

Description

Technical Field

[0001] The invention relates to a method for synthesizing chiral phthalate compounds through dynamic kinetic resolution, and belongs to the technical field of asymmetric synthesis in organic chemistry. Background Art

[0002] Phthaloyl esters are widely used clinically, primarily for their analgesic and anti-inflammatory properties. For example, talosalate is a prodrug with analgesic and anti-inflammatory properties; talniflumate is a prodrug with analgesic and anti-inflammatory properties; and tamethacin has antibacterial and anti-inflammatory effects. However, few methods have been reported to synthesize phthaloyl esters.

[0003] Angew. Chem., Int. Ed. 2020, 59, 3859-3863 discloses that when synthesizing phthalate drugs, an equivalent amount of oxidant must be added to ensure the reaction proceeds. Angew. Chem., Int. Ed. 2021, 60, 1641-1645 discloses that to obtain products with high enantioselectivity, the reaction must be carried out at ultra-low temperatures (-78°C).

[0004] Therefore, it is of great research significance to develop a more mild synthetic method to prepare chiral phthalate esters and their derivatives. Summary of the Invention

[0005] To address the above-mentioned technical problems, the present invention discloses a method for the dynamic kinetic resolution of 3-hydroxyphthaloyl compounds using a chiral ArPNO catalyst. Using racemic 3-hydroxyphthaloyl compound 1 and anhydride 2 as raw materials, a dynamic kinetic resolution reaction is carried out under the catalysis of chiral ArPNO to obtain chiral phthaloyl ester compound 3, and to synthesize talosalate and tamethacin prodrugs. The chiral ArPNO catalyst utilizes the oxygen atom of the pyridine nitrogen and oxygen as a nucleophilic site in the dynamic kinetic resolution reaction, while the hydrogen in the catalyst molecule also plays a key role.

[0006] The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution of the present invention comprises the following steps: using racemic 3-hydroxyphthalate compound 1 and acid anhydride 2 as raw materials, and performing a dynamic kinetic resolution reaction under the catalysis of a chiral catalyst ArPNO to obtain a chiral phthalate compound 3; the reaction equation is as follows:

[0007]

[0008] Among them, R 1 is selected from C1-C6 alkyl, halogenated alkane, nitrile, nitro or C1-C4 alkoxycarbonyl; R 2is selected from C1-C4 alkyl; Ar is selected from phenyl, substituted phenyl; R is selected from phenyl, substituted phenyl or diphenylmethyl; the substituents in the aforementioned substituted phenyl are selected from one or more of C1-C4 alkyl, C1-C4 alkoxy, and phenyl substitution.

[0009] Furthermore, among the above substituents, preferably: R 1 It is 5-substituted methoxycarbonyl, nitrile, methoxy, or halogen (fluorine, chlorine, or bromine).

[0010] Furthermore, in the above technical solution, the chiral catalyst ArPNO comprises the following structure:

[0011]

[0012] Furthermore, in the above technical solution, the chiral catalyst ArPNO preferably has a structure of C2d.

[0013] Furthermore, in the above technical solution, the reaction is carried out in an organic solvent, and the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, mesitylene, or toluene.

[0014] Furthermore, in the above technical solution, the yield and enantioselectivity of the reaction in the presence of a base are basically equivalent to those in the absence of a base and decrease to a certain extent. For example, the base is selected from triethylamine (no significant change in yield and enantioselectivity), diisopropylethylamine (no significant change in yield, reduced enantioselectivity) or potassium carbonate (slightly reduced yield, significantly reduced enantioselectivity).

[0015] Furthermore, in the above technical solution, the molar ratio of the racemic 3-hydroxyphthaloyl compound 1 to the acid anhydride 2 is 1:1-4.

[0016] Furthermore, in the above technical solution, the reaction temperature is 10-25° C. Compared with the previously reported method for synthesizing chiral phthalate compounds, room temperature is milder than the ultra-low temperature of -78° C. and has stronger operability.

[0017] The present invention also provides a method for synthesizing (R)-talosalate and (S)-tamethacin prodrugs, comprising the following steps: replacing the acid anhydride 2 in the above scheme with salicyloyl chloride and the corresponding acid chloride substrates of indomethacin: According to the aforementioned technical scheme for synthesizing chiral phthalate compounds, chiral prodrug compounds (R)-talosalate and (S)-tamethacin were obtained in the presence of an organic base. The specific corresponding reaction structures are as follows:

[0018]

[0019] Furthermore, in the above technical solution, the organic base is selected from triethylamine or diisopropylethylamine.

