Diverse derivatization method and application of 7-oxa-2-azabicyclo [3.2. 1] octyl-3-alkene compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a diversified derivatization method of a polysubstituted 7-oxa-2-azabicyclo [3.2. 1] octyl-3-alkene compound and application of the polysubstituted 7-oxa-2-azabicyclo [3.2. 1] octyl-3-alkene compound. According to the invention, a polysubstituted 7-oxa-2-azabicyclo [3.2. 1] octyl-3-alkene compound is used as a reaction raw material, and the polysubstituted 7-oxa-2-azabicyclo [3.2. 1] octyl-3-alkene compound reacts with a plurality of reagents under normal pressure, so that various derivative products with retained enantiomers can be prepared. The preparation method provided by the invention is simple to operate, mild in reaction condition and suitable for industrial production. The derivatization product prepared according to the preparation method provided by the invention has high yield and optical purity, and has good application prospects in the fields of organic synthesis and drug research and development.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for diversely derivatizing polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds and application thereof. BACKGROUND

[0002] 7-oxa-2-azabicyclo[3.2.1]oct-3-ene is the core skeleton of many natural products and biologically active molecules, and some of the compounds exhibit significant biological activity. However, there are few reports on the derivatization method for the skeleton. Therefore, developing an economical, universal and efficient method for diversely derivatizing 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds has important significance for organic synthesis and medicinal chemistry. SUMMARY

[0003] Therefore, the application provides a method for diversely derivatizing polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds and application thereof. The method for diversely derivatizing 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds provided by the application is simple and easy to operate, and the yield and optical purity of the derivatized product obtained are relatively high.

[0004] A method for diversely derivatizing polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds with high enantioselectivity, characterized by comprising the following steps:

[0005] mixing 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds, compound 1 and an organic solvent to perform a derivatization reaction, and obtaining the diversely derivatized product;

[0006] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound has the structure shown in formula 1, and the compound 1 has the structure shown in formula 2, formula 3, formula 4, formula 5, formula 6, formula 7 or formula 8:

[0007] LiAIH4 formula 5; MeMgBr formula 8;

[0008] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is , and the derivatized product is

[0009] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is the derivatized product is

[0010] when the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is the derivatized product is

[0011] when the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is LiAIH4, and the derivatized product is

[0012] when the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is the derivatized product is

[0013] when the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is the derivatized product is

[0014] when the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is MeMgBr, and the derivatized product is

[0015] when the polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is the compound 1 is a structure shown in Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8; and the derivatized product has a structure shown in Formula I-a~I-b, Formula II, Formula III, Formula IV, Formula V;

[0016]

[0017] wherein R 1 and R 2 are independently phenyl;

[0018] R 3 is independently alkyl;

[0019] R 4 is independently alkoxy;

[0020] R 5 is independently hydrogen atom;

[0021] R6 The independent atoms are alkyl, phenyl, and hydrogen atoms.

[0022] Preferably, the Including (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester.

[0023] Preferably, compound 1 includes methyl trifluoropyruvate, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour), N-bromosuccinimide (NBS), lithium aluminum hydride, 3-methylindole, methyl magnesium bromide, and phenyl magnesium bromide.

[0024] Preferably, the molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to the selective fluorine reagent is 1:1.5 to 2.5.

[0025] The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to N-bromosuccinimide is 1:2.0 to 2.5.

[0026] The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to lithium aluminum hydride is 1:1.5 to 2.0.

[0027] The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to 3-methylindole is 1:1.5 to 2.5.

[0028] The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to methyl magnesium bromide is 1:2.5 to 3.5.

[0029] The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to phenyl magnesium bromide is 1:2.5 to 3.5.

[0030] Preferably, the temperature of the derivatization reaction is 0℃~60℃ and the time is 2h-44h.

[0031] The present invention also provides a derivatized product prepared by the preparation method described above, characterized in that it has the structures shown in Formula I-a, Formula Ib, Formula II, Formula III, Formula IV, and Formula V;

[0032]

[0033] Among them, R 1 and R 2 The independent form is phenyl;

[0034] R 3 independently alkyl;

[0035] R 4 independently alkoxy;

[0036] R 5 independently hydrogen atom;

[0037] R 6 independently alkyl, phenyl, hydrogen atom. Preferably, the compound has a structure represented by any one of Formula I-a to I-b, Formula II-1, Formula III-1, Formula IV-1 to IV-3, Formula V-1:

[0038]

[0039] The present application also provides a derivative prepared from the above-mentioned poly-substituted fused compound having a structure represented by Formula IV-3 in the technical scheme, which has a structure represented by Formula a:

[0040]

