Chiral 1,4-benzoxazepine compounds, preparation and use thereof

Abstract

The application relates to a chiral 1,4-benzoxazepine compound and preparation and application thereof, which has a structure as shown in formula 1: wherein R 1 is one of a phenyl group, a p-methylphenyl group and a p-methoxyphenyl group; R 2 , R 3 are each independently one of a methyl group and a methoxy group; and R 4 is one of a p-nitrobenzenesulfonyl group and a p-toluenesulfonyl group. Compared with the prior art, raw materials of the application are easy to prepare, the catalyst has low consumption, high catalytic efficiency, flexible stereoselectivity control, simple ligand modification, and the additional acid catalyst is equivalent.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a chiral 1,4-benzoxazine Compounds and their preparation and applications. Background Technology

[0002] Benzene-based The compound possesses a wide range of medicinal and physiological activities. These include properties such as antidepressant, anticonvulsant, anti-anxiety, analgesic, hypnotic, sedative, anti-neurotic, and anti-inflammatory effects. For example, the squalene synthase inhibitor TAK-475 has been used to lower plasma cholesterol levels (see: doi.org / 10.1021 / op2001673); furthermore, studies have shown that Bozepinib has high anti-breast cancer cell proliferation activity (see: doi.org / 10.1016 / j.ejmech.2010.11.011); (1,2,3,5-tetrahydro-1,4-benzoxazine) (-3-methyl)pyrimidines possess high anticancer activity (see literature: doi.org / 10.1016 / j.bmcl.2007.12.070). Benzene-based... The compounds associated with these drugs have shown minimal side effects during use, attracting considerable attention from the pharmaceutical community. However, existing literature indicates that cycloaddition reactions can lead to the formation of benzoxazine due to unfavorable entropy factors and transcyclic interactions. There are relatively few studies on the reaction of this compound, and the synthesis of chiral benzo[a]hexane via catalytic asymmetric [4+3] cycloaddition reaction is limited. Even fewer compounds have been reported.

[0003] Therefore, the development of transition metal-catalyzed asymmetric [4+3] cycloaddition reactions for the synthesis of benzene-specific compounds is necessary. Synthetic methods for compounds are of significant research importance. The main synthetic methods reported in the literature include the following:

[0004] (I) In 2016, Glorius et al. synthesized a series of benzo[4+3] cycloaddition reactions using vinylbenzoxazinone and α,β-unsaturated aldehydes as starting materials, under the synergistic effect of palladium catalyst, nitrogen heterocyclic carbene catalyst, and Cs2CO3, through asymmetric [4+3] cycloaddition reactions. Derivative compounds (see reference: doi.org / 10.1002 / adsc.201800337).

[0005] (II) In 2018, Li Pengfei et al. synthesized a series of benzo[a]heterocyclic compounds with high yield and high enantioselectivity through the asymmetric [4+3] cycloaddition of indoleenal with o-hydroxyphenyl-substituted p-methylenequinone compounds under the catalysis of nitrogen-containing heterocyclic carbenes. Derivatives. (See reference: doi.org / 10.1002 / adsc.201800337)

[0006] (III) In 2018, Jiang Xianxing et al., starting from alkynyl-substituted benzoxazinone substrates and azomethylimine compounds, synthesized a series of benzoxazinone compounds through asymmetric [4+3] cycloaddition reactions under the synergistic catalysis of copper and chiral nitrogen heterocyclic carbene catalysts. Compound. (See reference: doi.org / 10.1021 / acs.orglett.8b02828.)

[0007] (IV) In 2021, Deng Weiping et al. synthesized a series of chiral benzo[a]hexane derivatives by asymmetric [4+3] cycloaddition reactions of 4-indolylallyl alcohol and iminomalonate derivatives through the synergistic catalysis of iridium catalyst and Zn(OTf)2. Compound. (See reference: doi.org / 10.1021 / acs.orglett.0c04132.)

[0008] (V) In 2024, Guo Hongchao's research group used 4-vinylbenzodioxanone and azomethylimine as raw materials to obtain 1,3,4-benzoxadiazine with excellent diastereoselectivity and enantioselectivity. Derivatives. (See reference: doi.org / 10.1039 / D3CC06012H.)

[0009] In summary, the current synthesis of benzene-specific heterocyclic compounds... The compounds can be synthesized mainly through the methods described above. However, some of these reactions have drawbacks, such as the difficulty in obtaining raw materials, the complexity of the preparation process, the need to add an equivalent amount of base or acid to promote the reaction, and the complexity of the reaction system. Furthermore, the synthesized benzoxazine... Many compounds are not chiral. Summary of the Invention

[0010] The purpose of this invention is to overcome the shortcomings of the prior art and provide a chiral 1,4-benzoxazine. The present invention relates to compounds, their preparation, and applications. The reaction raw materials are readily prepared, the catalyst dosage is low, the catalytic efficiency is high, the stereoselectivity is flexibly controlled, and the ligand modification is simple. Furthermore, the additional acid catalyst is equivalent in amount. The chiral 1,4-benzoxazine synthesized by the method of the present invention... The compound has good development potential and application prospects in the fields of organic synthesis and biomedical materials.

[0011] The objective of this invention can be achieved through the following technical solutions:

[0012] This invention provides a chiral 1,4-benzoxazine The compound has the structure shown in Formula 1:

[0013]

[0014] In the formula, R 1 It is one of phenyl, p-methylphenyl, and p-methoxyphenyl;

[0015] R 2 R 3 Each is independently either methyl or methoxy;

[0016] R 4 It is one of p-nitrobenzenesulfonyl or p-toluenesulfonyl.

