Chiral 6-hydroxypyridoxazoline compounds, methods of preparation and use

Abstract

The application discloses a chiral 6-hydroxypyridine oxazoline compound, a preparation method and application. The chiral 6-hydroxypyridine oxazoline compound is synthesized by using 1-cyanopyridine containing a substituent group and chiral 2-aminethanol as starting materials, and a series of novel chiral 6-hydroxypyridine oxazoline compounds are synthesized. The preparation method disclosed by the application has the advantages that the starting materials are easily obtained on the market or are easy to prepare, the cost of preparing target molecules is reduced, the synthetic route is simple and efficient, the reaction condition is mild and the operation is simple, chemical waste generated in preparation is reduced, the target molecule 6-hydroxypyridine oxazoline is a kind of novel chiral compound, has a potential application prospect of assisting transition metal catalytic asymmetric synthesis, the types of substituents of the starting materials are rich, the requirement of a synthesis strategy on the diversity of target molecules is met, and the product can be used to prepare more complex molecules through functional group transformation.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of chiral 6-hydroxypyridine oxazoline compound, preparation method and application, belong to organic synthesis technical field. BACKGROUND

[0002] Pyridine oxazoline is the first reported chiral oxazoline ligand, as analogous to bipyridine and phenanthroline ligand, can be prepared from various pyridine derivatives and chiral amino alcohol by simple conversion, stereoisomer and charge effect can be adjusted, stable to oxidative conditions, its structure and performance have been constantly modified adjustment for decades, has been successfully applied to a large number of asymmetric catalytic reactions.In recent years, hydroxypyridine ligand gradually emerges in the auxiliary transition metal catalyzed carbon hydrogen bond activation reaction, bipyridine bidentate ligand containing hydroxypyridine has also been reported. SUMMARY

[0003] The present application discloses a series of novel chiral 6-hydroxypyridine oxazoline compounds are synthesized with substituted 1-cyanopyridine and chiral 2-aminoethanol as starting material, which is a kind of chiral ligand combining pyridine oxazoline and hydroxypyridine, has potential application prospect in the auxiliary transition metal catalyzed asymmetric synthesis; Its synthetic route is simple, less steps, high total yield.

[0004] In the present application, hydroxypyridine and pyridine oxazoline are combined to create a novel chiral 6-hydroxypyridine oxazoline compound, and the synthesis method is improved.

[0005] According to one aspect of the present application, a chiral 6-hydroxypyridine oxazoline compound is provided, which has the structure shown in formula I;

[0006] Formula I;

[0007] R 1 At least one selected from halogen, trifluoromethyl, nitro, methyl, methoxy, phenyl, naphthyl;

[0008] R 2 At least one selected from isopropyl, tert-butyl, benzyl, phenyl, naphthyl;

[0009] The halogen is at least one selected from fluorine, chlorine, bromine and iodine.

[0010] According to another aspect of the present application, a preparation method of the above-mentioned chiral 6-hydroxypyridine oxazoline compound is provided, which comprises the following steps:

[0011] (1) taking 1-cyanopyridine containing R 1a mixture of a 1-cyanopyridine having a substituent, an oxidant, and a solvent I, reaction I, to obtain a pyridine N-oxide B;

[0012] (2) the pyridine N-oxide B is subjected to a Polonovski reaction to obtain an acetoxy-containing compound C;

[0013] (3) the acetoxy-containing compound C is hydrolyzed under alkaline conditions to obtain a hydroxypyridine D;

[0014] (4) a mixture of the hydroxypyridine D, an amine ethyl alcohol having a substituent R 2 , a Lewis acid, and a solvent II, reaction II, to obtain the chiral 6-hydroxypyridine oxazoline compound.

[0015] Optionally, the amine ethyl alcohol having a substituent R 1 The 1-cyanopyridine having a substituent is selected from compounds as shown in formula II

[0016] Formula II;

[0017] wherein R 1 is at least one selected from halogen, trifluoromethyl, nitro, methyl, methoxy, phenyl, and naphthyl.

[0018] Optionally, the amine ethyl alcohol having a substituent R 2 is selected from compounds as shown in formula III;

[0019] Formula III;

[0020] wherein R 2 is at least one selected from isopropyl, tert-butyl, benzyl, phenyl, and naphthyl.

[0021] Optionally, in the step (1), the oxidant is at least one selected from hydrogen peroxide, meta-chloroperoxybenzoic acid, urea peroxide, and tert-butyl hydroperoxide.