[0041] The present application also provides a preparation method of the derivative described in the above technical scheme, which comprises the following steps:

[0042] mixing 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a first organic solvent to perform an oxidation reaction, so as to obtain the compound 1; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a first organic solvent to perform an oxidation reaction, so as to obtain the compound 1;

[0043] The present application can prepare a high enantioselective derivative product from 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and compound 1 under normal pressure. The preparation method provided by the present application is simple in operation, the raw materials are cheap and easy to obtain, the reaction conditions are mild, and the method is easy to be industrialized. The derivative product prepared by the preparation method provided by the present application has high yield and optical purity, and has good application prospect and economic benefit in the field of synthesis and drug research and development. DETAILED DESCRIPTION

[0044] The present application provides a method for diversifying derivative of high enantioselective poly-substituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound, which comprises the following steps:

[0045] mixing 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound, compound 1 and an organic solvent to perform a derivative reaction, so as to obtain the diversifying derivative product;

[0046] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound has a structure shown in Formula 1, the compound 1 has a structure shown in Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8:

[0047] LiAIH4 Formula 5; MeMgBr Formula 8;

[0048] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is The derivatized product is

[0049] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is The derivatized product is

[0050] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is The derivatized product is

[0051] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is LiAIH4, and the derivatized product is

[0052] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is The derivatized product is

[0053] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is The derivatized product is

[0054] When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is , the compound 1 is MeMgBr, and the derivatized product is

[0055] When the polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When compound 1 has the structure shown in formula 2, formula 3, formula 4, formula 5, formula 6, formula 7, and formula 8; the derivatized product has the structure shown in formula I-a, formula Ib, formula II, formula III, formula IV, and formula V;

[0056]

[0057] In this invention, R 1 and R 2 The independent one is phenyl.

[0058] In this invention, R 3 The R is an alkyl group. 3 The alkyl group can be methyl.

[0059] In this invention, R 4 The R is an alkoxy group. 4 The alkoxy group can be an ethoxy group.

[0060] In this invention, R 5 It is a hydrogen atom.

[0061] In this invention, R 6 R is an alkyl, phenyl, or hydrogen atom. 6 The alkyl group can be methyl.

[0062] As a specific embodiment of the present invention, the Including (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester.

[0063] As a specific embodiment of the present invention, compound 1 includes methyl trifluoropyruvate, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour), N-bromosuccinimide (NBS), lithium aluminum hydride, 3-methylindole, methyl magnesium bromide, and phenyl magnesium bromide.

[0064] In this invention, because 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds contain N,O-acetal structural units and olefin functional groups, they can achieve highly enantioselective and diverse derivatization under normal pressure, and the reactants do not need to be activated in advance during the reaction process.

[0065] In one specific embodiment of the present invention, the organic solvent is toluene, dichloromethane, or tetrahydrofuran; the molar concentration of 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds in the derivatized reaction solution system can be 0.08 to 0.12 mol / L, specifically 0.1 mol / L.

[0066] As a specific embodiment of the present application, the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the methyl trifluoroacetate are in a molar ratio of 1:1.5-2.5, and specifically 1:2.

[0067] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the selective fluorine reagent are in a molar ratio of 1:1.5-2.5, and specifically 1:2.0.

[0068] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the N-bromosuccinimide are in a molar ratio of 1:2.0-2.5, and specifically 1:2.2.

[0069] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the lithium aluminum hydride are in a molar ratio of 1:1.5-2.0, and specifically 1:1.5.

[0070] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the 3-methylindole are in a molar ratio of 1:1.5-2.5, and specifically 1:2.

[0071] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the methyl magnesium bromide are in a molar ratio of 1:2.5-3.5, and specifically 1:3.

[0072] The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound and the phenyl magnesium bromide are in a molar ratio of 1:2.5-3.5, and specifically 1:3.

[0073] As a specific embodiment of the present application, the temperature of the derivatization reaction can be 0-60°C; and the time of the derivatization reaction can be 2-44 hours.

[0074] As a specific embodiment of the present application, the reaction equation for preparing the compound of formula (I) is as follows:

[0075]

[0076] In the present application, after the derivatization reaction, the system after the derivatization reaction is concentrated and then separated and purified by silica gel column chromatography to obtain the derivative product. The present application does not have special requirements for the concentration and silica gel column chromatography, and the conventional methods in the art can be used. ​

[0077] The present invention also provides highly enantioselective derivatized products prepared according to the preparation method described above, having the structures shown in Formula I-a, Formula Ib, Formula II, Formula III, Formula IV, and Formula V;

[0078]

[0079] Among them, R 1 and R 2 The independent form is phenyl;

[0080] R 3 Independently, it is an alkyl group;

[0081] R 4 Independently, it is an alkoxy group;

[0082] R 5 The independent atoms are hydrogen atoms;

[0083] R 6 The independent atoms are alkyl, phenyl, and hydrogen atoms.