[0020] Beneficial effects of the invention:

[0021] 1. The present invention uses racemic 3-hydroxyphthaloyl and salicyl chloride or the corresponding acyl chloride of indomethacin as raw materials, and a dynamic kinetic resolution reaction at room temperature is performed to obtain chiral phthaloyl esters in a single step. The raw materials are readily available, and the reaction yield and enantioselectivity can reach up to 92% and 92% ee, respectively.

[0022] 2. Unlike the previous ArPNO-type catalysts in which the nitrogen on pyridine participates in the nucleophilic reaction, the ArPNO-type chiral catalyst in the present invention uses the oxygen atom in the pyridine nitrogen and oxygen as the nucleophilic site to participate in the dynamic kinetic resolution reaction. At the same time, the hydrogen in the catalyst molecule also plays a key role. DETAILED DESCRIPTION

[0023] Example 1

[0024] Taking 3-hydroxyphthaloyl 1a and anhydride 2 as raw materials to produce phthaloyl ester 3 as an example, the reaction conditions were optimized and the reaction equation is as follows:

[0025]

[0026] The specific reaction results are shown in the following table:

[0027]

[0028] [a] Unless otherwise stated, the reaction conditions were as follows: 1a (0.05 mmol), 2 (0.1 mmol), catalyst (10 mol%), and base (1 eq) in an organic solvent (0.5 mL) at room temperature for 10 h; [b] NMR yield; [c] determined by chiral HPLC analysis; [d] 2c (0.2 mmol).

[0029] During the reaction condition screening process, the effects of the catalyst on the reaction were first investigated (labeled 1-10). Furthermore, by comparing the effects of different solvents, bases, anhydrides, and raw material equivalent ratios on the reaction, C2d was ultimately determined to be the optimal catalyst, with a 10 mol% addition amount, mesitylene as the optimal solvent, no base, and 4 equivalents of anhydride as the optimal reaction conditions.

[0030] Reaction conditions (using Reaction 19 as an example): To a 5 mL dry reaction tube, chiral catalyst C2d (4.7 mg, 0.01 mmol, 10 mol%), 3-hydroxyphthaloyl 1a (15.0 mg, 0.1 mmol), and pivalic anhydride 2c (81.0 μL, 0.4 mmol) were added, followed by mesitylene (2.0 mL). The reaction was stirred at room temperature (25°C) for 10 hours. Column chromatography afforded 22.5 mg of 3ac as a white solid in 96% yield and 97% ee. HPLC CHIR ALCEL IA, n-hexane / 2-propanol = 90 / 10, flow rate = 0.6 mL / min, λ = 256 nm, retention time: 10.338 min (major), 11.837 min (minor). [α] D 21 = +78.72 (c = 0.47, CHCl3). 1 H NMR (600MHz, CDCl3): δ7.93(d,J=7.8Hz,1H),7.74(t,J=8.4Hz,1H),7.65(t,J=7.2Hz,1H),7.55(d,J=7.8Hz,1H),7.42(s,1H),1.24(s,9H). 13 C NMR (150MHz, CDCl3): δ177.1,168.1,144.8,134.9,131.3,126.7,125.9,123.5,92.9,39.1,27.0.

[0031] Example 2

[0032] In a 5 mL dry reaction tube, chiral catalyst C2d (4.7 mg, 0.01 mmol, 10 mol%), hydroxyphthaloyl 1b-n (0.1 mmol), and pivalic anhydride 2c (81.0 μL, 0.4 mmol) were added, followed by mesitylene (2.0 mL). The reaction mixture was stirred at 25°C for 10 hours. After the reaction was complete, the product was obtained by column chromatography. The specific reaction results are as follows:

[0033]

[0034] Representative NMR characterization data are as follows:

[0035] (S)-5-Fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate (3bc): white solid, 21.4 mg, 85% yield, 93% ee; R f=0.62(Pet / EtOAc,5 / 1,v / v).HPLC CHIRALCEL ADH,n-hexane / 2-propanol=90 / 10,flow rate=0.8mL / min,λ=256nm,retention time:7.727min(major),10.508min(minor).[α] D 22 =+62.31(c=0.32,CHCl3); 1 H NMR(600MHz,CDCl3):δ7.58(dd,J=7.2,2.4Hz,1H),7.54(dd,J=8.4,4.2Hz,1H),7.44(td,J=8.4,2.4Hz,1H),7.40(s,1H),1.24(s,9H).

[0036] (S)-6-Fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate(3cc):白色固体,m.p.:114.9-115.2℃;21.9mg,87%yield,94%ee;R f =0.66(Pet / EtOAc,5 / 1,v / v).HPLC CHIRALCEL IA,n-hexane / 2-propanol=90 / 10,flow rate=0.6mL / min,λ=256nm,retention time:10.712min(major),19.403min(minor).[α] D 22 =+57.41(c=0.72,CHCl3). 1 H NMR(400MHz,CDCl3):δ7.93(dd,J=8.4,4.4Hz,1H),7.37(s,1H),7.36-7.32(m,1H),7.23(dd,J=7.6,2.4Hz,1H),1.25(s,9H).