[0022] Optionally, the 1-cyanopyridine having a substituent R 1 has a molar ratio of 1:3 to 1:5 with the oxidant.

[0023] Optionally, the solvent I is at least one selected from dichloromethane, dichloroethane, carbon tetrachloride, and chloroform.

[0024] Optionally, the 1-cyanopyridine having a substituent R 1 has a molar volume ratio of 0.1 to 0.3 mmol / mL with the solvent I.

[0025] Optionally, the amine ethyl alcohol having a substituent R 1The molar volume ratio of the 1-cyanopyridine to the solvent I is selected from any value or a range between any two values of the group consisting of 0.1 mmol / mL, 0.15 mmol / mL, 0.2 mmol / mL, 0.25 mmol / mL, 0.3 mmol / mL.

[0026] Optionally, in the step (3), the base in the basic condition is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide.

[0027] Optionally, the molar ratio of the acetoxy-containing compound C to the base is 1:3 to 1:5.

[0028] Optionally, the solvent in the step (3) is selected from at least one of isopropyl alcohol, tert-butyl alcohol, isobutyl alcohol, tert-amyl alcohol.

[0029] Optionally, in the step (4), the Lewis acid is selected from at least one of zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, magnesium chloride.

[0030] Optionally, the molar ratio of the hydroxypyridine D to the amine-containing ethyl alcohol containing R 2 The molar ratio of the amine-containing ethyl alcohol containing R

[0031] Optionally, the molar ratio of the hydroxypyridine D to the amine-containing ethyl alcohol containing R 2 The molar ratio of the amine-containing ethyl alcohol containing R is selected from any value or a range between any two values of the group consisting of 1:1.3, 1:1.5, 1:1.7, 1:2.

[0032] Optionally, the molar ratio of the hydroxypyridine D to the Lewis acid is 1:0.02 to 1:0.2.

[0033] Optionally, the molar ratio of the hydroxypyridine D to the Lewis acid is selected from any value or a range between any two values of the group consisting of 1:0.02, 1:0.04, 1:0.06, 1:0.08, 1:0.1, 1:0.15, 1:0.2.

[0034] Optionally, the solvent II is selected from xylene and / or toluene.

[0035] Optionally, the temperature of the reaction I is -20 to 20°C, and the time of the reaction I is 6 to 12 h.

[0036] Optionally, the temperature of the reaction I is selected from any value or a range between any two values of the group consisting of -20°C, -10°C, 0°C, 5°C, 10°C, 20°C.

[0037] Optionally, the time of the reaction I is selected from any value or a range between any two values of the group consisting of 6 h, 8 h, 10 h, 12 h.

[0038] Optionally, the temperature of the reaction II is 110-130℃, and the time of the reaction II is 12-24 h.

[0039] Optionally, the temperature of the reaction II is selected from any value of 110℃, 115℃, 120℃, 125℃, 130℃ or a range between any two of the above values.

[0040] Optionally, the time of the reaction II is selected from any value of 12 h, 14 h, 16 h, 18 h, 20 h, 24 h or a range between any two of the above values.

[0041] According to still another aspect of the present application, there is provided an application of the above-mentioned chiral 6-hydroxypyridine oxazoline compound or the chiral 6-hydroxypyridine oxazoline compound prepared by the above-mentioned preparation method in assisting transition metal catalyzed asymmetric synthesis.

[0042] The present application provides a preparation method for synthesizing 6-hydroxypyridine oxazoline, which comprises introducing a hydroxyl group at the 6th position of pyridine through Polonovski reaction from 1-cyanopyridine containing a substituent and chiral 2-aminethanol as starting materials, and then through condensation reaction. The starting materials have various substituents, are cheap and easy to obtain, and the synthesis route is short, the reaction is easy to operate, and the total yield is high. The target product 6-hydroxypyridine oxazoline is a new type of chiral compound, and the general structure is shown in formula T. The main structure is hydroxypyridine oxazoline, and the substituents R 1 at the 4th and 5th positions of pyridine can be hydrogen atoms, halogen atoms, or electron-withdrawing groups such as trifluoromethyl and nitro, or electron-donating groups such as methyl and methoxy, or aryl substituents such as benzene and naphthalene. The substituents R 2 at the oxazoline can be alkyl substituents such as isopropyl and tert-butyl, or aryl substituents such as benzene and naphthalene, and the chirality can be S configuration, or a racemic mixture. R configuration, or a racemic mixture.