[0084] As a specific embodiment of the present invention, the highly enantioselective derivatized product may have any of the structures shown in Formula I-a to Ib, Formula II-1, Formula III-1, Formula IV-1 to IV-3, and Formula V-1:

[0085]

[0086] This invention also provides derivatives prepared from polysubstituted cyclic compounds having the structure shown in Formula IV-3 in the above-described technical solutions, having the structure shown in Formula a:

[0087]

[0088] The present invention also provides a method for preparing the derivatives described in the above technical solution, comprising the following steps:

[0089] Will 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) is mixed with a first organic solvent and subjected to an oxidation reaction to obtain the [substance name missing]. In one specific embodiment of the present invention, the first organic solvent may be dichloromethane; The molar ratio of the 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) to the first organic solvent can be 1:2.4-2.6, and can be specifically 1:2.5. The application does not have special limitation on the amount of the first organic solvent, as long as it can be completely dissolved. As a specific embodiment of the application, the temperature of the oxidation reaction can be 0°C, and the time of the oxidation reaction can be 15 min. As a specific embodiment of the application, the oxidation reaction can be accompanied by stirring, and the application does not have special limitation on the stirring, as long as it can be sufficient for the reaction.

[0090] In the application, the equation of the oxidation reaction is as follows:

[0091]

[0092] In order to further illustrate the application, the technical solutions provided by the application are described in detail below in combination with examples, but they should not be understood as limitations on the protection scope of the application.

[0093] After each example is prepared, in order to further verify that the purified compound is indeed the target product prepared in the example, the obtained product is analyzed by using nuclear magnetic resonance, high-resolution mass spectrometry, specific optical rotation, and high-performance liquid chromatography, and the detection results are listed in each example.

[0094] Example 1

[0095] R 1 = R 2 is a phenyl group, R 3 is a methyl group, R 4 is an ethoxy group, R 5 is a hydrogen atom, (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (95% enantiomeric excess value) and methyl trifluoropyruvate are used as reaction raw materials, and toluene is used as a solvent to perform the reaction, and the specific implementation process is as follows:

[0096] (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (69.9 mg, 0.20 mmol) is dissolved in toluene (2.0 mL), methyl trifluoropyruvate (40.8 uL, 0.40 mmol) is added, and the reaction is performed at 60°C for 23 h. The reaction equation is as follows:

[0097]

[0098] After the reaction solution is concentrated, silica gel column chromatography is used to obtain solid product formula I-a: 36.8 mg, and the calculated yield is 38%, and the enantiomeric excess value is 95%.

[0099] [α] D 32 = 305.4 (c = 1.00, CHCI3). HPLC analysis: Daicel Chiralpak AD-H, 20% i-PrOH in hexanes, 1.0 mL / min, Retention time: 4.8 min (minor) and 12.9 min (major).

[0100] The analysis of the test is as follows:

[0101] 1. Hydrogen spectrum of nuclear magnetic resonance analysis, carbon spectrum:

[0102] 1 H NMR (300 MHz, CDCI3) δ 7.57 - 7.48 (m, 2H), 7.38 - 7.27 (m, 4H), 7.25 - 7.06 (m, 4H), 6.14 (d, J = 4.1 Hz, 1H), 4.40 (d, J = 3.6 Hz, 1H), 4.15 - 3.92 (m, 3H), 3.46 (d, J = 19.3 Hz, 1H), 2.95 (d, J = 19.4 Hz, 1H), 2.40 (dt, Ji = 11.7 Hz, J2= 4.2 Hz, 1H), 1.97 (d, J = 11.7 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H) ppm.

[0103] 13 C NMR (201 MHz, CDCI3) δ 167.4, 165.0, 144.7, 144.4, 142.6, 128.4, 127.7, 127.3, 126.9, 125.4, 125.1, 123.5 (q, J = 284.8 Hz), 109.7, 98.6, 79.8, 75.2 (q, J = 31.5 Hz), 60.5, 41.2 (d, J = 1.8 Hz), 34.3, 32.3, 14.2 ppm.

[0104] 19 F NMR (282 MHz, CDCI3) δ -80.6 ppm.

[0105] 2. High resolution mass spectrum: HRMS (ESI) C 25 H 23 F3NO5 [M + + H]: 474.1523, Found: 474.1522.