[0037] (S)-5-Chloro-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate(3dc):白色固体,24.7mg,92%yield,93%ee;R f= 0.70 (Pet / EtOAc, 5 / 1, v / v). HPLC CHIRALCEL IA, n-hexane / 2-propanol = 95 / 5, flow rate = 0.8 mL / min, λ = 250 nm, retention time: 9.956 min (major), 11.659 min (minor).[α] D 22 = +32.45 (c = 0.61, CHCI3). 1 H NMR (400 MHz, CDCI3): δ 7.89 (d, J = 2.0 Hz, 1 H), 7.70 (dd, J = 8.0, 1.6 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 1.24 (s, 9 H).

[0038] (S)-6-Chloro-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate (3ec): white solid; 25.4 mg, 95% yield, 92% ee; R f = 0.71 (Pet / EtOAc, 5 / 1, v / v). HPLC CHIRALCEL AD-H, n-hexane / 2-propanol = 90 / 10, flow rate = 0.8 mL / min, λ = 256 nm, retention time: 7.405 min (major), 14.288 min (minor).[α] D 22 = +90.39 (c = 0.62, CHCI3). 1 H NMR (600 MHz, CDCI3): δ 7.90 (d, J = 1.8 Hz, 1 H), 7.70 (dd, J = 8.4, 1.8 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 1.24 (s, 9 H). 13 C NMR (150 MHz, CDCI3): δ 177.0, 167.0, 146.4, 141.7, 132.1, 127.1, 125.2, 124.0, 92.3, 39.1, 27.0.

[0039] (S)-4-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate (3fc): white solid; m.p.: 100.4-101.5 °C; (29.3 mg, 94% yield, 93% ee); Rf =0.68(Pet / EtOAc,4 / 1,v / v).HPLC CHIRALCEL ADH,n-hexane / 2-propanol=90 / 10,flow rate=0.8mL / min,λ=256nm,retention time:8.548min(major),9.860min(minor).[α] D 22 =+75.10(c=0.71,CHCl3); 1 HNMR(600MHz,CDCl3):δ 7.80(d,J=7.2Hz,1H),7.58(t,J=7.8Hz,1H),7.49(dt,J=7.2,0.6Hz,1H),7.36(s,1H),1.24(s,9H). 13 C NMR(150MHz,CDCl3):δ177.1,165.5,147.1,136.0,135.9,125.2,122.5,121.2,91.3,39.1,27.0.

[0040] (S)-5-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate(3gc):白色固体;m.p.:89.7-92.6℃;27.8mg,89%yield,97%ee;R f =0.78(Pet / EtOAc,3 / 1,v / v).HPLCCHIRALCEL IA,n-hexane / 2-propanol=95 / 5,flow rate=0.4mL / min,λ=256nm,retention time:19.023min(major),21.162min(minor).[α] D 22 =+32.69(c=0.52,CHCl3). 1 H NMR(600MHz,CDCl3):δ7.89(d,J=7.8Hz,1H),7.86(d,J=7.8Hz,1H),7.54(td,J=7.8,1.2Hz,1H),7.43(s,1H),1.27(s,9H). 13 C NMR(100MHz,CDCl3):δ177.0,166.6,143.4,138.1,129.0,128.8,125.7,125.0,92.8,39.1,27.0.

[0041] (S)-6-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-yl pivalate(3hc): white solid; 27.5 mg, 88% yield, 94% ee; R f =0.63(Pet / EtOAc,5 / 1,v / v).HPLC CHIRALCEL ADH,n-hexane / 2-propanol=90 / 10, flow rate=0.8mL / min, λ=256nm, retention time:7.143min(major),13.032min(minor).[α] D 22 = +58.19 (c = 0.58, CHCl3). 1 H NMR (600MHz, CDCl3): δ7.79 (d, J = 1.2Hz, 2H), 7.72-7.71 (m, 1H), 7.37 (s, 1H), 1.26 (s, 9H). 13 C NMR (150MHz, CDCl3): δ177.0,167.1,146.5,134.9,130.2,127.2,127.0,125.7,92.2,39.2,27.0.

