CN117800935B - Method for synthesizing chiral phthalate compounds by dynamic kinetic resolution - Google Patents
Method for synthesizing chiral phthalate compounds by dynamic kinetic resolutionInfo
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- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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Abstract
本发明公开了动态动力学拆分合成手性邻苯二甲酰酯类化合物的方法，属于有机合成技术领域。以消旋3‑羟基邻苯二甲酰类化合物1和酸酐2为原料，在手性ArPNO催化下，进行动态动力学拆分反应，得到手性邻苯二甲酰酯类化合物3，并合成了他洛柳酯和他美辛前药。本发明中手性ArPNO催化剂是利用吡啶氮氧中的氧原子作为亲核位点参与动态动力学拆分反应，同时催化剂分子中的氢也起到了关键性作用。该方法具有条件温和，没有加入任何添加剂，收率良好，对映选择性高等优势。The present invention discloses a method for synthesizing chiral phthalate compounds by dynamic kinetic resolution, and belongs to the field of organic synthesis technology. Using racemic 3-hydroxyphthalate compound 1 and acid anhydride 2 as raw materials, a dynamic kinetic resolution reaction is carried out under the catalysis of chiral ArPNO to obtain chiral phthalate compound 3, and synthesize talosalate and tamethacin prodrug. In the present invention, the chiral ArPNO catalyst utilizes the oxygen atom in the pyridine nitrogen and oxygen as a nucleophilic site to participate in the dynamic kinetic resolution reaction, while the hydrogen in the catalyst molecule also plays a key role. The method has the advantages of mild conditions, no addition of any additives, good yield, and high enantioselectivity.
Description
Technical Field
The invention relates to a method for synthesizing chiral phthaloyl ester compounds by dynamic kinetic resolution, belonging to the technical field of asymmetric synthesis in organic chemistry.
Background
The phthaloyl ester medicine is widely applied to clinic and mainly has the effects of easing pain and resisting inflammation. For example, tamsulosin is a prodrug with analgesic and anti-inflammatory properties, and tammetacin has antibacterial and anti-inflammatory effects. Few methods for synthesizing phthaloyl ester medicines are reported in the past.
Literature Angew.Chem., int.Ed.2020,59,3859-3863 discloses that the synthesis of phthalates requires the addition of an equivalent amount of oxidizing agent to ensure the reaction. Document Angew.Chem., int.Ed.2021,60,1641-1645 discloses that it is necessary to ensure that the process is carried out at ultra-low temperatures (-78 ℃) when obtaining products with a higher enantioselectivity.
Therefore, the development of a synthesis method with milder conditions for preparing chiral phthaloyl esters and derivatives thereof has important research significance.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a dynamic kinetic resolution method for catalyzing 3-hydroxyphthaloyl compounds by using a chiral ArPNO catalyst. The method is characterized in that racemic 3-hydroxyphthaloyl compound 1 and anhydride 2 are used as raw materials, dynamic kinetic resolution reaction is carried out under the catalysis of chiral ArPNO, chiral phthaloyl compound 3 is obtained, and tamsulosin ester and tammetacin prodrugs are synthesized. According to the ArPNO chiral catalyst disclosed by the invention, an oxygen atom in pyridine nitrogen oxide is used as a nucleophilic site to participate in dynamic kinetic resolution reaction, and meanwhile, hydrogen in a catalyst molecule plays a key role.
The method for synthesizing the chiral phthaloyl ester compound by dynamic kinetic resolution comprises the following steps of taking a racemized 3-hydroxyphthaloyl compound 1 and anhydride 2 as raw materials, and carrying out dynamic kinetic resolution reaction under the catalysis of a chiral catalyst ArPNO to obtain the chiral phthaloyl ester compound 3, wherein the reaction equation is as follows:
Wherein R 1 is selected from C1-C6 alkyl, halogenated alkyl, nitrile group, nitro or C1-C4 alkoxycarbonyl, R 2 is selected from C1-C4 alkyl, ar is selected from phenyl, substituted phenyl or diphenylmethyl, and the substituents in the substituted phenyl are selected from one or more of C1-C4 alkyl, C1-C4 alkoxy and phenyl substitution.
Further, among the above substituents, R 1 is preferably methoxycarbonyl group, nitrile group, methoxy group, halogen (fluorine, chlorine, bromine) substituted at the 5-position.
Further, in the above technical solution, the chiral catalyst ArPNO includes the following structure:
Further, in the above technical solution, the chiral catalyst ArPNO preferably has a structure of C2d.
Further, in the above technical scheme, the reaction is performed in an organic solvent selected from one or more of dichloromethane, tetrahydrofuran, mesitylene, or toluene.
Further, in the above-described schemes, the reaction is substantially equivalent to and somewhat reduced in yield and enantioselectivity in the presence of a base as compared to the absence of a base, e.g., 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).