[0043]

[0044] Formula T.

[0045] In the present application, the terms "methyl", "phenyl", "naphthyl", "isopropyl", "tert-butyl" and the like refer to groups formed by losing any one hydrogen atom from the molecules of methane, benzene, naphthalene, isopropane and tert-butane.

[0046] The beneficial effects that can be achieved by the present application include:

[0047] 1) The starting materials of the present application are commercially available and easy to prepare, which reduces the cost of preparing the target molecules.

[0048] 2) The synthetic route of the present application is simple and efficient, with mild reaction conditions and easy operation, reducing the chemical waste generated in preparation.

[0049] 3) The target molecule 6-hydroxypyridyloxazoline prepared in the present application is a new class of chiral compounds, which has potential application prospect in assisting transition metal catalyzed asymmetric synthesis.

[0050] 4) The starting material of the present application has a variety of substituents, which meets the requirement of the synthesis strategy for the diversity of the target molecule, and the product can be used to prepare more complex molecules through functional group transformation. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 Figure 1 is the HPLC spectrum of the racemic mixture of compound T1-4 in Example 4 of the present application. 1 H NMR).

[0052] Figure 2 Figure 2 is the HPLC spectrum of compound T1-4 in Example 4 of the present application. 13 C NMR).

[0053] Figure 3 Figure 3 is the HPLC spectrum of the racemic mixture of compound T1-4 in Example 4 of the present application.

[0054] Figure 4 Figure 4 is the HPLC spectrum of compound T1-4 in Example 4 of the present application. DETAILED DESCRIPTION

[0055] The present application will be described in detail below with reference to examples, but the present application is not limited to these examples.

[0056] Unless otherwise specified, the raw materials in the examples of the present application are purchased through commercial channels.

[0057] The analytical instruments and equipment used in this example are: nuclear magnetic resonance instrument, AVANCE III 400 MHz (TMS internal standard, Bruker Company); high resolution mass spectrometer, Impact II UHR-TOF (ESI source, Bruker Company); melting point instrument, AFSGHK (Shanghai Technology Co., Ltd.); high performance liquid chromatograph, Shimadzu LC-20AD; polarimeter, INESA SGW-1.

[0058] In the examples of the present application, room temperature refers to 25°C.

[0059] Specifically, the technical scheme adopted by the present application for preparing the above-mentioned compounds is as follows:

[0060] The R 1The 1-cyanopyridine A substituted with a group is oxidized to form a pyridine N-oxide B by an oxidant, which can be hydrogen peroxide, meta-chloroperbenzoic acid, urea-hydrogen peroxide, tert-butyl hydroperoxide, and the like, and the solvent can be dichloromethane, dichloroethane, and the like containing chlorine. Compound B is subjected to a Polonovski reaction to introduce an acetoxy group at the 6-position to obtain compound C. Compound C is hydrolyzed under alkaline conditions to obtain a hydroxypyridine D, and the base can be sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, and the solvent can be isopropanol, tert-butanol, and the like. Finally, the hydroxypyridine D is reacted with an amino alcohol E containing R 2 The amine group of the amino alcohol E substituted with a group is dehydrated under the catalysis of a Lewis acid to obtain the target compound T, and the Lewis acid is mainly zinc chloride, zinc trifluoromethanesulfonate, and the like, and the solvent is xylene, toluene, and the like with high boiling points. The specific synthesis route is as follows:

[0061]

[0062] Through the comparison of a large number of control experiments, the preferred scheme of the above technical route is determined as follows: dichloroethane (0.1-0.3 mol / L) is used as the solvent, urea-hydrogen peroxide (3-5 equivalents) is used as the oxidant, and trifluoroacetic anhydride (3-5 equivalents) is used under the action of -20-20 ℃ for 6-12 hours, and then ice water is used for quenching, and the pH value of the system is adjusted to 8-9 with a saturated NaHCO3 solution, so that the raw material 1-cyanopyridine A (1 equivalent) is almost quantitatively converted into pyridine oxide B; the crude product B obtained after washing, extraction, drying, and concentration can be directly heated to reflux (140 ℃) in acetic anhydride (8-15 equivalents), and the reaction is carried out for 48-72 hours, and then the crude product obtained after concentration is purified by silica gel column chromatography, and ethyl acetate / petroleum ether is used as the eluent to obtain compound C at a yield of 35-55%. The subsequent operation takes compound C as the reference substance (1 equivalent). Isopropanol / water (v / v = 1:1, 0.05-0.2 mol / L) is used as the solvent, lithium hydroxide (3-5 equivalents) is used as the base, and compound C is reacted at room temperature for 1-2 hours, and then the pH value of the system is adjusted to weak acidity (pH = 3-6) with dilute hydrochloric acid, and then hydrolysis product D is almost quantitatively obtained through extraction, drying, and concentration; compound D is reacted with amino alcohol E (1.3-2.0 equivalents) in toluene solution (0.05-0.2 mol / L) under the action of zinc chloride (0.02-0.2 equivalents) by heating to reflux (110 ℃) for 12-24 hours, and then the mother liquor after cooling is washed with a saturated sodium bicarbonate solution, and then the target compound T is obtained through extraction, drying, concentration, and silica gel column chromatography purification at a yield of more than 50%, with ethyl acetate / petroleum ether as the eluent.