[0017] Furthermore, the compound is selected from the group consisting of:

[0018]

[0019] The present invention further provides a chiral 1,4-benzoxazine as described above. The method for preparing the compound includes the following steps:

[0020] Under nitrogen protection, a mixture of o-aminobenzyl alcohol, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive was reacted in an organic solvent via an intermolecular asymmetric [4+3] cycloaddition reaction. The mixture was extracted and purified by silica gel column chromatography to obtain chiral 1,4-benzoxazine. Compounds.

[0021] Furthermore, the catalyst is [Ir(COD)Cl]2, and the ligand is a Carreira ligand.

[0022] Furthermore, the first additive is TMSOTf, and the second additive is Ti(O) i Pr)4.

[0023] Furthermore, the organic solvent is 1,2-dichloroethane.

[0024] Furthermore, the molar ratio between the o-aminobenzyl alcohol compound, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive is 1:(2-4):(0.01-0.03):(0.06-0.10):(0.1-0.3):(0.1-0.3).

[0025] Furthermore, the conditions for the addition reaction are as follows:

[0026] The reaction temperature is 5–15°C, and the reaction time is 8–16 h.

[0027] Furthermore, it also includes:

[0028] After monitoring with TLC until the raw material completely disappeared, it was quenched with water and then extracted.

[0029] The present invention also provides a chiral 1,4-benzoxazine as described above. Application of compounds in lowering plasma cholesterol.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The chiral 1,4-benzoxazine obtained in this application These compounds have good development potential and application prospects in organic synthesis, biomedicine, and materials science, and benzoxazine is one of the best existing technologies. Many compounds are not chiral.

[0032] 2. This application achieves chiral 1,4-benzoxazine using inexpensive and readily available polysubstituted o-aminobenzyl alcohol compounds and non-toxic and easy-to-handle liquid alkenyl ethylene oxide reagents as raw materials. The synthesis of compounds is achieved with low catalyst dosage, high catalytic efficiency, flexible stereoselectivity control, and simple ligand modification. In particular, the additional acid catalyst does not need to be added in excess. Attached Figure Description

[0033] Figure 1 The chiral 1,4-benzoxazine provided by the present invention A schematic diagram of the compound preparation process.

[0034] Figure 2 The compound prepared in Example 1 1 H spectrum.

[0035] Figure 3 The compound prepared in Example 1 13 C-spectrum. Detailed Implementation

[0036] To facilitate understanding of this application, it will be described more fully below through embodiments. However, this application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0037] For simplicity, this application only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly stated; and any lower limit can be combined with other lower limits to form a range not explicitly stated, just as any upper limit can be combined with any other upper limit to form a range not explicitly stated. Furthermore, although not explicitly stated, every point or individual value between the endpoints of the range is included within that range. Therefore, each point or individual value can be used as its own lower or upper limit and combined with any other point or individual value or with other lower or upper limits to form a range not explicitly stated.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. It should be noted that, unless otherwise stated, the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items, "above," "below," includes the stated number, and "one or more" with "multiple" means two or more.

[0039] The reagents involved in the following implementation methods and examples are shown below:

[0040]

[0041] Homemade reagents, as shown below:

[0042] The synthetic steps of N-(2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide:

[0043] Under nitrogen protection, a magnetic stir bar was added to a 250 mL three-necked flask, and the mixture was dried under reduced pressure using a hot gun, with nitrogen purging performed three times. After the flask returned to room temperature, 2-aminobenzyl alcohol (1.0 eq, 30 mmol) and anhydrous DCM (90 mL) were added sequentially. After the reaction mixture was stirred thoroughly, anhydrous pyridine (1.2 eq, 36 mmol) was added. The reaction mixture was then cooled to 0 °C, and p-toluenesulfonyl chloride (1.0 eq, 30 mmol) was added to the reaction mixture in small amounts multiple times under a nitrogen atmosphere. The reaction was then brought back to room temperature and stirred. The reaction was monitored by TLC until the starting material disappeared. The reaction was stopped, and water (50 mL) was added to the mixture to separate the organic phase. The organic phase was extracted three times with DCM, and the organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by concentration under reduced pressure to obtain N-(2-(hydroxymethyl)phenyl)-p-toluenesulfonamide, which could be directly used for the next reaction without further purification.

[0044] In air, a magnetic stir bar, the N-(2-(hydroxymethyl)phenyl)-p-toluenesulfonamide (1.0 eq, 28 mmol) obtained in the previous step, CHCl3 (84 mL), and silica gel of equal mass to PCC were added sequentially to a 250 mL round-bottom flask. The reaction mixture was stirred until homogeneous. Then, PCC (3.0 eq, 84 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature. The reaction was monitored by TLC until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through a sintered glass funnel containing silica gel, the filtrate was dried over anhydrous Na2SO4, the solvent was removed by concentration under reduced pressure, and the solution was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain N-(2-formylphenyl)-p-toluenesulfonamide.

[0045] Under nitrogen protection, a magnetic stir bar was added to a 250 mL three-necked flask, and the mixture was dried under reduced pressure using a hot gun, with nitrogen purging performed three times. After the flask returned to room temperature, N-(2-formylphenyl)-p-toluenesulfonamide (1.0 eq, 25 mmol) and anhydrous THF (75 mL) obtained in the previous step were added. The reaction mixture was stirred thoroughly and then cooled to 0 °C in an ice-water bath. At 0 °C, a tetrahydrofuran solution of magnesium phenyl bromide (2.0 eq, 50 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to return to room temperature. The reaction was monitored by TLC until the starting material disappeared. After the reaction was complete, 50 mL of saturated NH4Cl solution was slowly added dropwise to the reaction mixture at 0 °C. The organic phase was separated, extracted three times with EA, and the organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by concentration under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1-5:1) to obtain product 1a.