[0106] From the results, the theoretical mass is 474.1523, while the observed value of the peak found in the actual mass spectrum is 474.1522; and in combination with nuclear magnetic resonance, the structure of the product formula I-a is determined as follows:

[0107] The product of this example.

[0108] Solid product formula I-b: 34.3 mg, calculated yield of 36%, 93% enantiomeric excess value. [α] D 31 = 203.6 (c = 1.00, CHCl3). HPLC analysis: Daicel Chiralpak AD-H, 10% i-PrOH in hexanes, 1.0 mL / min, retention time: 7.1 min (minor) and 9.9 min (major).

[0109] The analysis of the test is as follows:

[0110] 1. Hydrogen spectrum and carbon spectrum of nuclear magnetic resonance analysis:

[0111] 1 H NMR (300 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.38-7.29 (m, 4H), 7.25-7.04 (m, 4H), 6.16 (d, J = 4.0 Hz, 1H), 4.42 (d, J = 3.8 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.59 (s, 1H), 3.38 (d, J = 19.6 Hz, 1H), 3.00 (d, J = 19.6 Hz, 1H), 2.39 (dt, J1= 11.7 Hz, J2= 4.1 Hz, 1H), 2.01 (d, J = 11.6 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H) ppm.

[0112] 13 C NMR (201 MHz, CDCl3) δ 167.5, 165.1, 144.8, 144.6, 142.7, 128.4, 127.6, 127.3, 126.9, 125.3, 125.0, 123.4 (q, J = 284.1 Hz), 109.6, 98.5, 79.6, 75.7 (q, J = 31.5 Hz), 60.6, 41.3 (d, J = 1.9 Hz), 33.9, 32.3, 14.3 ppm

[0113] 19 F NMR (282 MHz, CDCl3) δ -80.5 ppm.

[0114] 2. High resolution mass spectrum: C 25 H 23 F3NO5[M + +H]: 474.1523, Found: 474.1527.

[0115] From the result, it can be seen that the theoretical mass is 474.1523, while the observed value of the peak found in the actual mass spectrum is 474.1527; combined with nuclear magnetic resonance, the structure of the product formula I-b can be determined as follows:

[0116] The product of this example.

[0117] Example 2

[0118] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, and R 5 is a hydrogen atom, (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylate (95% enantiomeric excess value) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour) were used as the reaction raw materials, and dichloromethane was used as the solvent to carry out the reaction, and the specific implementation process is as follows:

[0119] (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4- carboxylate (69.9 mg, 0.20 mmol) and 1-chloromethyl-4-fluoro-1,4- diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour) (142.0 mg, 0.40 mmol) were dissolved in dichloromethane (2.0 mL) and reacted at room temperature for 2 h. The reaction equation is as follows:

[0120]

[0121] After the reaction solution was concentrated, silica gel column chromatography was used to obtain solid products: 57.1 mg, the calculated yield was 78%, and the enantiomeric excess value was 95%.

[0122] [α] D 33= 122.8 (c = 1.00, CHCI3). HPLC analysis: Daicel Chiralpak AD-H, 10% i-PrOH in hexanes, 1.0 mL / min, Retention time: 6.5 min (major) and 19.4 min (minor).

[0123] The analysis of the test is as follows:

[0124] 1. Hydrogen spectrum of nuclear magnetic resonance analysis, carbon spectrum:

[0125] 1 H NMR (300 MHz, CDCI3) δ 7.57 - 7.27 (m, 5H), 7.25 - 7.03 (m, 5H), 5.74 (d, J = 3.8 Hz, 1H), 4.05 (dd, Ji = 12.2 Hz, J2= 3.8 Hz, 1H), 3.74 - 3.60 (m, 1H), 3.43 - 3.29 (m, 1H), 2.17 (d, J = 12.0 Hz, 1H), 2.10 (s, 3H), 2.03 (dt, Ji = 12.0 Hz, J2= 4.0 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H) ppm.

[0126] 13 C NMR (75 MHz, CDCI3) δ 165.9 (d, J = 18.0 Hz), 165.6 (d, J = 25.5 Hz), 146.6 (d, J = 1.8 Hz), 141.0, 128.4, 127.6, 127.1, 127.0, 124.9, 91.3 (d, J = 177.8 Hz), 86.9 (d, J = 9.0 Hz), 84.3 (d, J = 1.1 Hz), 61.8, 47.9 (d, J = 22.8 Hz), 34.0, 22.5, 13.4 ppm.

[0127] 19 F NMR (282 MHz, CDCI3) δ -131.6 ppm.

[0128] 2. High resolution mass spectrometry: HRMS (ESI) C 22 H 23 F NO3 [M + + H]: 368.1656, Found: 368.1663.