[0063] Example 1: S -phenyl- 5 trifluoromethyl-6 Synthesis of hydroxyl-pyridoxazoline (T1-1)

[0064] To a solution of 5-trifluoromethyl-2-cyanopyridine (A1, 1.0 g, 5.8 mmol) and urea hydrogen peroxide (2.13 g, 23.2 mmol, 4 eq) in dichloroethane (DCE, 45 mL) was added trifluoroacetic anhydride (TFAA, 2.6 mL, 18.6 mmol, 3.2 eq) dropwise at 0 °C. The reaction was stirred at 0 °C for 12 h. The reaction was quenched with ice water, and the pH of the solution was adjusted to 8-9 with saturated NaHC03solution. The solution was extracted, dried, filtered, and concentrated to give crude product B1, which was dissolved in acetic anhydride (Ac20, 5.5 mL, 58.0 mmol, 10 eq) and heated to reflux (140 °C) for 60 h. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 : 15-1 : 10) as eluent to give yellow solid C1 (694 mg, 52% yield). Compound C1 (694 mg, 3.0 mmol) was dissolved in isopropanol (15 mL), and a solution of lithium hydroxide (LiOH-H20, 378 mg, 9.0 mmol, 3 eq) in water (15 mL) was added at 0 °C. The reaction was stirred at room temperature for 1 h. The pH of the solution was adjusted to weakly acidic (pH = 3-6) with dilute hydrochloric acid. The solution was extracted, dried, and concentrated to give hydrolysis product D1. Compound D1 and L-2-phenylglycinol (E1, 617 mg, 4.5 mmol, 1.5 eq) were dissolved in toluene (20 mL), and zinc chloride (ZnCl2, 82 mg, 0.6 mmol, 0.2 eq) was added. The reaction was heated to reflux (110 °C) for 16 h. The cooled mother liquor was washed with saturated NaHC03solution, extracted, dried, concentrated, and purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 : 10-1 : 5) as eluent to give yellow solid T1-1 (600 mg, 65% yield).

[0065] The characterization data of target compound T1-1 are as follows:

[0066] The enantiomeric excess of the product was determined by high performance liquid chromatography to be >99% (chiral column: Chiralpak column OD-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropanol = 80 / 20, flow rate: 1.0 mL / min, 40 °C, peak time: t major = 25.16 min, t minor = 14.41 min). [α]D 22 : +91.5 (c = 1.0, CHCl3). Mp: 184 o C~186 o C. 1 H NMR (400 MHz, CDCl3): δ = 10.77 (brs, 1H), 7.86 (d, J = 7.2 Hz, 1H),7.48–7.31 (m, 3 H), 7.31–7.16 (m, 2 H), 6.84 (d, J = 7.2 Hz, 1 H), 5.68 (dd, J =10.4, 8.4 Hz, 1H), 4.96 (dd, J = 10.4, 8.5 Hz,1 H), 4.41 (t, J = 8.5 Hz, 1 H). 13 CNMR (101 MHz, CDCl3): δ = 158.18, 157.96, 140.5, 139.3 (q, J = 5.2 Hz),135.9, 128.9, 128.1, 126.5, 124.6 (q, J = 31.3 Hz), 122.1 (q, J = 271.4 Hz),105.4, 76.2, 69.5. 19 F NMR (376 MHz, CDCl3): δ = -66.20. HRMS (ESI) m / z : [M+H] + Calcd for C 15 H 12 F3N2O2 + : 309.0845; Found: 309.0844.

