Processes for making magnolol derivatives

Abstract

Described herein are high yield methods for making magnolol derivatives, together with novel intermediates and uses thereof.

Claims

1. A method for making 3,3-diallyl-biphenyl-2,2-diol or 3,3-dipropyl-biphenyl-2,2-diol, comprising heating neat 2,2-di(allyloxy)-biphenyl at a temperature of about 210 C. for a period of about six hours until it is substantially converted to 3,3-diallyl-biphenyl-2,2-diol, and optionally hydrogenating the 3,3-diallyl-biphenyl-2,2-diol to obtain 3,3-dipropyl-biphenyl-2,2-diol.

2. The method of claim 1, further comprising reacting biphenyl-2,2-diol with an allyl halide to obtain 2,2-di(allyloxy)-biphenyl.

3. The method of claim 2 wherein the allyl halide is selected from 3-chloroprop-1-ene and 3-bromoprop-1-ene.

4. The method of claim 1 comprising hydrogenating 3,3-diallyl-biphenyl-2,2-diol to obtain 3,3-dipropyl-biphenyl-2,2-diol.

5. The method of claim 4 wherein the hydrogenation is accomplished using a metal catalyst.

6. The method of claim 4, wherein the hydrogenation is accomplished with palladium/10% charcoal in methanol under hydrogen at 25 C. for 12 hours.

7. The method of claim 5, wherein the metal catalyst is Raney nickel.

Description

DETAILED DESCRIPTION

(1) The invention thus provides a method (Method 1) for making isomagnolol (3,3-diallyl-biphenyl-2,2-diol) or tetrahydro-isomagnolol, (3,3-dipropyl-biphenyl-2,2-diol), comprising heating 2,2-di(allyloxy)-biphenyl until it is substantially converted to 3,3-diallyl-biphenyl-2,2-diol, 1.1. Method 1 wherein the 2,2-di(allyloxy)-biphenyl is heated neat at a temperature in excess of 175 C., e.g. 200-220 C., e.g., about 210 C. 1.2. Any of the foregoing methods wherein the period of heating is at least 4 hrs, e.g. 408 hrs, e.g. about 6 hrs. 1.3. Any of the foregoing methods further comprising hydrogenating the 3,3-diallyl-biphenyl-2,2-diol e.g., in the presence of a metal catalyst, e.g., a palladium or nickel catalyst, to obtain 3,3-dipropyl-biphenyl-2,2-diol. 1.4. Any of the foregoing methods further comprising reacting biphenyl-2,2-diol with an allyl halide, e.g., 3-chloroprop-1-ene or 3-bromoprop-1-ene to obtain 2,2-di(allyloxy)-biphenyl.

(2) In another embodiment, the invention provides 2,2-di(allyloxy)-biphenyl, together with methods of making it comprising reacting biphenyl-2,2-diol with an allyl halide, e.g., 3-chloroprop-1-ene or 3-bromoprop-1-ene, e.g., in the presence of a base, e.g. potassium carbonate, in the presence of a polar aprotic solvent, e.g., acetone, e.g., at reflux.

(3) As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

(4) Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material.

(5) The invention is further described in the following examples. The examples are merely illustrative and do not in any way limit the scope of the invention as described and claimed.

EXAMPLES

Example 1

Synthesis of 2,2 -di(allyloxy)-biphenyl

(6) In the first step of the synthesis, 2,2-di(allyloxy)-biphenyl is made as follows, using either allyl bromide or allyl chloride to react with biphenyl-2,2-diol:

(7) ##STR00001##

Example 2

Synthesis of 3,3-diallyl-biphenyl-2,2-diol (isomagnolol)

(8) 3,3-diallyl-biphenyl-2,2-diol is made as follows, simply by heating the material of the previous example:

(9) ##STR00002##

Example 3

Synthesis of 3,3-dipropyl-biphenyl-2,2-diol (tetrahydro-isomagnolol)

(10) 3,3-diallyl-biphenyl-2,2-diol is hydrogenated in the presence of a metal catalyst to obtain the title compound:

(11) ##STR00003##