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Process for preparation of bicyclo [2.2. 2] octane-1, 4-diol

A kind of technology of 2-a, cyclohexane, applied in the field of synthetic organic chemistry

Pending Publication Date: 2022-06-03
EASTMAN CHEM CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Unfortunately, the bridgehead substituents of various bicyclic systems including the bicyclo[2.2.2]octane system are inert to nucleophilic substitution

Method used

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  • Process for preparation of bicyclo [2.2. 2] octane-1, 4-diol
  • Process for preparation of bicyclo [2.2. 2] octane-1, 4-diol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 1,4-bis((trimethylsilyl)oxy)cyclohexane-1,3-diene

in consecutive N 2 The oven-dried 100 mL round bottom flask was cooled with a purge. The flask was then charged with 1,4-cyclohexane-1,4-dione (1 g, 8.9 mmol, 1.00 equiv) and CH 2 Cl 2 (30 mL), followed by the separator. 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) (CAS number: 6674-22-2) (6.79 g, 44.6 mmol, 5.00 equiv) and trimethylchlorosilane (TMSCl) (3.88 g, 35.7 mmol, 4.00 equiv) was added dropwise resulting in a mild exotherm. Once the addition of TMSCl was complete, the reaction mixture was heated to 40°C and stirred until 1 H NMR analysis showed complete conversion of the starting material, usually in 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated on a rotary evaporator at room temperature. The resulting slurry was diluted with heptane (30 mL) causing the phases to separate. The upper phase was decanted in a separation funnel and washed with wa...

Embodiment 2

[0021] Example 2 (1s,4s)-1,4-bis((trimethylsilyl)oxy)bicyclo[2.2.2]octane-2-ene

A 100 mL autoclave was charged with 1,4-bis((trimethylsilyl)oxy)cyclohexane-1,3-diene (3 g, 11.70 mmol, 1.00 equiv) and p-xylene. The autoclave was sealed and purged three times under nitrogen atmosphere. The autoclave was pressurized to 500 psi with ethylene, the stirring speed was set to 500 rpm, and the autoclave was heated to 250 °C, resulting in an internal pressure of 4000 psi. This condition was maintained for 6 hours. Once this holding period was over, stirring was stopped and the autoclave was allowed to cool. The reaction mixture was then transferred to a separation funnel and washed with water (3 x 20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give crude product (2.2 g, 66% yield).

[0022] 1 H NMR (CDCl 3 , 500MHz) δ 6.04(s, 2H), 1.74(d, J =6.9 Hz, 4H), 1.53(d, J =6.3, 4H), 0.15 (s, 18H).

Embodiment 3

[0023] Example 3 Bicyclo[2.2.2]octane-1,4-diol (1)

Option A method:

The crude (1s,4s)-1,4-bis((trimethylsilyl)oxy)bicyclo[2.2.2]octane-2-ene from Example 2 was placed in a Paar shaker vessel Dissolve in 30 mL of methanol. To this vessel was added 2.2 grams of Pd / C. The vessel was pressurized to 20 psi under an atmosphere of hydrogen and the mixture was shaken for 6 hours. Subsequently, the reaction mixture was filtered through a pad of celite and concentrated. by using CH 2 Cl 2 The crude product was isolated by trituration with heptane to give the title compound in 51% yield.

[0024] Option B method:

Alternatively, to crude (1s,4s)-1,4-bis((trimethylsilyl)oxy)bicyclo[2.2.2]octane-2-ene (8.39 g) The same hydrogenation conditions were described using 2.2 grams of Pd / C and the mixture was shaken under 20 psig of hydrogen for 6 hours. After filtration and concentration, 1 H NMR analysis showed complete reduction of the olefin, but retention of the trimethylsilyl g...

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Abstract

The present invention provides a process for the preparation of a bicyclo [2.2. 2] octane-1, 4-diol starting from a cyclohexane-1, 4-dione. The diketone is reacted with certain trialkylsilyl halides or trimethylsilyl trifluoromethanesulfonic acid esters in the presence of a non-nucleophilic base to obtain silyl-substituted dienes, which in turn are reacted with ethylene and subsequently reduced to obtain the title compound.

Description

Field of Invention [0001] The invention belongs to the field of synthetic organic chemistry. In particular, it relates to a process for the preparation of bicyclo[2.2.2]octane-1,4-diol starting from cyclohexane-1,4-dione. Background of the Invention Bicyclo[2.2.2]octane substituted at the 1- and / or 4-position is of great commercial interest. See, for example: (a) Joel G. Whitney, W. A. ​​Gregory, J. C. Kauer, J. R. Roland, Jack A. Snyder, R. E. Benson and E. C. Hermann "Antiviral agents. I. Bicyclo[2.2.2]octan- and-oct-2 -enamines", J. Med. Chem., 1970, 13, 254-60; (b) US Patent No. 3,546,290; (c) "4-Pyridyl and 4-(substituted-pyridyl) bicyclo[2.2.2]octane- 1-amines", US Patent No. 3,367,941; and (d) Bicyclo [2.2.2] Acid GPR120 Modulators, US Patent Application No. 2016 / 0039780. [0003] Unfortunately, the bridgehead substituents of various bicyclic ring systems, including the bicyclo[2.2.2]octane system, are inert to nucleophilic substitution. Therefore, it would be us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804
Inventor R·J·夏普
Owner EASTMAN CHEM CO
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