[0067]

[0068] Example 2: (R)-isopropyl-3,3,3-trifluoro-2-hydroxy-pyrrolidin-1-yl S )-isopropyl- 5 trifluoromethyl- 6 Synthesis of hydroxyl-pyrrolooxazoline (T1-2)

[0069] The hydrolysate D1 in Example 1 was dissolved in toluene (20 mL) with L- valinol (E2, 620 mg, 6.0 mmol, 2 eq), zinc chloride (82 mg, 0.6 mmol, 0.2 eq) was added, heated to reflux (110 °C) for 20 hours, the mother liquor after cooling was washed with saturated sodium bicarbonate solution, then extracted, dried, concentrated, purified by silica gel column chromatography, ethyl acetate / petroleum ether as eluent (1:10-1:5), to obtain white solid T1-2 (450 mg, 55% yield) in 55% yield.

[0070] The characterization data of the target compound T1-2 are as follows:

[0071] The product enantiomeric excess value was determined by high performance liquid chromatography >99%, (chiral column: Chiralpak column AS-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 40 °C, peak time: t major = 6.82 min, t minor = 11.01 min). [α] D 22 : +33.3 (c = 1.0, CHCl3). Mp: 117 ℃~119 ℃. 1 H NMR (400 MHz, CDCl3): δ = 10.45 (brs, 1H), 7.82 (d, J = 7.2 Hz, 1H),6.74 (d, J = 7.2 Hz, 1H), 4.65–4.43 (m, 1H), 4.23 (m, 2H), 1.93–1.70 (m, 1H),1.01 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ =158.1, 157.0, 139.4 (q, J = 5.3 Hz), 136.2, 124.3 (q, J = 31.8 Hz), 122.2 (q, J =272.5 Hz), 105.1, 72.4, 72.2, 32.9, 18.48, 18.44. 19F NMR (376 MHz, CDCl3): δ =-66.11. HRMS (ESI) m / z : [M+H] + Calcd for C 12 H 14 F3N2O2 + : 275.1002; Found: 275.1001.

[0072]

[0073] Example 3: Synthesis of (1 S ,2 R )-indole- 5 trifluoromethyl- 6 hydroxyl-pyridine oxazoline (T1-3)

[0074] The hydrolysis product D1 in Example 1 was dissolved in toluene (20 mL) with (1 S ,2 R )-1-amino-2-indanol (E3, 582 mg, 3.9 mmol, 1.3 eq), zinc chloride (40 mg, 0.3 mmol, 0.1 eq) was added, and heated to reflux (110 ℃) for 12 hours. The mother liquor after cooling was washed with saturated sodium bicarbonate solution, then extracted, dried, concentrated, and purified by silica gel column chromatography with ethyl acetate / petroleum ether as eluent (1:10-1:5) to give white solid T1-3 (674 mg, 70% yield).

[0075] The characterization data of the target compound T1-3 are as follows:

[0076] The product enantiomeric excess value was determined by high performance liquid chromatography to be >99% (chiral column: Chiralpak column OD-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 40 ℃, peak time: t major = 16.84 min, t minor = 11.96 min). [α] D 22 : +16.3 (c = 1.0, CHCl3). Mp: 228℃~230 ℃. 1 H NMR (400 MHz, CDCl3): δ = 10.46 (brs, 1H), 7.78 (d, J= 7.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.28 (m, 3H), 6.75 (d, J = 7.2 Hz, 1H), 5.85 (d, J =7.7 Hz, 1H), 5.59 (t, J = 7.1 Hz, 1H), 3.52 (dd, J = 18.2, 6.7 Hz, 1H), 3.38 (d, J = 18.2 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ = 156.9, 156.5, 139.4, 138.3 (q, J =4.8 Hz), 138.2, 135.3, 128.0, 126.8, 124.5, 124.4, 123.4 (q, J = 31.7), 121.2(q, J = 271.6 Hz), 104.1, 84.6, 75.6, 38.3. 19 F NMR (376 MHz, CDCl3): δ = -66.13.HRMS (ESI) m / z [M+H] + Calcd for C 16 H 12 F3N2O2 + Found: 321.0845; Found: 321.0844.