[0046] White solid, 7.78 g, yield: 88%; 1

[0047] H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.48-7.43 (m, 3H), 7.34-7.28 (m, 3H), 7.21 (t, J = 7.8Hz, 1H), 7 .18-7.10(m,4H),7.04-7.00(m,1H),6.94-6.91(m,1H),5.67(s,1H),2.88(brs,1H),2.37(s,3H);

[0048] 13 C NMR (101MHz, CDCl3) δ143.7,141.1,136.6,135.8,133.1,129.5,129.2,129.1,128.6,128.0,127.2,126.3,124.6,122.1,74.7,21.6.

[0049] Synthetic steps of N-(2-(hydroxy)phenyl)methyl)phenyl)-p-nitrobenzenesulfonamide:

[0050] The experimental procedure was the same as above: p-nitrobenzenesulfonyl chloride (1.0 equiv, 5 mmol), phenyl magnesium bromide in tetrahydrofuran solution (2.0 equiv, 8 mmol), silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-3:1), pale orange solid, 1.53 g, yield: 88%, mp: 131-133℃.

[0051] 1 H NMR (400MHz, CDCl3) δ8.56 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.68-7.51 (m, 3H), 7.33-7.16 (m, 4H), 7.14-7.02 (m, 4H), 5.77 (s, 1H), 3.06 (s, 1H);

[0052] 13 C NMR (101MHz, CDCl3) δ150.0,145.0,140.9,135.4,132.0,129.8,129.5,128.8,128.2,128.0,125.9,124.9,124.2,121.0,75.7;

[0053] IR(KBr,cm -1 )3511,3141,1528,1449,1403,1347,1305,1245,1162,1089,1013,854,768,740,697,616,605,553;

[0054] HRMS(ESI): m / z Calcd for C 19 H 20 N3O5S[M+NH4] + 402.1118; found 402.1114.

[0055] Synthetic steps of N-(2-(hydroxy(p-tolyl)methyl)phenyl)-p-toluenesulfonamide:

[0056] The experimental procedure was the same as above. p-Toluene-magnesium bromide was dissolved in tetrahydrofuran solution (2.0 equiv, 6 mmol), and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1-3:1). The product was a white solid, 1.03 g, yield: 94%.

[0057] 1H NMR(400MHz, CDCl3)δ8.07(s,1H),7.47(d,J=8.1Hz,3H),7.21(t,J=7.8Hz,1H),7.16-7.08(m,4H),7.05- 6.98(m,3H),6.91(d,J=7.7Hz,1H),5.60(d,J=2.9Hz,1H),2.80(d,J=2.9Hz,1H),2.38(s,3H),2.36(s,3H)

[0058] 13C NMR (101MHz, CDCl3) δ143.5,138.0,137.5,136.5,135.8,133.1,129.4,129.3,128.9,128.8,127.1,126.2,124.5,121.9,74.5,21.5,21.1.

[0059] Synthesis of N-(2-(hydroxy(4-methoxyphenyl)methyl)phenyl)-p-toluenesulfonamide

[0060] The experimental procedure was the same as above. 4-Methoxyphenyl magnesium bromide in tetrahydrofuran solution (2.0 equiv, 6 mmol), silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-3:1), white solid, 1.07 g, yield: 93%;

[0061] 1H NMR (400MHz, CDCl3) δ8.10(s,1H),7.48(d,J=8.0Hz,3H),7.21(t,J=7.6Hz,1H),7.14(d,J=7.9Hz,2H),7.09-6.97(m,3H ),6.91(d,J=7.7Hz,1H),6.81(d,J=8.3Hz,2H),5.59(d,J=3.2Hz,1H),3.81(s,3H),2.81(d,J=3.2Hz,1H),2.38(s,3H);

[0062] 13C NMR (101MHz, CDCl3) δ159.4,143.7,136.7,135.9,133.2,129.6,129.0,127.8,127.3,124.6,122.0,114.1,74.5,55.4,21.7.

[0063] Synthetic steps of N-(2-(hydroxy(phenyl)methyl)-4-methylphenyl)-p-toluenesulfonamide:

[0064] The experimental procedure was the same as above. The tetrahydrofuran solution of phenyl magnesium bromide (2.0 equiv, 7.6 mmol) was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-5:1). The solid was white, 1.34 g, yield: 91%.

[0065] 1 H NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.46 (d, J = 8.3Hz, 2H), 7.35-7.23 (m, 4H), 7.19-7.12 (m, 4H), 6.99 (dd,J=8.3,2.1Hz,1H),6.74(d,J=2.0Hz,1H),5.65(s,1H),2.95(brs,1H),2.38(s,3H),2.20(s,3H);

[0066] 13 C NMR (101MHz, CDCl3) δ143.7,141.4,136.6,135.0,134.3,132.9,129.74,129.66,129.6,128.7,127.8,127.3,126.4,123.1,74.2,21.6,21.0.

[0067] Synthetic steps of N-(2-(hydroxy(phenyl)methyl)-4-methoxyphenyl)-p-toluenesulfonamide:

[0068] The experimental procedure was the same as above. The tetrahydrofuran solution of phenyl magnesium bromide (2.0 equiv, 8 mmol) was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-3:1). The result was a white solid, 1.41 g, with a yield of 92%.