[0042] Example 3

[0043]

[0044] To a 5 mL dry reaction tube, chiral catalyst C2d (4.7 mg, 0.01 mmol, 10 mol%), 3-hydroxyphthaloyl 1a (15.0 mg, 0.1 mmol), salicyloyl chloride 4a (39.6 mg, 0.2 mmol), and toluene (2.0 mL) were added. Finally, triethylamine (14 μL, 0.1 mmol) was added, and the reaction mixture was stirred at 25°C for 6 hours. Column chromatography afforded 28.7 g of 5aa as a white solid in a 92% yield and 85% ee. HPLC CHIRALCEL IA, n-hexane / 2-propanol = 70 / 30, flow rate = 0.8 mL / min, λ = 256 nm, retention time: 12.460 min (major), 14.637 min (minor) [α] D 22 = +15.69 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDC13): δ 8.03 (dd, J = 8.0, 2.0 Hz, 1H), 7.97 (dt, J = 7.2, 1.2 Hz, 1H), 7.79-7.75 (m, 1H), 7.70-7.66 (m, 2H), 7.64-7.59 (m, 2H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.13 (dd, J = 8.0, 1.2 Hz, 1H), 2.22 (s, 3H). 13 C NMR (100 MHz, CDC13): δ 169.7, 167.9, 163.0, 151.4, 144.4, 135.2, 135.1, 132.4, 131.6, 126.6, 126.3, 126.0, 124.3, 124.1, 121.7, 93.3, 21.0.

[0045] Example 4

[0046]

[0047] In a 5 mL dry reaction tube, chiral catalyst C2d (4.7 mg, 0.01 mmol, 10 mol%), 3-hydroxyphthalic acid la (15.0 mg, 0.1 mmol), indomethacinyl chloride 4b (75.0 mg, 0.2 mmol) and toluene (2.0 mL) were added successively, and finally triethylamine (14 μL, 0.1 mmol). The reaction was stirred at 25 °C for 6 h. Column chromatography gave 43.5 mg of white solid 5ab in 89% yield with 92% ee. HPLC CHIRALCEL IA, n-hexane / 2-propanol = 60 / 40, flow rate = 0.8 mL / min, λ = 256 nm, retention time: 15.310 min (major), 17.478 min (minor). [a] D 22 = -21.31 (c = 0.51, CHCl3). 1 H NMR (400 MHz, CDC13): δ 8.03 (dd, J = 8.0, 2.0 Hz, 1H), 7.97 (dt, J = 7.2, 1.2 Hz, 1H), 7.79-7.75 (m, 1H), 7.70-7.66 (m, 2H), 7.64-7.59 (m, 2H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.13 (dd, J = 8.0, 1.2 Hz, 1H), 2.22 (s, 3H). 13C NMR (100 MHz, CDC13): δ 169.5, 168.4, 167.9, 156.2, 144.2, 139.6, 136.4, 135.0, 133.9, 131.5, 131.4, 130.9, 130.3, 129.3, 126.6, 126.0, 123.7, 115.2, 112.1, 111.3, 101.2, 93.2, 55.8, 30.3, 13.6.

[0048] The above examples describe the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A method for synthesizing chiral phthalate compounds by dynamic kinetic resolution, characterized in that: The method comprises the following steps: using racemic 3-hydroxyphthaloyl compound 1 and acid anhydride 2 as raw materials, and performing dynamic kinetic resolution reaction under the catalysis of chiral catalyst ArPNO to obtain chiral phthaloyl ester compound 3; the reaction equation is as follows: Among them, R 1 is selected from C1-C6 alkyl, halogen, nitrile, nitro or C1-C4 alkoxycarbonyl; R 2 is selected from C1-C4 alkyl; Ar is selected from phenyl, substituted phenyl; R is selected from phenyl, substituted phenyl or diphenylmethyl; the substituents in the aforementioned substituted phenyl are selected from one or more of C1-C4 alkyl, C1-C4 alkoxy, and phenyl substitution.

2. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 1, characterized in that: The chiral catalyst ArPNO has the following structure:

3. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 2, characterized in that: The chiral ArPNO-type catalyst is C2d.

4. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 1, characterized in that: The reaction is carried out in an organic solvent, which is selected from one or more of dichloromethane, tetrahydrofuran, mesitylene and toluene.

5. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 4, characterized in that: The organic solvent is selected from mesitylene or toluene.

6. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 1, characterized in that: The molar ratio of the racemic 3-hydroxyphthaloyl compound 1 to the acid anhydride 2 is 1:1-4.

7. The method for synthesizing chiral phthalate compounds by dynamic kinetic resolution according to claim 1, characterized in that: The reaction temperature is 10-25°C.

8. A method for synthesizing (R)-talosalate and (S)-tamethacin, characterized in that: The steps include: replacing anhydride 2 with According to the method according to any one of claims 1 to 7, (R)-talosalate and (S)-tamethacin are obtained in the presence of an organic base.

9. The method for synthesizing (R)-talosalate and (S)-tamethacin according to claim 8, characterized in that: The organic base is selected from triethylamine or diisopropylethylamine.

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