A kind of highly enantioselective C-5 α-stereocenter 4-nitroisoxazole alcohol compound, its preparation method and application

A nitroisoxazolol and enantioselectivity technology, applied in the field of drug synthesis, can solve problems such as not being reported, and achieve the effects of low reaction cost, reasonable reaction path and high efficiency

Active Publication Date: 2020-02-07
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the method of organic asymmetric catalysis for the synthesis of chiral 4-nitroisoxazole C-5-position isoxazolol derivatives with α-stereocenter has not been reported.

Method used

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  • A kind of highly enantioselective C-5 α-stereocenter 4-nitroisoxazole alcohol compound, its preparation method and application
  • A kind of highly enantioselective C-5 α-stereocenter 4-nitroisoxazole alcohol compound, its preparation method and application
  • A kind of highly enantioselective C-5 α-stereocenter 4-nitroisoxazole alcohol compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The structural formula of compound 3a is as follows:

[0049]

[0050] Product name: (R)-2-(3-methyl-4-nitroisoxazole-5)-propan-1 alcohol.

[0051] The synthetic route of compound 3a is as follows:

[0052]

[0053] The synthetic steps of compound 3a are as follows:

[0054] (1) 3-methyl-5-ethyl-4-nitroisoxazole 1a (0.1mmol, 1.0equiv.), catalyst A (0.01mmol, 0.1equiv.), sodium acetate (0.1mmol, 1.0equiv. )and Molecular sieves (50 mg) were dissolved in 1.0 mL of cyclopentyl methyl ether, and stirred at room temperature for 15 minutes;

[0055] (2) Add paraformaldehyde 2a (0.3mmol, 3.0equiv.), and continue the reaction at room temperature until the raw material 1a disappears completely (about 70h) as monitored by TLC;

[0056] (3) Spin to dry the solvent and separate by column chromatography (eluent: petroleum ether and ethyl acetate volume ratio from 10:1 to 3:1) to obtain colorless oily liquid 3a (85% yield).

[0057] Colorless oily liquid, 97%ee, 1 H NMR...

Embodiment 2

[0060]

[0061] Product name: Product name: (R)-2-(3-ethyl-4-nitroisoxazole-5)-propan-1 alcohol.

[0062] In step (1), replace 3-methyl, 5-ethyl, 4-nitroisoxazole 1a with 3,5-ethyl-4-nitroisoxazole 1b, and refer to the implementation of other experimental steps and purification methods Carried out in Example 1; Pale yellow oil, 97%ee, 86%yield, 1 H NMR (300MHz, CDCl 3 )δ4.11-3.85 (m, 3H), 3.00 (q, J = 7.4Hz, 2H), 1.91 (s, 1H), 1.39 (d, J = 6.8Hz, 3H), 1.33 (t, J = 7.4 Hz,3H), specifically as image 3 shown; 13 C NMR (75MHz, CDCl 3 )δ176.3, 160.1, 129.8, 64.9, 36.2, 19.8, 13.8, 11.1; HRMS (ESI) m / z 201.0878 (M+H + ), calc.for C 8 h 13 N 2 o 4 201.0875.

[0063] The ee value of the compound was analyzed by high performance liquid chromatography (HPLC), CHIRALPAK IE (4.6mm×250mmi.d.), n-hexane / isopropanol=80 / 20 (V / V), flow rate 1.0mL / min, 25°C, 254nm, t R = 7.8 min (small peak) and 8.3 min (large peak).

Embodiment 3

[0065] Product name: (R)-2-(3-phenyl-4-nitroisoxazole-5)-propan-1 alcohol.

[0066] In step (1), replace 3-methyl, 5-ethyl, 4-nitroisoxazole 1a with 3-phenyl-5-ethyl-4-nitroisoxazole 1c, other experimental steps and purification The method is carried out with reference to the steps of Example 1; light yellow oil, 85%ee, 95%yield, 1 H NMR (300MHz, CDCl 3 )δ7.47-7.61 (m, 5H), 4.00-4.07 (m, 3H), 2.01 (s, 1H), 1.46 (d, J = 6.0Hz, 3H), specifically as Figure 4 shown; 13 C NMR (75MHz, CDCl 3 )δ176.6, 157.9, 130.7, 129.7, 129.2, 128.5, 125.7, 64.9, 36.3, 13.9; HRMS (ESI) m / z 249.0877 (M+H + ), calc.forC 12 h 13 N 2 o 4 249.0875.

[0067] The ee value of the compound was analyzed by high performance liquid chromatography (HPLC), CHIRALPAK IE (4.6mm×250mmi.d.), n-hexane / isopropanol=80 / 20 (V / V), flow rate 1.0mL / min, 25°C, 254nm, t R = 7.6 min (small peak) and 9.2 min (large peak).

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Abstract

Provided are a C-5 alpha-stereocenter 4-nitro isoxazole alcohol compound with high enantioselectivity and a preparation method and application thereof. The structural formula is shown in the description, wherein R1 refers to Me, Et, Ph and thienyl, and R2 refers to Me and normal-butyl. By adopting the new method to synthesize the C-5 alpha-stereocenter 4-nitro isoxazole alcohol compound with the high enantioselectivity, the C-5 alpha-stereocenter 4-nitro isoxazole alcohol compound with the high enantioselectivity serves as an initiator to synthesize a fungicide pyrazol compound (CAS: 1845899-33-3) with a high yield through four synthesis steps, and the specific information is shown in the description. At present, this kind of method is not reported, and the new method has the advantages ofbeing applicable in common use, low in cost, reasonable in reaction path, simple in post-processing and efficient in preparation of the compound with high optical purity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a highly enantioselective C-5 α-stereocenter 4-nitroisoxazole alcohol compound, a preparation method and application thereof. Background technique [0002] Isoxazoles are a very important class of compounds with heterocyclic structures widely used in organic synthesis. This kind of compound has a great promoting effect on human beings in reducing human blood sugar, eliminating human pain, resisting human inflammation, killing harmful bacteria, controlling and reducing the harm of HIV and the like. In addition, some isoxazole derivatives also exhibit pesticide chemical effects, and have the effect of inhibiting the growth of weeds and soil bacteria. Therefore, they also have broad application prospects in the field of pesticides and insecticides. The isoxazole ring structure also exists in some natural products, such as the steroid drug danazol containing the isoxazole r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/14C07D409/04C07D231/38A01N43/56A01P3/00C07D233/48B01J31/02
Inventor 江智勇朱博赵筱薇李江涛尹艳丽
Owner HENAN UNIVERSITY
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