[0069] 1 H NMR (400MHz, CDCl3) δ7.49 (d, J=8.0Hz, 2H), 7.33-7.25 (m, 4H), 7.20-7.10 (m, 5H), 6.70 (dd, J=8.8, 3.0 Hz,1H),6.49(d,J=3.0Hz,1H),5.58(d,J=3.7Hz,1H),3.66(s,3H),2.99(d,J=3.9Hz,1H),2.40(s,3H);

[0070] 13 C NMR (101MHz, CDCl3) δ157.7,143.8,141.3,138.6,136.6,129.7,128.7,127.9,127.6,127.4,126.64,126.57,114.8,113.4,73.15,55.5,21.7.

[0071] Synthetic steps of N-(2-(hydroxy(phenyl)methyl)-5-methylphenyl)-p-toluenesulfonamide:

[0072] The experimental procedure was the same as above. The tetrahydrofuran solution of phenyl magnesium bromide (2.0 eq, 4.6 mmol) was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-3:1). The solid was white, 828.38 mg, yield: 94%.

[0073] 1H NMR(400MHz, CDCl3)δ8.02(s,1H),7.46-7.43(m,2H),7.30-7.27(m,4H),7.14-7. 12(m,4H),6.83-6.75(m,2H),5.60(s,1H),2.85(s,1H),2.37(s,3H),2.26(s,3H);

[0074] 13C NMR (101MHz, CDCl3) δ143.7,141.4,136.6,135.0,134.3,132.9,129.8,129.7( 2C),129.5,128.6(2C),127.8,127.3(2C),126.4(2C),123.1,74.2,21.6,21.0.

[0075] Synthetic steps of N-(2-(hydroxy(phenyl)methyl)-5-methoxyphenyl)-p-toluenesulfonamide:

[0076] The experimental procedure was the same as above. The tetrahydrofuran solution of phenyl magnesium bromide (2.0 eq, 4.6 mmol) was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1-3:1). The solid was white, 828.30 mg, yield: 94%.

[0077] 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.48-7.45(m,2H),7.32-7.29(m,3H),7.16-7.13(m,4H),7.08(d,J=2.6Hz ,1H),6.77(d,J=8.6Hz,1H),6.52(dd,J=8.5,2.6Hz,1H),5.61(s,1H),3.74(s,3H),2.61(s,1H),2.38(s,3H);

[0078] 13 C NMR (101MHz, CDCl3) δ157.6,143.8,141.4,138.6,136.5,129.7(2C),128.6(2C ),127.8,127.6,127.4(2C),126.5(2C),126.4,114.8,113.4,73.1,55.4,21.6.

[0079] Benzene-based The compound possesses an extremely wide range of medicinal value and physiological activities. These include properties such as antidepressant, anticonvulsant, anti-anxiety, analgesic, hypnotic, sedative, anti-neurotic, and anti-inflammatory effects. (Benzene-derived compound) The compounds involved in the drug have few side effects during use, which has attracted considerable attention from the pharmaceutical community. However, due to unfavorable entropy factors and transcyclic interactions, the cycloaddition reaction in the existing technology generates benzoxazine. There are relatively few studies on the reaction of this compound, and most reaction routes involve difficult and expensive raw material sources, complex preparation processes, and the need to add an equivalent amount of base or acid to promote the reaction. These conditions are harsh, the systems are complex, and existing technologies for synthesizing benzoxazepam are limited. Many compounds are not chiral.

[0080] Based on this, the first aspect of the embodiments of this application provides a chiral 1,4-benzoxazine The compound has the structure shown in Formula 1;

[0081]

[0082] In the formula, R 1 It is one of phenyl, p-methylphenyl, and p-methoxyphenyl;

[0083] R 2 R 3 Each is independently either methyl or methoxy;

[0084] R 4 It is one of p-nitrobenzenesulfonyl or p-toluenesulfonyl.

[0085] In some embodiments, the compound is selected from the group consisting of:

[0086]

[0087] The chiral 1,4-benzoxazine obtained in the embodiments of this application The compound can bring at least the following beneficial effects:

[0088] The chiral 1,4-benzoxazine obtained in this application These compounds have good development potential and application prospects in organic synthesis, biomedicine, and materials science, and benzoxazine is one of the best existing technologies. Many compounds are not chiral.

[0089] A second aspect of this application provides a chiral 1,4-benzoxazine as described above. The method for preparing the compound includes the following steps:

[0090] Under nitrogen protection, a mixture of o-aminobenzyl alcohol, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive was reacted in an organic solvent via an intermolecular asymmetric [4+3] cycloaddition reaction. The mixture was extracted and purified by silica gel column chromatography to obtain chiral 1,4-benzoxazine. Compounds.

[0091] In some embodiments, the catalyst is [Ir(COD)Cl]2.

[0092] In some implementations, the ligand is a Carreira ligand.

[0093] In some embodiments, the first additive is TMSOTf.

[0094] In some embodiments, the second additive is Ti(O) i Pr)4.

[0095] In some embodiments, the organic solvent is 1,2-dichloroethane.

[0096] In some embodiments, the ratio of the o-aminobenzyl alcohol compound to the organic solvent is 0.2 mol: 0.5 to 1.5 ml.

[0097] Preferably, the ratio of the amount of the o-aminobenzyl alcohol compound to the organic solvent is 0.2 mol: 0.8 to 1.2 ml.

[0098] Preferably, the ratio of the o-aminobenzyl alcohol compound to the organic solvent is 0.2 mol: 1 ml.

[0099] In some embodiments, the molar ratio between the o-aminobenzyl alcohol compound, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive is 1:(2-4):(0.01-0.03):(0.06-0.10):(0.1-0.3):(0.1-0.3).

