Manufacturing method for high-purity cyclohexenone long-chain alcohol

Patent metadata

Field	Value
Publication number	US-11485696-B2
Application number	US-201716071709-A
Country	US
Kind code	B2
Filing date	Jan 22, 2017
Priority date	Jan 22, 2016
Publication date	Nov 1, 2022
Grant date	Nov 1, 2022

Abstract

This invention relates to a method for producing a high-purity cyclohexenone long-chain alcohol represented by formula I, and produces the compound of formula I by a metal-mediated Barbier reaction. The method of the present invention has advantages in its short scheme, high yield, and high-purity product, and is suitable for industrial scale up.

First claim

The invention claimed is:

1. A method for producing a high-purity cyclohexenone long-chain alcohol represented by formula I, as shown in the following reaction scheme:

wherein
R 4 represents

and R 5 represents amino;
the method comprising the steps of
(1a) subjecting a cyclohexenone long-chain alcohol crude product III and a hydrazine derivative R 4 NHNH 2 to a condensation reaction to obtain a compound II, and
(1b) hydrolyzing the compound II in the presence of an acidic substance to obtain the high-purity compound I.

2. The production method according to claim 1 , wherein the high-purity cyclohexenone long-chain alcohol represented by formula I has a purity by HPLC of more than 95%.

3. The production method according to claim 1 , wherein
step (1a) is performed in the presence of an acid, an alkali, or a desiccant;
the alkali is one member or two or more members selected from the group consisting of sodium alkoxide, potassium alkoxide, magnesium oxide, calcium oxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, calcium carbonate, sodium acetate, potassium acetate, lithium acetate, sodium benzoate, potassium benzoate, lithium benzoate, triethylamine, trimethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, and triethylenediamine;
the acid is one member or two or more members selected from the group consisting of acetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, boron trifluoride ethyl ether, scandium trifluoromethanesulfonate, indium trifluoromethanesulfonate, and bismuth trifluoromethanesulfonate; and
the desiccant is one member or two or more members selected from the group consisting of a molecular sieve, magnesium sulfate, sodium sulfate, and calcium hydride.

4. The production method according to claim 1 , wherein the molar ratio of the hydrazine derivative R 4 NHNH 2 to the cyclohexenone long-chain alcohol crude product III is 0.8:1 to 3:1.

5. The production method according to claim 1 , wherein
the condensation reaction is performed in a solvent;
the solvent is one member or two or more members selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-pentanol, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dioxane, acetone, 2-butanone, ethyl acetate, isobutyl acetate, toluene, xylene, chlorobenzene, benzene, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, chloroform, n-hexane, n-heptane, cyclohexane, and water;
the temperature of the condensation reaction is 0 to 149° C.; and
the reaction time of the condensation reaction is 0.5 to 24 hours.

6. The production method according to claim 1 , wherein
the acidic substance recited in step (1b) is one member or two or more members selected from the group consisting of an organic acid, an inorganic acid, a Lewis acid, an acid salt, and other acidic substance;
the inorganic acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, and phosphotungstic acid;
the organic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid;
the Lewis acid is selected from the group consisting of boron trifluoride ethyl ether, aluminum trichloride, iron trichloride, bismuth trifluoromethanesulfonate, and scandium trifluoromethanesulfonate;
the acid salt is selected from the group consisting of sodium hydrogensulfate, ammonium hydrogensulfate, magnesium hydrogensulfate, pyridinium p-toluenesulfonate, triethylamine hydrochloride, and pyridine hydrochloride;
the other acidic substance is silica gel or acidic resin;
and
the molar ratio of the added amount of the compound II to the added amount of the acidic substance is 1:0.2 to 1:10.

7. The production method according to claim 1 , wherein
the hydrolysis reaction is performed in a solvent;
the solvent is one member or two or more members selected from the group consisting of benzene, toluene, chlorobenzene, xylene, acetonitrile, 2-butanone, acetone, 1,2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphoric triamide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, polyethylene glycol, dioxane, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, chloroform, and water;
the reaction temperature of the hydrolysis reaction is 20 to 139° C., and the reaction time of the hydrolysis reaction is 0.5 to 24 hours.

8. The production method according to claim 1 , wherein the cyclohexenone long-chain alcohol crude product III is produced as shown in the following reaction scheme:

wherein X represents halogen, R 8 represents C 1-7 alkyl, C 6-14 aryl, or

wherein n represents 1 to 12,
PG represents

the method comprising the steps of
(2a) subjecting a compound IV and a compound V to a metal-mediated Barbier reaction to generate a compound VI, and
(2b) subjecting the compound VI to a deprotection reaction in the presence of an acidic substance to remove a protective group, thereby obtaining the cyclohexenone long-chain alcohol crude product III.

9. The production method according to claim 8 , wherein in step (2a),
the metal is selected from the group consisting of lithium, sodium, strontium, magnesium, and zinc,
the molar ratio of the metal to the compound IV is 1:1 to 12:1, and
the molar ratio of the compound V to the compound IV is 0.6:1 to 6:1.

10. The production method according to claim 8 , wherein
the Barbier reaction is performed in the presence or absence of a catalyst,
the catalyst is one member or two or more members selected from the group consisting of tetramethylethylenediamine and hexamethylphosphoric triamide,
the molar ratio of the catalyst to the compound IV is 0.2:1 to 2:1,
the Barbier reaction is performed in a suitable solvent,
the solvent is one member or two or more members selected from the group consisting of benzene, toluene, chlorobenzene, xylene, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, acetonitrile, hexamethylphosphoric triamide, and sulfolane,
the temperature of the Barbier reaction is −20 to 100° C., and
the reaction time of the Barbier reaction is 1 to 36 hours.

11. The production method according to claim 8 , wherein in step (2b),
the acidic substance is one member or two or more members of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, triethylamine hydrochloride, hydrochloric acid, sulfuric acid, phosphoric acid, sodium

Assignees

• Taiho Pharmaceutical Co Ltd

Inventors

• Zhang Jian
• Jiang Dehui
• Shen Xiaojun

Classifications

• C07C311/49

  to nitrogen atoms · CPC title

• C07C45/42 Primary

  by hydrolysis · CPC title

• C07C49/753

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C45/45 Primary

  by condensation · CPC title

• C07C249/16

  of hydrazones · CPC title