[0077]

[0078] Example 4: ( S )-Terbutyl- 5 Trifluoromethyl- 6 Synthesis of hydroxy-pyridineoxazoline (T1-4)

[0079] The hydrolysis product D1 from Example 1 was combined with ( S)-tert-Leucinol (E4, 456 mg, 3.9 mmol, 1.3 eq) was dissolved in toluene (20 mL), zinc chloride (40 mg, 0.3 mmol, 0.1 eq) was added, heated to reflux (110 °C) for 12 h, the cooled mother liquor was washed with saturated sodium bicarbonate solution, then extracted, dried, concentrated, purified by silica gel column chromatography with ethyl acetate / petroleum ether as eluent (1:10-1:5) to give T1-4 as a white solid (822 mg, 95% yield).

[0080] As shown in Figures 1-4 , the characterization data of the target compound T1-4 are as follows:

[0081] The product enantiomeric excess value was >99% by HPLC (Chiralpak column OD-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 40 °C, peak time: t major = 8.51 min, t minor = 5.77 min). [α] D 22 : +7.64 (c = 1.0, CHCl3). Mp: 151 ℃~153 ℃. 1 H NMR (400 MHz, CDCl3): δ = 10.40 (brs, 1H), 7.82 (d, J = 7.2 Hz, 1H),6.73 (d, J = 7.2 Hz, 1H), 4.48 (dd, J = 10.0, 8.6 Hz, 1H), 4.31 (t, J = 8.5 Hz,1H), 4.23 (dd, J = 10.0, 8.4 Hz, 1H), 0.94 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ =157.9, 156.9, 139.5 (q, J = 5.1 Hz), 136.0, 124.3 (q, J = 31.0 Hz), 122.2 (q, J =272.2 Hz), 104.9, 75.9, 70.5, 34.0, 25.7. 19F NMR (376 MHz, CDCl3): δ = -66.12.HRMS (ESI) m / z [M+H] + Calcd for C 13 H 16 F3N2O2 + Found: 289.1158; Found: 289.1157.

[0082]

[0083] Example 5: ( S )-Phenyle 5 methyl- 6 Synthesis of hydroxy-pyridineoxazoline (T2-1)

[0084] At 0 °C, trifluoroacetic anhydride (2.6 mL, 18.6 mmol, 3.2 eq) was slowly added dropwise to a solution of 5-methyl-2-cyanopyridine (A2, 686 mg, 5.8 mmol) and urea peroxide (2.13 g, 23.2 mmol, 4 eq) in dichloroethane (45 mL). The reaction was carried out at 0 °C for 12 hours, quenched with ice water, and the pH of the system was adjusted to 8-9 with saturated sodium bicarbonate solution. After extraction, drying, filtration, and concentration, crude product B2 was obtained. This crude product was then directly dissolved in acetic anhydride (5.5 mL, 58.0 mmol, 10 eq) and heated under reflux (140 °C) for 60 hours. The concentrated crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether as eluent (1:15-1:10) to obtain a pale yellow solid C2 (562 mg, 55% yield) in 55% yield. Compound C2 (528 mg, 562 mg, 55% yield) was then purified by silica gel column chromatography. Compound D2 was obtained by dissolving L-2-phenylglycine (E1, 617 mg, 4.5 mmol, 1.5 eq) in isopropanol (15 mL) at 0 °C, adding an aqueous solution of lithium hydroxide (378 mg, 9.0 mmol, 3 eq), and reacting at room temperature for 1 hour. The pH of the system was then adjusted to weakly acidic (pH = 3-6) with dilute hydrochloric acid. The mixture was extracted, dried, and concentrated to obtain the hydrolysis product D2. Compound D2 was dissolved in toluene (20 mL) with L-2-phenylglycine (E1, 617 mg, 4.5 mmol, 1.5 eq), and zinc chloride (82 mg, 0.6 mmol, 0.2 eq) was added. The mixture was heated under reflux (110 °C) for 16 hours. The cooled mother liquor was washed with saturated sodium bicarbonate solution, and then purified by extraction, drying, concentration, and silica gel column chromatography. Ethyl acetate / petroleum ether was used as the eluent (1:10-1:5) to obtain a pale yellow solid T2-1 (445 mg, 58% yield) in 58% yield.