[0100] Preferably, the molar ratio between the o-aminobenzyl alcohol compound, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive is 1:(2.5-3.5):(0.015-0.025):(0.07-0.09):(0.15-0.25):(0.15-0.25).

[0101] Preferably, the molar ratio of the o-aminobenzyl alcohol compound, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive is 1:3:0.02:0.08:0.20:0.20.

[0102] In some embodiments, the conditions for the addition reaction are:

[0103] The reaction temperature is 5–15℃, and the reaction time is 8–16 h.

[0104] Preferably, the conditions for the addition reaction are:

[0105] The reaction temperature is 8–12℃, and the reaction time is 10–14 h.

[0106] Preferably, the conditions for the addition reaction are:

[0107] The reaction temperature was 10℃ and the reaction time was 12h.

[0108] In some implementations, it also includes:

[0109] After monitoring with TLC until the raw material completely disappeared, it was quenched with water and then extracted.

[0110] Specifically, after TLC monitoring showed that the raw material had completely disappeared, it was quenched with 3 ml of water, followed by extraction with ethyl acetate at least 3 times, each time 5 ml.

[0111] In some embodiments, when purifying by silica gel column chromatography, the developing solvent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1.

[0112] The chiral 1,4-benzoxazine provided in the embodiments of this application The preparation method of the compound can bring at least the following beneficial effects:

[0113] This application utilizes inexpensive and readily available polysubstituted o-aminobenzyl alcohol compounds and non-toxic and easily manipulated liquid alkenyl ethylene oxide reagents as raw materials to achieve chiral 1,4-benzoxazine The synthesis of compounds is achieved with low catalyst dosage, high catalytic efficiency, flexible stereoselectivity control, and simple ligand modification. In particular, the additional acid catalyst does not need to be added in excess.

[0114] A third aspect of the embodiments of this application provides a chiral 1,4-benzoxazine as described above. Application of compounds in lowering plasma cholesterol.

[0115] The above implementation methods will be described in more detail below with reference to specific embodiments.

[0116] Preparation Example

[0117] Example 1

[0118] This embodiment provides a (2S,5S)-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For preparation methods, please refer to [link / reference]. Figure 1 It includes the following steps:

[0119] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and L-ligand (Carreira's Ligand) (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide (0.2 mol, 73.82 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0120] (2) The reaction was stopped by TLC plate detection until the raw material disappeared. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0121] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (62.4 mg, 77%), namely (2S,5S)-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0122]

[0123] Melting point: mp: 120-121℃.

[0124] The basic parameters of this compound are as follows:

[0125] Chiral HPLC: 93%ee [Chiral MQ (2), 250×4.6, i-PrOH / n-heptane=2 / 97, 0.5mL / min, 210nm, tR=41.250min (minor), 48.621min (major)];

[0126] Optical Rotation: [α] 23 =29.6 (c 1.0, CHCl3);

[0127] 1H NMR (400MHz, DMSO-d6) δ7.68(d,J=8.4Hz,2H),7.46(d,J=8.0Hz,2H),7.40-7.31(m,5H),7.18-7.14(m,1H),6.98(d,J=6.6Hz,2H),6.28(d,J=7. 2Hz,1H),5.57-5.48(m,1H),5.37-5.32(m,1H),5.13-5.10(m,1H),5.04 -5.01(m,1H),4.93(s,1H),3.94-3.84(m,2H),3.34(s,1H),2.43(s,3H);

[0128] 13 C NMR(101MHz,DMSO-d6)δ144.5,140.0,140.2,139.1,137.6,136.3,134.4,131.2, 130.1,128.6,128.3,128.0,127.9,127.8,127.0,126.7,118.5,80.0,59.1,21.0;

[0129] HRMS(ESI): m / z Calcd for C 24 H 24 NO3S[M+H] + :406.1468, found 406.1472.

[0130] Example 2

[0131] This embodiment provides a (2S,5S)-1-(4-nitrophenyl)sulfonyl)-5-phenyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0132] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)phenyl)-4-nitrobenzenesulfonamide (0.2 mol, 76.81 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). iPr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0133] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0134] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (49.76 mg, 57%), namely (2S,5S)-1-(4-nitrophenyl)sulfonyl)-5-phenyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0135]

[0136] Melting point: 126-128℃.

[0137] The basic parameters of this compound are as follows:

[0138] Chiral HPLC: 75%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=5 / 95, 0.7mL / min, 254nm), tR=70.494min (minor), 84.335min (major)];

[0139] Optical Rotation: [α] 23 D = -15.8 (c 1.0, CHCl3);

[0140] 1 H NMR (400MHz, CDCl3) δ8.40-8.36(m,2H),8.01-7.98(m,2H),7.39-7.31(m,3H),7 .29-7.21(m,2H),7.16(td,J=7.4,1.7Hz,1H),7.10-7.08(m,2H),6.49(dd,J=7.8 ,1.5Hz,1H),5.60(ddd,J=17.3,10.4,6.9Hz,1H),5.38(dt,J=17.3,1.2Hz,1H), 5.24(s,1H),5.18(dt,J=10.4,1.1Hz,1H),5.07-5.03(m,1H),4.09-3.97(m,2H);

[0141] 13C NMR (101MHz, CDCl3) δ150.2,147.0,142.2,139.1,135.8,133.5,130.8,129. 1,128.9,128.8,128.6,128.5,128.1,127.0,124.6,119.4,81.1,72.7,60.8;

[0142] HRMS(ESI): m / z Calcd for C 23 H 20 N₂O₅SNa[M+Na] + :459.0985,found 459.0985.