Further, in the technical scheme, the molar ratio of the racemized 3-hydroxyphthaloyl compound 1 to the anhydride 2 is 1:1-4.
Further, in the above technical scheme, the reaction temperature is 10-25 ℃. Compared with the method for synthesizing chiral phthaloyl ester compounds reported before, the room temperature is milder than the ultralow temperature of-78 ℃, and the operability is stronger.
The invention also provides a method for synthesizing (R) -tamsulosin ester and (S) -tammetacin prodrug, which comprises the following steps that anhydride 2 in the scheme is changed into acyl chloride substrates corresponding to salicyloyl chloride and indometacin:
according to the technical scheme for synthesizing chiral phthaloyl ester compounds, chiral prodrug compounds (R) -tamsulosin and (S) -tamoxifen are respectively obtained in the presence of organic alkali, and the specific corresponding reaction structures are as follows:
further, in the above technical scheme, the organic base is selected from triethylamine or diisopropylethylamine.
The invention has the beneficial effects that:
1. the invention takes racemized 3-hydroxyphthaloyl and acyl chloride corresponding to salicyloyl chloride or indometacin as raw materials, and the chiral phthaloyl ester product can be obtained by dynamic kinetic resolution reaction at room temperature in one step. The raw materials of the reaction are easy to obtain, and the highest reaction yield and enantioselectivity can reach 92% ee and 92% ee respectively.
2. Unlike the prior ArPNO class of catalysts, the nitrogen on pyridine participates in nucleophilic reaction, the ArPNO class of chiral catalysts in the invention take advantage of oxygen atoms in pyridine nitrogen oxide as nucleophilic sites to participate in dynamic kinetic resolution reaction, and simultaneously hydrogen in catalyst molecules plays a key role.
Detailed Description
Example 1
Taking 3-hydroxyphthaloyl 1a and anhydride 2 as raw materials to generate phthaloyl ester 3 as an example, optimizing reaction conditions, and adopting the following reaction equation:
the specific reaction results are shown in the following table:
[a] Unless otherwise indicated, the reaction conditions were 1a (0.05 mmol), 2 (0.1 mmol), catalyst (10 mol%), base (1 eq) in organic solvent (0.5 mL) at room temperature for 10 hours, [ b ] nuclear magnetic resonance yield, [ c ] determined by chiral HPLC analysis, [ d ]2c (0.2 mmol).
In the screening process of the reaction conditions, the effect of the catalyst on the reaction was first examined (reference numerals 1 to 10). Meanwhile, by comparing the influence of the equivalent ratios of different solvents, alkali, anhydride and raw materials on the reaction, the method finally determines that C2d is the optimal catalyst, the addition amount is 10mol%, mesitylene is the optimal reaction solvent, no alkali is added, and 4 times of equivalent anhydride is the optimal reaction condition.
Investigation of reaction conditions (reference numeral 19, for example) in a 5mL dry reaction tube, chiral catalyst C2d (4.7 mg,0.01mmol,10 mol%), 3-hydroxyphthaloyl 1a (15.0 mg,0.1 mmol) and pivalic anhydride 2C (81.0. Mu.L, 0.4 mmol) were added, respectively, and then mesitylene (2.0 mL) was added, and the reaction solution was stirred at room temperature (25 ℃) for 10 hours. Column chromatography separation gave 22.5mg of white solid 3ac, yield 96％,97％ee.HPLC CHIR ALCEL IA,n-hexane/2-propanol＝90/10,flow rate＝0.6mL/min,λ＝256nm,retention time:10.338min(major),11.837min(minor).[α]D 21＝+78.72(c＝0.47,CHCl3).1H 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).13C 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.
Example 2
To a 5mL dry reaction tube were added chiral catalyst C2d (4.7 mg,0.01mmol,10 mol%), hydroxyphthaloyl 1b-n (0.1 mmol) and pivalic anhydride 2C (81.0. Mu.L, 0.4 mmol), respectively, and then mesitylene (2.0 mL) and the reaction solution was stirred at 25℃for 10 hours. And after the reaction is finished, obtaining a product after column chromatography. The specific reaction results are as follows:
Representative nuclear magnetic characterization data are as follows:
(S) -5-Fluoro-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 bc) white solid ,21.4mg,85％yield,93％ee;Rf＝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);1H 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).
(S) -6-Fluoro-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 cc) white solid ,m.p.:114.9-115.2℃;21.9mg,87％yield,94％ee;Rf＝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).1H 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).
