Efficient scalable syntheses of abscisic acid, 8′-acetylene abscisic acid and 8′-cyclopropyl abscisic acid

Patent metadata

Field	Value
Publication number	US-9725392-B2
Application number	US-201615241564-A
Country	US
Kind code	B2
Filing date	Aug 19, 2016
Priority date	Aug 27, 2015
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Methods are provided for synthesis of abscisic acid and 8′ analogues thereof (including an enantiopure 8′-acetylene analogue) including methods wherein the previously reported first step of oxidation of 2,6-dimethylphenol (VI) to 2,6-dimethylbenzoquinone, mono ketal (VII) is replaced by a novel two step process comprising (i) oxidation of 2,6-dimethylphenol (VI) using potassium peroxymonosulfate with a catalytic amount of iodobenzene to produce 2,6-dimethylbenzoquinone (XVI) and (ii) ketalization of 2,6-dimethylbenzoquinone (XVI) using ethylene glycol, trimethylorthoformate with a catalytic amount of p-toluenesulfonic acid to produce 2,6-dimethylbenzoquinone, mono ketal (VII).

First claim

The invention claimed is:

1. A method of making a compound of formula 1

wherein R is alkyl, cycloalkyl, alkenyl or alkynyl, said method comprising:
a) reacting 2,6-dimethylphenol (VI) with potassium peroxymonosulfate and a catalytic amount of iodobenzene to produce 2,6-dimethylbenzoquinone (XVI);
b) reacting 2,6-dimethylbenzoquinone (XVI) with ethylene glycol and a catalytic amount of p-toluenesulfonic acid to produce 2,6-dimethylbenzoquinone, mono ketal (VII);
c) reacting 2,6-dimethylbenzoquinone, mono ketal (VII) with (Z)-3-methylpent-2-en-4-yn-1-ol (VIII), followed by reduction of the propargylic triple bond to provide allylic alcohol (X);
d) reacting allylic alcohol (X) with MnO 2 to form aldehyde (XI) followed by addition of an organic acid and an alcohol to produce ester (XII), followed by in situ deprotection of ester (XII) in the presence of an acid to produce quinol (XIII); and
e) reacting quinol (XIII) with a carbanion magnesium halide, followed by ester hydrolysis to produce the compound of Formula 1.

2. The method of claim 1 wherein the reduction at step c is performed using Red Al.

3. The method of claim 1 wherein the organic acid is acetic acid and the alcohol is methanol.

4. The method of claim 1 wherein R is a methyl group and the carbanion magnesium halide is methylmagnesium chloride.

5. The method of claim 1 wherein R is a cyclopropyl group and the carbanion magnesium halide is cyclopropylmagnesium bromide.

6. The method of claim 1 wherein R is an alkynyl group and the carbanion magnesium halide is ethynylmagnesium chloride.

7. A method of making a (+)-enantiomer of a compound of formula 1

wherein R is ethynyl, said method comprising:
a) reacting 2,6-dimethylphenol (VI) with potassium peroxymonosulfate and a catalytic amount of iodobenzene to produce 2,6-dimethylbenzoquinone (XVI);
b) reacting 2,6-dimethylbenzoquinone (XVI) with ethylene glycol and a catalytic amount of p-toluenesulfonic acid to produce 2,6-dimethylbenzoquinone, mono ketal (VII);
c) reacting 2,6-dimethylbenzoquinone, mono ketal (VII) with (Z)-3-methylpent-2-en-4-yn-1-ol (VIII), followed by reduction of the triple bond to provide allylic alcohol (X);
d) reacting allylic alcohol (X) with MnO 2 to form aldehyde (XI) followed by addition of an organic acid and an alcohol to produce ester (XII), followed by in situ deprotection of ester (XII) in the presence of an acid to produce quinol (XIII); and
e) reacting quinol (XIII) with (−)-cinchonidine, with an organic or inorganic salt, water and an ethynylmagnesium halide followed by ester hydrolysis to produce the (+)-enantiomer of the compound of Formula 1.

8. The method of claim 7 wherein the reduction at step c is performed using Red Al.

9. The method of claim 7 wherein the organic acid is acetic acid and the alcohol is methanol.

10. The method of claim 7 wherein and the ethynylmagnesium halide is ethynylmagnesium chloride.

11. The method of claim 7 wherein the organic or inorganic salt is lithium triflate.

12. The method of claim 1 wherein the carbanion magnesium halide is alkylmagnesium chloride, cycloalkylmagnesium chloride, alkenylmagnesium chloride or alkynylmagnesium chloride.

Assignees

• Nat Res Council Canada

Inventors

• JHEENGUT Vishal
• Nelson Ken M
• Abrams Suzanne R

Classifications

• C07C67/327

  by elimination of functional groups containing oxygen only in singly bound form · CPC title

• C07C67/40

  by oxidation of primary alcohols · CPC title

• C07C51/09 Primary

  from carboxylic acid esters or lactones · CPC title

• C07C46/06 Primary

  of at least one hydroxy group on a six-membered aromatic ring · CPC title

• C07C2101/16

  Chemistry & Metallurgy · mapped topic