[0129] From this result, it can be seen that the theoretical mass is 368.1656, and the observed value of the peak found in the actual mass spectrum is 368.1663; combined with nuclear magnetic resonance, the product structure can be determined as follows:

[0130] was the product of this example.

[0131] Example 3

[0132] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, R 5 is hydrogen atom, ethyl (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylate (95% e.e. value) and N- bromosuccinimide were used as the starting materials, and dichloromethane was used as the solvent, and the reaction was carried out as follows:

[0133] Ethyl (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4- carboxylate (70.0 mg, 0.20 mmol) was dissolved in dry dichloromethane (2.0 mL), and N-bromosuccinimide (78.0 mg, 0.44 mmol) was added at 0 °C to start the reaction, and the reaction was gradually returned to room temperature for 1 h. The reaction equation is as follows:

[0134]

[0135] The reaction solution was concentrated and column chromatography on silica gel was used to obtain the solid product: 66.5 mg, calculated yield 66%, 95% e.e. value.

[0136] [α] D 31 = 193.6 (c = 1.00, CHCl3). HPLC analysis: Daicel Chiralpak AD-H, 5% i-PrOH in hexanes, 1.0 mL / min, retention time: 7.2 min (major) and 16.5 min (minor).

[0137] The analysis of the test is as follows:

[0138] 1. Hydrogen spectrum and carbon spectrum of nuclear magnetic resonance analysis:

[0139] 1H NMR (300 MHz, CDC13) δ 7.75 (s, 1H), 7.52-7.41 (m, 4H), 7.37-7.29 (m, 2H), 7.26-7.05 (m, 4H), 5.87 (d, J = 3.6 Hz, 1H), 5.34 (t, J = 4.1 Hz, 1H), 4.26 (d, J = 3.5 Hz, 1H), 4.07-3.87 (m, 2H), 2.27 (dt, Ji = 10.9 Hz, J2= 4.1 Hz, 1H), 2.06 (d, J = 10.0 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H) ppm.

[0140] 13 C NMR (75 MHz, CDC13) δ 165.1, 149.3, 145.8, 143.0, 128.2, 127.3, 126.9, 126.7, 126.1, 125.2, 100.4, 99.5, 82.0, 60.1, 40.9, 35.1, 31.1, 14.2 ppm.

[0141] 2. High resolution mass spectrum: HRMS (ESI) C 22 H 21 Br2NNaO3[M + + Na]: 527.9780, Found: 527.9786.

[0142] From this result, it can be seen that the theoretical mass is 527.9780, while the observed value of the peak found in the actual mass spectrum is 527.9786; combined with nuclear magnetic resonance, the product structure can be determined as follows:

[0143] The product of this example.

[0144] Example 4

[0145] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, R 5 is a hydrogen atom, (1S, 5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (95% enantiomeric excess value) and lithium aluminum hydride were used as the reaction raw materials, dry tetrahydrofuran was used as the solvent, and the specific implementation process was as follows:

[0146] Lithium aluminum hydride (11.4 mg, 0.30 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) and the reaction was started by adding (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (69.9 mg, 0.20 mmol) at 0 °C and the reaction was allowed to gradually come to room temperature for 18 h. The reaction scheme is as follows:

[0147]

[0148] The reaction was concentrated and purified by silica gel column chromatography to give the solid product: 36.8 mg, 60% yield, 95% enantiomeric excess.

[0149] [α] D 33 = -225.5 (c = 1.00, CHCI3). HPLC analysis: Daicel Chiralpak AD-H, 20% i-PrOH in hexanes, 1.0 mL / min, retention time: 10.2 min (major) and 13.1 min (minor).

[0150] The analysis of the test is as follows:

[0151] 1. Nuclear magnetic resonance analysis of hydrogen spectrum, carbon spectrum:

[0152] 1 H NMR (300 MHz, CDCI3) δ 7.47 (d, J = 7.2 Hz, 2H), 7.41 - 7.26 (m, 3H), 7.25 - 7.15 (m, 3H), 7.12 - 7.04 (m, 2H), 4.83 (s, 1H), 3.79 (dd, Ji = 11.5 Hz, J2= 3.9 Hz, 1H), 3.35 - 3.18 (m, 2H), 2.25 (s, 3H) 2.05 (d, J = 11.0 Hz, 1H), 0.85 - 0.67 (m, 1H) ppm.

[0153] 13 C NMR (75 MHz, CDCI3) δ 171.3, 152.6, 144.4, 142.0, 128.2, 127.73, 127.67, 127.1, 126.5, 126.3, 88.1, 87.6, 45.1, 41.1, 24.6, 16.4 ppm.