[0085] The characterization data of the target compound T2-1 are as follows:

[0086] High performance liquid chromatography (HPLC) determination of enantiomeric excess of the product >99% (chiral column: Chiralpak column OD-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropanol = 90 / 10, flow rate: 1.0 mL / min, 40 ℃, peak time: t major = 21.82 min, t minor = 25.76 min). [α] D 22 : +149.8 (c = 1.0, CHCl3). Mp:125 o C~127 o C. 1 H NMR (400 MHz, CDCl3): δ = 7.23-7.36 (m, 6H), 6.74 (d, J = 7.2 Hz, 1H), 5.52 (t, J = 8.4 Hz, 1 H), 4.85 (dd, J = 10.2, 8.4 Hz, 1 H), 4.30 (t, J = 8.4Hz, 1 H), 2.20 (s, 3 H). 13 CNMR (101 MHz, CDCl3): δ = 161.4, 158.0, 140.1,135.8, 134.5, 128.7, 127.9, 127.7, 125.5, 106.7, 74.8, 68.6, 16.1. HRMS (ESI) m / z [M+Na] + Calcd for C 15 H 14 N2NaO2 + Found: 277.0947; Found: 277.0949.

[0087]

[0088] Example 6: ( R )-Benzyl- 5 methyl- 6 Synthesis of hydroxy-pyridineoxazoline (T2-2)

[0089] The hydrolysis product D2 in Example 5 was dissolved in toluene (20 mL) with D-(+)-2-benzylglycinol (E5, 590 mg, 3.9 mmol, 1.3 eq), zinc chloride (40 mg, 0.3 mmol, 0.1 eq) was added, heated to reflux (110 °C) for 16 h, the mother liquor after cooling was washed with saturated sodium bicarbonate solution, then extracted, dried, concentrated, purified by silica gel column chromatography, ethyl acetate / petroleum ether as eluent (1:10-1:5), to give white solid T2-2 (440 mg, 55% yield) in 55% yield.

[0090] The characterization data of the target compound T2-2 are as follows:

[0091] The product enantiomeric excess value was determined by high performance liquid chromatography >99%, (chiral column: Chiralpak column OD-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropyl alcohol = 90 / 10, flow rate: 1.0 mL / min, 40 °C, peak time: t major = 21.55 min, t minor = 14.35 min). [α] D 22 : -34.1 (c = 1.0, CHCl3). Mp: 62 ℃~64 ℃. 1 H NMR (400 MHz, CDCl3): δ = 7.17-7.29 (m, 6H), 6.61 (d, J = 6.8 Hz, 1H),4.60-4.68 (m, 1H), 4.41 (t, J = 8.4Hz, 1H), 4.13 (t, J = 8.4 Hz, 1H), 3.05 (dd, J =13.8, 6.3 Hz, 1H), 2.75 (dd, J = 13.8, 6.3 Hz, 1H), 2.16 (s, 3 H). 13 C NMR (101MHz, CDCl3): δ = 161.4, 157.3, 136.2, 135.9, 134.1, 128.9, 128.2, 127.6,125.7, 106.4, 72.0, 66.5, 40.4, 16.1. HRMS (ESI) m / z : [M+Na]+ Calcd for C 16 H 16 N2NaO2 + : 291.1104; Found: 291.1107.

[0092]

[0093] Application of chiral 6-hydroxypyridyloxazoline compound T1-4 prepared by the above preparation method (Example 4) in assisted transition metal catalyzed asymmetric synthesis:

[0094] Example 7: N -tert-butoxycarbonyl-(6 S )-phenyl-2,5-dihydropyridinone (G)

[0095] Into a 10 mL flask was added palladium acetate (2.7 mg, 0.012 mmol, 0.06 eq), copper trifluoromethanesulfonate (2.2 mg, 0.006 mmol, 0.03 eq), 6-hydroxypyridyloxazoline compound T1-4 (5.8 mg, 0.02 mmol, 0.1 eq), 50 mg of 3A molecular sieves, and N , N dimethylformamide (1 mL) at room temperature. The mixture was stirred under an oxygen atmosphere for 10 minutes, followed by the addition of N -tert-butoxycarbonyl-3,4-dihydropyridinone (F, 40 mg, 0.20 mmol, 1.0 eq) and phenylboronic acid (49 mg, 0.40 mmol, 2.0 eq) in N , N dimethylformamide (1 mL) at room temperature. The mixture was stirred under an oxygen atmosphere for 36 hours. Purification by concentration and silica gel column chromatography with ethyl acetate / petroleum ether as eluent (1:5) gave the target product G (20 mg) in 36% yield and an enantiomeric excess value of >99%.