[0143] Example 3

[0144] This embodiment provides a (2S,5S)-5-(p-tolyl)-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0145] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(p-tolyl)methyl)phenyl)-4-methylbenzenesulfonamide (0.2 mol, 70.62 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0146] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0147] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (50.29 mg, 60%), namely (2S,5S)-5-(p-tolyl)-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0148]

[0149] Melting point: 122-123℃.

[0150] The basic parameters of this compound are as follows:

[0151] Chiral HPLC: 95%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=3 / 97, 0.5mL / min, 254nm, tR=49.405min (minor), 62.509min (major)];

[0152] Optical Rotation: [α] 23 D = -42.6 (c 1.0, CHCl3);

[0153] 1 H NMR (400MHz, Acetone-d6) δ7.69(d,J=8.4Hz,2H),7.47-7.41(m,3H),7.34-7.30(m,1H),7.19-7.13(m,3H),6.92(d,J=7.6Hz,2H),6.40-6.37(m,1H), 5.65-5.56(m,1H),5.40-5.35(m,1H),5.14-5.05(m,2H),4.96(s,1H),3.99 (dd,J=12.8,3.0Hz,1H),3.90(d,J=12.8Hz,1H),2.47(s,3H),2.34(s,3H);

[0154] 13 C NMR (101MHz, Acetone-d6) δ144.1,141.5,138.7,137.1,136.9,136.8,134.9,131.7,1 30.0,128.8,128.3,128.2,127.9,127.3,126.9,117.8,80.5,71.9,59.8,20.6,20.3;

[0155] HRMS(ESI): m / z Calcd for C 25 H 26 NO3S[M+H] + :420.1628,found 420.1622.

[0156] Example 4

[0157] This embodiment provides a (2S,5S)-5-(p-methoxyphenyl)-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0158] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun, purged with nitrogen three times, and brought to room temperature. [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and the tubes were purged with nitrogen three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(p-methoxyphenyl)methyl)phenyl)-4-methylbenzenesulfonamide (0.2 mol, 76.62 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture. Following this, TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂) were added. i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0159] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0160] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (61.79 mg, 71%).

[0161] That is, (2S,5S)-5-(p-methoxyphenyl)-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine The compound has the following structural formula:

[0162]

[0163] Melting point: 149-150℃.

[0164] The basic parameters of this compound are as follows:

[0165] Chiral HPLC: 93%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=3 / 97, 0.7mL / min, 254nm, tR=64.489min (minor), 89.978min (major)];

[0166] Optical Rotation: [α]23 D = -51.1 (c 1.0, CHCl3);

[0167] 1 H NMR(400MHz, Acetone-d6)δ7.69(d,J=8.3Hz,2H),7.47-7.41(m,3H),7.34-7.30( m,1H),7.19-7.14(m,1H),6.97-6.92(m,4H),6.41(dd,J=7.8,1.6Hz,1H),5.65-5 .56(m,1H),5.40-5.35(m,1H),5.12-5.09(m,1H),5.08-5.04(m,1H),4.94(s,1H) ,3.99(dd,J=12.8,3.0Hz,1H),3.89(d,J=12.4Hz,1H),3.81(s,3H),2.47(s,3H);

[0168] 13 C NMR (101MHz, Acetone-d6) δ160.1,144.9,142.2,139.5,137.6,135.7,132.5,130. 8,129.1,129.0,128.9,128.7,128.1,118.5,114.3,81.1,72.6,60.6,55.5,21.4;

[0169] HRMS(ESI): m / z Calcd for C 25 H 26 NO4S[M+H] + :436.1577,found 436.1573.

[0170] Example 5

[0171] This embodiment provides a (2S,5S)-7-methyl-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0172] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)-4-methylphenyl)-4-methylbenzenesulfonamide (0.2 mmol, 76.63 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0173] (2) The reaction was stopped when the starting material disappeared by TLC plate analysis. The mixture was then extracted three times with ethyl acetate (5 mL), and the organic phases were combined.

[0174] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (63.71 mg, 76%), namely (2S,5S)-7-methyl-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0175]

[0176] Melting point: 124-125℃.

[0177] The basic parameters of this compound are as follows:

[0178] Chiral HPLC: 92%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=3 / 97, 0.7mL / min, 254nm, tR=37.778min (major), 50.279min (minor)].

[0179] Optical Rotation: [α] 23 D = -18.2 (c 1.0, CHCl3);

[0180] 1H NMR(400MHz, CDCl3) δ77.65(d,J=8.3Hz,2H),7.37-7.26(m,6H),7.07-7.02(m,3H),6.19(d,J=2.1Hz,1H),5.67-5 .59(m,1H),5.39-5.34(m,1H),5.16-5.12(m,1H),5.04-5.00(m,2H),4.02-3.90(m,2H),2.45(s,3H),2.14(s,3H);

[0181] 13 C NMR (101MHz, CDCl3) δ143.7,140.6,139.6,138.5,138.1,134.5,133.8,131.4,129. 9,129.20,129.17,128.3,127.7,127.3,127.1,118.6,80.8,72.2,60.0,21.6,21.4;

[0182] HRMS(ESI): m / z Calcd for C 25 H 26 NO3S[M+H] + :420.1628, found 420.1616.

[0183] Example 6

[0184] This embodiment provides a (2S,5S)-7-methoxy-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0185] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)-4-methoxyphenyl)-4-methylbenzenesulfonamide (0.2 mmol, 79.83 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0186] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0187] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (67.88 mg, 78%), namely (2S,5S)-7-methoxy-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0188]

[0189] Melting point: 125-126℃.