[0154] 2. High resolution mass spectrometry: HRMS (ESI) C 20 H 19 N NaO2 [M ++ Na]: 328.1308, Found: 328.1315.

[0155] From the result, it can be seen that the theoretical mass is 328.1308, while the observed value of the peak found in the actual mass spectrum is 328.1315; combined with nuclear magnetic resonance, the product structure can be determined as follows:

[0156] The product of the present example.

[0157] Example 5

[0158] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, R 5 is hydrogen atom, (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (95% enantiomeric excess value) and 3-methylindole as the reaction raw material, tetrahydrofuran as the solvent, the specific implementation process is as follows:

[0159] (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4- carboxylic acid ethyl ester (70.0 mg, 0.20 mmol), 3-methylindole (52.4 mg, 0.4 mmol), sodium hydroxide (16.2 mg, 0.40 mmol) were dissolved in tetrahydrofuran (2.0 mL) and reacted at room temperature for 44 h. The reaction equation is as follows:

[0160]

[0161] After the reaction solution was concentrated, silica gel column chromatography was used to obtain solid products: 53.4 mg, the calculated yield was 61%, and the enantiomeric excess value was 96%.

[0162] [α] D 32 = 38.4 (c = 1.00, CHCl3). HPLC analysis: Daicel Chiralpak AD-H, 10% i-PrOH in hexanes, 1.0 mL / min, retention time: 9.9 min (minor) and 11.7 min (major).

[0163] The analysis of the test is as follows:

[0164] 1. Hydrogen spectrum and carbon spectrum of nuclear magnetic resonance analysis:

[0165] 1H NMR (300 MHz, CDC13) δ 7.65-7.58 (m, 1H), 7.28-7.11 (m, 11H), 7.04-6.96 (m, 2H), 6.76 (d, J = 0.7 Hz, 1H), 5.80-5.70 (m, 1H), 5.26 (d, J = 4.7 Hz, 1H), 3.74-3.62 (m, 1H), 2.42 (d, J = 1.6 Hz, 3H), 2.35-2.18 (m, 4H), 1.00 (td, J1= 12.9 Hz, J2= 3.9 Hz, 1H) ppm.

[0166] 13 C NMR (75 MHz, CDC13) δ 170.8, 150.1, 143.4, 141.6, 134.6, 129.4, 128.3, 128.0, 127.8, 127.4, 126.4, 126.2, 122.2, 121.9, 119.6, 119.4, 111.7, 108.5, 90.3, 88.3, 61.2, 40.2, 31.1, 16.1, 9.7 ppm.

[0167] 2. High resolution mass spectrum: HRMS (ESI) C 29 H 27 N2O2[M + +H]: 435.2067, Found: 435.2075.

[0168] From this result, it can be seen that the theoretical mass is 435.2067, while the observed value of the peak found in the actual mass spectrum is 435.2075; combined with nuclear magnetic resonance, the product structure can be determined as follows:

[0169] The product of this example.

[0170] Example 6

[0171] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, R 5 is a hydrogen atom, (1S, 5R)-3-methyl-6,6-diphenyl-7-oxa-2- azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (95% enantiomeric excess value) and phenylmagnesium bromide as the reaction raw material, dry tetrahydrofuran as the solvent, the specific implementation process is as follows:

[0172] (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (69.8 mg, 0.20 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) and the reaction was initiated by the addition of phenylmagnesium bromide (0.6 mL, 0.60 mmol, 1.0 mol / L in THF) at 0 °C and allowed to gradually warm to room temperature over 2 h. The reaction scheme is as follows:

[0173]

[0174] The reaction was concentrated and purified by silica gel column chromatography to give the product as a solid: 73.2 mg, 96% yield, 95% enantiomeric excess.

[0175] [α] D 34 = 0.7 (c = 1.00, CHCI3). HPLC analysis: Daicel Chiralpak AD-H, 20% i-PrOH in hexanes, 1.0 mL / min, Ret. Time: 6.0 min (major) and 7.3 min (minor).

[0176] The analysis of the test is as follows:

[0177] 1. Nuclear magnetic resonance analysis of hydrogen spectrum, carbon spectrum:

[0178] 1 H NMR (300 MHz, CDCI3) δ 7.35 - 7.25 (m, 2H), 7.26 - 7.08 (m, 11H), 7.04 - 6.97 (m, 2H), 5.56 - 5.45 (m, 1H), 4.54 (t, J = 4.0 Hz, 1H), 3.47 - 3.30 (m, 1H), 2.38 (s, 3H), 2.08 (dd, Ji = 12.1 Hz, J2= 3.8 Hz, 1H), 0.92 (td, Ji = 12.3 Hz, J2= 5.1 Hz, 1H) ppm.

