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Reaction sequence for the synthesis of nootkatone, dihydronootkatone, and tetrahydronootkatone

A technology of dihydronokadone and tetrahydronokadone, which is applied in the field of reaction sequence for synthesizing nokadone, dihydronokadone and tetrahydronokadone, can solve the problem of low yield and hinder commercial application , expensive raw materials and other issues, to achieve the effect of high yield

Inactive Publication Date: 2018-08-21
BOARD OF SUPERVISORS OF LOUISIANA STATE UNIV & AGRI & MECHANICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Valencene is an expensive raw material, but a viable commercial production avoiding its use has yet to be developed
[0008] Existing synthetic methods for the preparation of nokadone suffer from one or more of the following disadvantages: tedious synthesis; relatively expensive starting materials required for synthesis; low yield; purification of intermediates required; use of excess solvent causing waste problems in commercial production ; difficult to handle by-products; synthesis yields a racemic mixture; or one or more starting materials are not on the GRAS list
While the current high price of nokatone may be tolerable in some areas of use (such as seasonings and spices), the lack of less expensive sources of nokatone hinders commercial application in other fields, such as as a drug against termites, Repellants or poisons for ticks, mosquitos or other pests

Method used

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  • Reaction sequence for the synthesis of nootkatone, dihydronootkatone, and tetrahydronootkatone
  • Reaction sequence for the synthesis of nootkatone, dihydronootkatone, and tetrahydronootkatone
  • Reaction sequence for the synthesis of nootkatone, dihydronootkatone, and tetrahydronootkatone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0018] 6,6-Dimethyl-bicyclo[3.3.1]heptan-2-one, nopinone (compound 2): freeze in 160 ml of CH on dry ice at -78 °C 2 Cl 2 β-pinene (compound 1) (40.0g, 294mmol) solution in, and by ozone / O 2 Bubble overnight until blue color persists. Nitrogen was then bubbled through the reaction mixture for 30 minutes. Add CH 2 Cl 2 (160ml) followed by the addition of AcOH (80ml). At 0°C, Zn (40 g) was added in 1 g portions over 4 hours, dry ice was added to the solution to control the temperature. The solution was rotated on a rotary evaporator at 30 °C for 1 h. TLC (10% EtOAc / Hexane, 5% H 2 SO 4 / EtOH dye) showed complete reaction. Then 300ml of water were added and stirred for 10 minutes. Zn was removed by filtration and CH 2 Cl 2 rinse. CH 2 Cl 2 layer and washed again with water, followed by saturated Na 2 CO 3 solution, followed by brine, MgSO 4 Drying and concentration afforded 33.1 g (82% yield) of a colorless oil. The crude product was used directly in the next st...

Embodiment 1B

[0020] 6,6-Dimethyl-bicyclo[3.3.1]heptan-2-one, nopinone (compound 2): Ozone was bubbled through β- Pinene (compound 1) 4.60mL (29.36mmol, 1 equivalent) solution. After 3 hours, use O again 2 Bubbling was carried out for 30 minutes, after which a characteristic blue color in the solution indicated excess ozone and substrate depletion. Adding (CH 3 ) 2 After S (3.7 mL, 49.91 mmol, 1.7 equiv), the mixture was allowed to warm to room temperature and stirred for another 12 h. Transfer the reaction mixture to a separatory funnel and use CH 2 Cl 2 (10mL) and H 2 O (10 mL) diluted. Collect the organic phase and use CH 2 Cl 2 (2 x 10 mL) to extract the aqueous layer. The combined organic extracts were washed with brine and washed with Na 2 SO 4 dry. Concentration under reduced pressure yielded an oil. Flash column chromatography on silica gel using 3.5% to 8.5% EtOAc in hexanes as the detergent yielded a clear oil which was confirmed to be the title compound by NMR spect...

Embodiment 2

[0022] (1R,5R)-6,6-Dimethyl-3-E-ethylenebicyclo[3.3.1]heptan-2-one (Compound 3): Nopinone (9.9g, 71.6mmol) The solution with EtOH (172ml) was cooled to 5°C and KOH (4.72g) was added while stirring. Acetaldehyde (5.74ml dissolved in 43ml EtOH) was added to the reaction over 30 minutes. Four additional portions of acetaldehyde (same amount) were added to the solution at 12 h intervals. The reaction was stirred for an additional 6 hours. p-Toluenesulfonic acid monohydrate was added and the solution was concentrated on a rotary evaporator. Add a small amount of CH 2 Cl 2to dissolve the residue, then hexane was added and the solution was vortexed. The solution was transferred to another flask and concentrated. After flash chromatography (10% EtOAc in hexanes), a colorless oil was obtained (8.6 g, 73% yield). Further purification using Kugelrohr distillation (250°C, 10 mmHg) afforded 6.5 g of product (55% yield). 1 HNMR: (250MHz, CDCl 3 ), δ6.89–6.86(m,1H),2.59–2.56(m,4H),2...

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Abstract

An inexpensive, stereoselective synthesis for nootkatone, tetrahydronootkatone, and their derivatives is disclosed utilizing ozonolysis. The starting materials used in the synthesis are inexpensive and the reactions are commercially feasible and amenable to scaling up. The principal starting material, (-)-[beta]-Pinene, is on the GRAS list (generally recognized as safe).

Description

[0001] priority [0002] This application claims priority to US Provisional Application No. 62 / 265,723, filed December 10, 2015, the contents of which are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to the synthesis of nokadone and its derivatives using ozone oxidation. Background technique [0004] Nokadone (compound 9 in Scheme I) having the structure below occurs naturally in certain plant sources including cedar, vetiver and citrus oils. Nokatone has an aroma reminiscent of grapefruit and is used commercially as a flavoring or aroma ingredient. Nokadone is non-toxic to humans and other mammals, and is considered a GRAS substance by the FDA. [0005] [0006] Nokadone is also active as a repellent or poison against various arthropods including termites, ants, flies, mosquitoes, fleas, lice, ticks, and against certain other invertebrates including nematodes bugs, moles crickets and cockroaches. No new co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12A61K31/35A61K31/122C07C45/00C07C45/27C07C45/40
CPCA61K31/122C07C29/40C07C45/40C07C45/512C07C45/66C07C45/68C07C45/74C07C2602/28C07C2602/42C07C49/433C07C49/653C07C35/28C07C49/693
Inventor 罗格·莱恩
Owner BOARD OF SUPERVISORS OF LOUISIANA STATE UNIV & AGRI & MECHANICAL COLLEGE
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