[0190] The basic parameters of this compound are as follows:

[0191] Chiral HPLC: 90%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=5 / 95, 0.7mL / min, 254nm, tR=35.015min (major), 42.343min (minor)];

[0192] Optical Rotation: [α] 23 D = -44.5 (c 1.0, CHCl3);

[0193] 1 H NMR (400MHz, CDCl3) δ7.64 (d, J = 8.3Hz, 2H), 7.35-7.29 (m, 6H), 7.01 (d, J = 7.1 Hz,2H),6.76(dd,J=8.7,3.0Hz,1H),5.93(d,J=3.0Hz,1H),5.69-5.61(m,1H), 5.40-5.35(m,1H),5.17-5.14(m,1H),5.05-5.01(m,1H),4.91(s,1H),4.01(d d,J=12.8,3.0Hz,1H),3.93(dd,J=12.9,3.3Hz,1H),3.61(s,3H),2.46(s,3H);

[0194] 13C NMR (101MHz, CDCl3) δ158.9,143.7,142.6,139.4,138.5,134.5,129.9,128.9, 128.3,127.9,127.4,127.1,118.6,115.2,112.4,80.9,72.4,60.0,55.3,21.6;

[0195] HRMS(ESI): m / z Calcd for C 25 H 26 NO4S[M+H]+:436.1577, found 436.1566.

[0196] Example 7

[0197] This embodiment provides a (2S,5S)-8-methyl-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0198] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)-5-methylphenyl)-4-methylbenzenesulfonamide (0.2 mmol, 76.63 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0199] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0200] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (54.49 mg, 65%), namely (2S,5S)-8-methyl-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0201]

[0202] Melting point: 127-128℃.

[0203] The basic parameters of this compound are as follows:

[0204] Chiral HPLC: 78%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=5 / 95, 0.7mL / min, 254nm, tR=31.167min (minor), 40.314min (major)];

[0205] Optical Rotation: [α] 23 D = -18.7 (c 1.0, CHCl3);

[0206] 1 H NMR (400MHz, Acetone-d6) δ7.72-7.69(m,2H),7.47-7.45(m,2H),7.38-7.29( m,3H),7.27-7.25(m,1H),7.04-6.96(m,3H),6.23(d,J=7.9Hz,1H),5.67-5.5 8(m,1H),5.41-5.36(m,1H),5.13-5.10(m,1H),5.07-5.03(m,1H),4.94(s,1H ),3.98(dd,J=12.8,3.0Hz,1H),3.90-3.86(m,1H),2.47(s,3H),2.30(s,3H);

[0207] 13 C NMR (101MHz, Acetone-d6) δ144.8,140.8,139.5,139.1,138.9,137.5,135.7,133.0,1 30.8,129.3,128.9,128.8,128.3,128.1,127.7,118.5,81.1,72.5,60.8,21.4,20.9;

[0208] HRMS(ESI): m / z Calcd for C 25 H 26 NO3S[M+H] + :420.1628,found 420.1619.

[0209] Example 8

[0210] This embodiment provides a (2S,5S)-8-methoxy-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine For the preparation method of the compound, see [link to compound preparation method]. Figure 1 It includes the following steps:

[0211] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, [Ir(COD)Cl]₂ (0.004 mmol, 2.68 mg) and the ligand (0.016 mmol, 8.12 mg) were added, and nitrogen was purged three times. 1 mL of anhydrous 1,2-dichloroethane was added, and the mixture was stirred at room temperature for 15 min. Then, N-(2-(hydroxy(phenyl)methyl)-5-methoxyphenyl)-4-methylbenzenesulfonamide (0.2 mmol, 76.62 mg) and alkenyl ethylene oxide (0.6 mol, 42.02 mg) were added sequentially to the mixture, followed by TMSOTf (0.04 mol, 8.89 mg) and Ti(O₂). i Pr)4 (0.04 mol, 11.36 mg) was reacted at 10 °C for 12 h.

[0212] (2) The reaction was stopped when the starting material disappeared by TLC plate monitoring. Water (3 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL).

[0213] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1, yielding a white solid (54.49 mg, 65%), namely (2S,5S)-8-methoxy-5-phenyl-1-toluenesulfonyl-2-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazine. The compound has the following structural formula:

[0214] #imgpt66#

[0215] Melting point: 118-119℃.

[0216] The basic parameters of this compound are as follows:

[0217] Chiral HPLC: 92%ee [Chiral MX (2), 250×4.6, i-PrOH / n-heptane=5 / 95, 0.7mL / min, 254nm, tR=26.213min (minor), 33.691min (major)];

[0218] Optical Rotation: [α] 23 D= -69.0 (c 1.0, CHCl3);

[0219] 1 H NMR (400MHz, Acetone-d6) δ7.75-7.71(m,2H),7.48-7.46(m,2H),7.38-7.29(m,3H),7.0 4(d,J=7.1Hz,2H),6.95(d,J=2.6Hz,1H),6.72(dd,J=8.6,2.7Hz,1H),6.26(dd,J=8.7,0 .6Hz,1H),5.68-55.61(m,1H),5.43-5.38(m,1H),5.14-5.11(m,1H),5.09-5.05(m,1H), 4.98(s,1H),3.99(dd,J=12.8,3.0Hz,1H),3.92-3.89(m,1H),3.75(s,3H),2.47(s,3H);

[0220] 13 C NMR (101MHz, Acetone-d6) δ160.3,144.9,141.0,139.5,138.7,135.6,134.0,130.8,1 29.9,129.0,128.3,128.1,127.7,118.6,118.2,113.5,80.9,72.6,61.0,55.8,21.4;

[0221] HRMS(ESI): m / z Calcd for C 25 H 26 NO4S[M+H] + :436.1577,found 436.1571.