[0179] 13 C NMR (75 MHz, CDCI3) δ 171.3, 152.1, 144.0, 143.4, 142.1, 128.6, 128.1, 127.7, 127.5, 127.3, 127.1, 126.3, 126.1, 125.3, 87.9, 87.7, 54.0, 40.1, 31.5, 16.3 ppm.

[0180] 2. High resolution mass spectrometry: HRMS (ESI) C 26 H 24NO2[M + +H]: 382.1802, Found: 382.1809.

[0181] From the results, it can be seen that the theoretical mass is 382.1802, while the observed value of the peak found in the actual mass spectrum is 382.1809; in combination with nuclear magnetic resonance, the product structure can be determined as follows:

[0182] is the product of the present example.

[0183] Example 7

[0184] R 1 = R 2 is phenyl, R 3 is methyl, R 4 is ethoxy, R 5 is a hydrogen atom, (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (95% enantiomeric excess value) and methyl magnesium bromide as the reaction raw materials, dry tetrahydrofuran as the solvent, the specific implementation process is as follows:

[0185] (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester (69.9 mg, 0.20 mmol) was dissolved in dry tetrahydrofuran (2.0 mL), methyl magnesium bromide (0.6 mL, 0.60 mmol, 1.0 mol / L in THF) was added at 0°C to start the reaction, and gradually returned to room temperature for 2 h. The reaction equation is as follows:

[0186]

[0187] After the reaction solution was concentrated, silica gel column chromatography was used to obtain solid products: 52.1 mg, the calculated yield was 82%, the diastereoselectivity ratio was 93 / 7, and the 95% enantiomeric excess value.

[0188] [α] D 33= -125.8 (c = 1.00, CHCI3). HPLC analysis: Daicel Chiralpak AD-H, 20% i-PrOH in hexanes, 1.0 mL / min, Retention time: [For the major diastereoisomer, 6.3 min (major), 10.5 min (minor)] and [For the minor diastereoisomer, 6.9 min (major), 7.4 min (minor)].

[0189] The analysis of the test is as follows:

[0190] 1. Hydrogen spectrum of nuclear magnetic resonance analysis, carbon spectrum:

[0191] 1 H NMR (300 MHz, CDCI3) δ 7.55 - 7.45 (m, 2H), 7.42 - 7.14 (m, 6H), 7.13 - 7.01 (m, 2H), [4.94 (d, J = 3.7 Hz, 0.9H), 4.30 (s, 0.06H), 1H], 3.94 - 3.76 (m, 1H), 3.62 - 3.48 (m, 1H), 2.31 - [2.28 (d, J = 1.1 Hz, 2.66H), 2.25 (d, J = 1.3 Hz, 0.20H), 3H], 1.86 (dd, Ji = 12.6 Hz, J2= 4.8 Hz, 1H), [1.21 (d, J = 6.7 Hz, 2.76H), 1.16 (d, J = 6.5 Hz, 0.19H), 3H], [0.72 (td, Ji = 12.5 Hz, J2= 5.1 Hz, 0.93H), 0.53 (q, J = 11.4 Hz, 0.07H), 1H] ppm.

[0192] 13 C NMR (75 MHz, CDCI3) δ 171.4, 151.3, 144.5, 142.0, 128.2, 127.71, 127.66, 127.0, 126.5, 126.3, 87.8, 86.8, 46.0, 40.9, 30.0, 23.1, 16.6 ppm.

[0193] 2. High resolution mass spectrum: HRMS (ESI) C 21 H 22 NO2[M + + H]: 320.1645, Found: 320.1652.

[0194] From the results, it can be seen that the theoretical mass is 320.1645, while the observed value of the peak found in the actual mass spectrum is 320.1652; in combination with nuclear magnetic resonance, the product structure can be determined as follows:

[0195] The product of this example.

[0196] Example 8

[0197] (6R,7aR)-4,6-dimethyl-1,1-diphenyl-5,6,7,7a-tetrahydrofuro[3,4-c]pyridin-3(1H)-one and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the reaction raw material, dichloromethane as the solvent, the specific implementation process is as follows:

[0198] (6R,7aR)-4,6-dimethyl-1,1-diphenyl-5,6,7,7a-tetrahydrofuro[3,4-c]pyridin-3(1H)-one (64.0 mg, 0.20 mmol) was dissolved in dry tetrahydrofuran (2.0 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (114.0 mg, 0.50 mmol) was added to start the reaction, and the reaction was carried out at 0°C for 2h. The reaction equation is as follows:

[0199]

[0200] After the reaction solution was concentrated, silica gel column chromatography was used to obtain solid products: 31.5 mg, the calculated yield was 50%.