[0096] Compound G is a known compound, and the characterization data are as follows:

[0097] The enantiomeric excess value of the product was determined by high performance liquid chromatography to be >99% (chiral column: Chiralpak column OJ-H, absorption wavelength: λ = 254 nm, eluent: n-hexane / isopropyl alcohol = 96 / 4, flow rate: 0.6 mL / min, 40 °C, peak time: t major = 21.16 min, t minor = 24.22 min). [α]D 22 : +85.5 (c = 1.0, CHCl3). Mp: 88 ℃~90℃. 1 H NMR (400 MHz, CDCl3): δ = 7.19-7.44 (m, 5H), 6.47-6.51 (m, 1H), 6.02(dd, J = 9.9, 2.9 Hz, 1H), 5.60 (d, J = 6.6 Hz, 1H), 3.00-3.08 (m, 1H), 2.68(ddd, J = 18.4, 6.2, 2.3 Hz, 1H), 1.45 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ =163.8, 152.5, 140.9, 140.0, 128.5, 127.4, 126.5, 125.8, 83.2, 56.6, 31.7,27.9.

[0098]

[0099] The above is only a few embodiments of the present application, not any form of the application does not limit, although the application is disclosed as above, however, not to limit the application, any skilled in the art, without departing from the scope of the application, using the above disclosed technical content of a little change or modification are equivalent to equivalent embodiments, all within the scope of the technical solutions.

Claims

1. A chiral 6-hydroxypyridoxazoline compound, characterized in that, The chiral 6-hydroxypyridine oxazoline compound has a structure shown in formula I. Formula I; R 1 at least one selected from halogen, trifluoromethyl, methyl, methoxy; R 2 at least one selected from the group consisting of isopropyl, tert-butyl, benzyl, phenyl, naphthyl; The halogen is at least one selected from fluorine, chlorine and bromine.

2. The process for the preparation of chiral 6-hydroxypyridoxazoline compounds according to claim 1, characterized in that, The preparation method comprises the following steps: (1) reacting a 1-cyanopyridine containing R 1 substituent, an oxidizing agent, and solvent I, reaction I, to yield pyridine N-oxide B; (2) The pyridine N-oxide B is subjected to Polonovski reaction to obtain an acetoxy-containing compound C; (3) The acetoxy-containing compound C is hydrolyzed under alkaline conditions to obtain a hydroxypyridine D; (4) reacting a mixture comprising hydroxypyridine D, an amine group ethanol containing R 2 substituents, a Lewis acid, and a solvent II, reaction II, to obtain said chiral 6-hydroxypyridine oxazoline compound.

3. The preparation method according to claim 2, characterized in that, In the step (1), the oxidant is at least one selected from hydrogen peroxide, meta-chloroperoxybenzoic acid, urea peroxide and tert-butyl hydroperoxide.

4. The preparation method according to claim 2, characterized in that, said R 1 the molar ratio of the 1-cyanopyridine containing R substituent to the oxidizing agent is 1 :3 to 1 :

5. The solvent I is at least one selected from dichloromethane, dichloroethane, carbon tetrachloride and chloroform; said R 1 The molar volume ratio of the 1-cyanopyridine containing R substituent to the solvent I is 0.1 to 0.3 mmol / mL.

5. The preparation method according to claim 2, characterized in that, In the step (3), the base in the alkaline condition is at least one selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.

6. The preparation method according to claim 2, characterized in that, The molar ratio of the acetoxy-containing compound C to the base is 1:3 to 1:

5. The solvent in the step (3) is at least one selected from isopropyl alcohol, tert-butyl alcohol, isobutyl alcohol and tert-amyl alcohol.

7. The preparation method according to claim 2, characterized in that, In the step (4), the Lewis acid is at least one selected from zinc chloride, zinc trifluoromethanesulfonate, zinc acetate and magnesium chloride.

8. The preparation method according to claim 2, characterized in that, The compound containing hydroxypyridine D and R 2 The molar ratio of substituents to aminoethanol is 1:1.3 to 1:2; The molar ratio of the hydroxypyridine D to the Lewis acid is 1:0.02 to 1:0.

2.

9. The preparation method according to claim 2, characterized in that, The solvent II is selected from xylene and / or toluene.

10. The method of claim 2, wherein, The temperature of the reaction I is -20 to 20°C, and the time of the reaction I is 6 to 12 hours. The temperature of the reaction II is 110 to 130°C, and the time of the reaction II is 12 to 24 hours.

11. The chiral 6-hydroxypyridine oxazoline compound of claim 1 or the chiral 6-hydroxypyridine oxazoline compound prepared by the preparation method of any one of claims 2 to 10 is applied to assist transition metal catalyzed asymmetric synthesis.

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