[0222] Comparative Example 1

[0223] It is almost identical to Example 1, except that L-ligand is not added.

[0224] Comparative Example 2

[0225] It is almost identical to Example 1, except that the L ligand is replaced with the L2 ligand.

[0226] Comparative Example 3

[0227] It is almost identical to Example 1, except that the L ligand is replaced with the L3 ligand.

[0228] Comparative Example 4

[0229] It is almost identical to Example 1, except that the L ligand is replaced with the L4 ligand.

[0230] Comparative Example 5

[0231] It is almost identical to Example 1, except that the L ligand is replaced with the L5 ligand.

[0232] Comparative Example 6

[0233] It is almost identical to Example 1, except that the second additive Ti(O) is not added. i Pr)4.

[0234] Comparative Example 7

[0235] It is almost identical to Example 1, except for Ti(O) i Pr)4 is changed to Ti(OEt)4.

[0236] Comparative Example 8

[0237] It is almost identical to Example 1, except for Ti(O) i Pr)4 is changed to Ti[(CH3)2N]4.

[0238] Comparative Example 9

[0239] It is almost identical to Example 1, except for Ti(O) i Pr)4 was changed to Ti(OC3H7)4.

[0240] Comparative Example 10

[0241] It is almost identical to Example 1, except for Ti(O) i Pr)4 was changed to Ti(OC3H7)4.

[0242] Comparative Example 11

[0243] It is almost identical to Example 1, except that dichloroethane is replaced with dichloromethane.

[0244] Comparative Example 12

[0245] It is almost identical to Example 1, except that dichloroethane is replaced with chlorobenzene.

[0246] Comparative Example 13

[0247] It is almost identical to Example 1, except that dichloroethane is replaced with trichloromethane.

[0248] Comparative Example 14

[0249] It is almost identical to Example 1, except that dichloroethane is replaced with tetrahydrofuran.

[0250] Comparative Example 15

[0251] It is almost identical to Example 1, except that dichloroethane is replaced with diethyl ether.

[0252] Comparative Example 16

[0253] It is almost identical to Example 1, except that dichloroethane is replaced with dimethylformamide.

[0254] Comparative Example 17

[0255] It is almost identical to Example 1, except that dichloroethane is replaced with dimethylformamide.

[0256] Separation yield, dr value, and ee value were tested for Example 1, Comparative Examples 1 to 17, using 400MHz. 1 The dr value was determined by HNMR, and the ee value was determined by chiral high-performance liquid chromatography. The results are shown below:

[0257] yield (%) dr ee(%) Example 1 77 >20:1 92 Comparative Example 1 Productivity Unable to test Unable to test Comparative Example 2 55 >20:1 -81 Comparative Example 3 Productivity Unable to test Unable to test Comparative Example 4 Productivity Unable to test Unable to test Comparative Example 5 21 none 35 Comparative Example 6 31 >20:1 81 Comparative Example 7 Productivity Unable to test Unable to test Comparative Example 8 33 none none Comparative Example 9 10 none none Comparative Example 10 62 >20:1 89 Comparative Example 11 58 >20:1 93 Comparative Example 12 60 >20:1 91 Comparative Example 13 29 >20:1 22 Comparative Example 14 Productivity Unable to test 8 Comparative Example 15 Productivity Unable to test Unable to test Comparative Example 16 Productivity Unable to test Unable to test Comparative Example 17 Productivity Unable to test Unable to test Comparative Example 18 Productivity Unable to test Unable to test

[0258] As shown in the table above, Example 1 has the highest yield. Compared with other ligands, additives and organic solvents, it can achieve a high yield with an equivalent amount of catalyst. If other reagents are used, the consumption is large, which is not conducive to large-scale production.

[0259] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing a chiral 1,4-benzoxazine compound, characterized in that, Includes the following steps: Under nitrogen protection, o-aminobenzyl alcohol, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive were mixed and subjected to an intermolecular asymmetric [4+3] cycloaddition reaction in an organic solvent. After extraction and purification by silica gel column chromatography, a chiral 1,4-benzoxazine compound was obtained. The catalyst is [Ir(COD)Cl]2, and the ligand is a Carreira ligand with the structure shown in Formula 10: Formula 10; The first additive is TMSOTf, and the second additive is Ti(O) i Pr)4; The organic solvent is 1,2-dichloroethane; The chiral 1,4-benzoxazine compound has the structure shown in Formula 1: Formula 1 In the formula, R 1 It is one of phenyl, p-methylphenyl, and p-methoxyphenyl; R 2 R 3 Each is independently either methyl or methoxy; R 4 It is one of p-nitrobenzenesulfonyl and p-toluenesulfonyl.

2. The method for preparing a chiral 1,4-benzoxazine compound according to claim 1, characterized in that, The molar ratio of the o-aminobenzyl alcohol compound, alkenyl ethylene oxide, catalyst, ligand, first additive, and second additive is 1:(2~4):(0.01~0.03):(0.06~0.10):(0.1~0.3):(0.1~0.3).

3. The method for preparing a chiral 1,4-benzoxazine compound according to claim 1, characterized in that, The conditions for the addition reaction are: The reaction temperature is 5~15℃, and the reaction time is 8~16h.

4. The method for preparing a chiral 1,4-benzoxazine compound according to claim 1, characterized in that, Also includes: After monitoring with TLC until the raw material completely disappeared, it was quenched with water and then extracted.

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