[0201] The analysis of the test is as follows:

[0202] 1. Hydrogen spectrum and carbon spectrum of nuclear magnetic resonance analysis:

[0203] 1 H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 10H), 7.19 (s, 1H), 2.89 (s, 3H), 2.65 (s, 3H) ppm.

[0204] 13 C NMR (75 MHz, CDCl3) δ 168.6, 163.0, 161.3, 159.9, 139.9, 128.8, 128.6, 127.0, 116.5, 116.0, 90.2, 25.3, 20.8 ppm.

[0205] 2. High-resolution mass spectrum: HRMS (ESI) C 21 H 18 NO2[M + +H]: 316.1332, Found: 316.1341.

[0206] From this result, it can be seen that the theoretical mass is 316.1332, while the observed value of the peak found in the actual mass spectrum is 316.134; in combination with nuclear magnetic resonance, the product structure can be determined as follows:

[0207] The product of this example.

[0208] Although the above examples make a detailed description of the present application, it is only a part of the embodiments of the present application, but not all the embodiments, and people can also obtain other embodiments according to the above embodiments without creativity, which all belong to the protection scope of the present application.

Claims

1. A method and application for the diverse derivatization of polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds, characterized in that, Includes the following steps: 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds, compound 1, and an organic solvent were mixed and subjected to a derivatization reaction to obtain the aforementioned diverse derivatized products; The 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compounds have the structure shown in Formula 1, and compound 1 has the structures shown in Formulas 2, 3, 4, 5, 6, 7, and 8: LiAIH4 type 5; MeMgBr formula 8; When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When, compound 1 is The derivative is When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When, compound 1 is The derivative is When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When, compound 1 is The derivative is When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When compound 1 is LiAlH4, the derivatized product is... When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When, compound 1 is The derivative is When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When, compound 1 is The derivative is When the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When compound 1 is MeMgBr, the derivatized product is... When the polysubstituted 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound is When compound 1 has the structure shown in formula 2, formula 3, formula 4, formula 5, formula 6, formula 7, and formula 8; the derivatized product has the structure shown in formula I-a, formula I-b, formula II, formula III, formula IV, and formula V; Among them, R 1 and R 2 The independent form is phenyl; R 3 Independently, it is an alkyl group; R 4 Independently, it is an alkoxy group; R 5 The independent atoms are hydrogen atoms; R 6 The independent atoms are alkyl, phenyl, and hydrogen atoms.

2. The preparation method according to claim 1, characterized in that, The Including (1S,5R)-3-methyl-6,6-diphenyl-7-oxa-2-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid ethyl ester.

3. The preparation method according to claim 1 or 2, characterized in that, Compound 1 includes methyl trifluoropyruvate, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectflour), N-bromosuccinimide (NBS), lithium aluminum hydride, 3-methylindole, methyl magnesium bromide, and phenyl magnesium bromide.

4. The preparation method according to claim 1 or 3, characterized in that, The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to methyl trifluoropyruvate is 1:1.5 to 2.

5. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to the 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt is 1:1.5 to 2.

5. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to N-bromosuccinimide is 1:2.0 to 2.

5. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to lithium aluminum hydride is 1:1.5 to 2.

0. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to 3-methylindole is 1:1.5 to 2.

5. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to methyl magnesium bromide is 1:2.5 to 3.

5. The molar ratio of the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene compound to phenyl magnesium bromide is 1:2.5 to 3.

5.

5. The preparation method according to claim 1, characterized in that, The derivatization reaction is carried out at a temperature of 0℃ to 60℃ for a duration of 2h to 44h.

6. The derivatized product prepared according to the preparation method of any one of claims 1 to 5, characterized in that, It has the structures shown in Equations I-a, I-b, II, III, IV, and V; Among them, R 1 and R 2 The independent form is phenyl; R 3 Independently, it is an alkyl group; R 4 Independently, it is an alkoxy group; R 5 The independent atoms are hydrogen atoms; R 6 The independent atoms are alkyl, phenyl, and hydrogen atoms.

7. The derivatized product according to claim 6, characterized in that, It has any of the structures shown in Formula I-a to Ib, Formula II-1, Formula III-1, Formula IV-1 to IV-3, and Formula V-1:

8. A derivative obtained by further reacting the polysubstituted cyclic compound having the structure shown in Formula IV-3 of claim 7 as a starting material, characterized in that, It has the structure shown in equation a:

9. A method for preparing the derivative of claim 8, comprising the following steps: Will 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) is mixed with a first organic solvent and subjected to an oxidation reaction to obtain the [substance name missing].

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