(S) -5-Chloro-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 dc) white solid ,24.7mg,92％yield,93％ee;Rf＝0.70(Pet/EtOAc,5/1,v/v).HPLC CHIRALCEL IA,n-hexane/2-propanol＝95/5,flow rate＝0.8mL/min,λ＝250nm,retention time:9.956min(major),11.659min(minor).[α]D 22＝+32.45(c＝0.61,CHCl3).1H NMR(400MHz,CDCl3):δ7.89(d,J＝2.0Hz,1H),7.70(dd,J＝8.0,1.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.40(s,1H),1.24(s,9H).
(S) -6-Chloro-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 ec) white solid ;25.4mg,95％yield,92％ee;Rf＝0.71(Pet/EtOAc,5/1,v/v).HPLC CHIRALCEL AD-H,n-hexane/2-propanol＝90/10,flow rate＝0.8mL/min,λ＝256nm,retention time:7.405min(major),14.288min(minor).[α]D 22＝+90.39(c＝0.62,CHCl3).1H NMR(600MHz,CDCl3):δ7.90(d,J＝1.8Hz,1H),7.70(dd,J＝8.4,1.8Hz,1H),7.50(d,J＝8.4Hz,1H),7.40(s,1H),1.24(s,9H).13C NMR(150MHz,CDCl3):δ177.0,167.0,146.4,141.7,132.1,127.1,125.2,124.0,92.3,39.1,27.0.
(S) -4-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 fc) as a white solid ;m.p.:100.4-101.5℃;(29.3mg,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);1H NMR(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).13C 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.
(S) -5-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 gc) white solid ;m.p.:89.7-92.6℃;27.8mg,89％yield,97％ee;Rf＝0.78(Pet/EtOAc,3/1,v/v).HPLC CHIRALCEL 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).1H 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).13C 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.
(S) -6-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-YL PIVALATE (3 hc) white solid ;27.5mg,88％yield,94％ee;Rf＝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).1H NMR(600MHz,CDCl3):δ7.79(d,J＝1.2Hz,2H),7.72-7.71(m,1H),7.37(s,1H),1.26(s,9H).13C 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.
Example 3
To a 5mL dry reaction tube were added chiral catalyst C2d (4.7 mg,0.01mmol,10 mol%), 3-hydroxyphthaloyl chloride 1a (15.0 mg,0.1 mmol), salicyloyl chloride 4a (39.6 mg,0.2 mmol) and toluene (2.0 mL), respectively, and finally triethylamine (14. Mu.L, 0.1 mmol) was added and the reaction mixture was stirred at 25℃for 6 hours. Column chromatography separation gave 28.7g of a white solid 5aa, yield 92％,85％ee.HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝256nm,retention time:12.460min(major),14.637min(minor)[α]D 22＝+15.69(c＝0.48,CHCl3).1H NMR(400MHz,CDCl3):δ8.03(dd,J＝8.0,2.0Hz,1H),7.97(dt,J＝7.2,1.2Hz,1H),7.79-7.75(m,1H),7.70-7.66(m,2H),7.64-7.59(m,2H),7.31(td,J＝7.6,1.2Hz,1H),7.13(dd,J＝8.0,1.2Hz,1H),2.22(s,3H).13C NMR(100MHz,CDCl3):δ169.7,167.9,163.0,151.4,144.4,135.2,135.1,132.4,131.6,126.6,126.3,126.0,124.3,124.1,121.7,93.3,21.0.
Example 4
To a 5mL dry reaction tube were added chiral catalyst C2d (4.7 mg,0.01mmol,10 mol%), 3-hydroxyphthaloyl chloride 1a (15.0 mg,0.1 mmol), indomethacin-carbonyl chloride 4b (75.0 mg,0.2 mmol) and toluene (2.0 mL), respectively, and finally triethylamine (14. Mu.L, 0.1 mmol) was added, and the reaction solution was stirred at 25℃for 6 hours. Column chromatography separation gives 43.5mg of white solid 5ab in yield 89％,92％ee.HPLC CHIRALCEL IA,n-hexane/2-propanol＝60/40,flow rate＝0.8mL/min,λ＝256nm,retention time:15.310min(major),17.478min(minor).[α]D 22＝-21.31(c＝0.51,CHCl3).1H NMR(400MHz,CDCl3)：δ7.92(d,J＝7.6Hz,1H),7.72(td,J＝7.6,1.2Hz,1H),7.67-7.63(m,3H),7.49-7.45(m,3H),7.41(s,1H),6.91-6.87(m,2H),6.67(dd,J＝9.2,2.4Hz,1H),3.78(s,2H),3.76(s,3H),2.36(s,3H).13C NMR(100MHz,CDCl3):δ169.5,168.4,167.9,156.2,144.2,139.6,136.4,135.0,133.9,131.5,131.4,130.9,130.3,129.3,126.6,126.0,123.7,115.2,112.1,111.3,101.2,93.2,55.8,30.3,13.6.
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
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