AU654937B2 - Racemic nordihydroguaiaretic acid and intermediates - Google Patents

Description

la RACEMIC NORDIHYDROGUAIARETIC ACID AND INTERMEDIATES Technical Field This invention pertains to organic compounds and their syntheses, in particular to d,l-nordihydroguaiaretic acid, and optically active intermediates.

Background Art In the past, meso-nordihydroguaiaretic acid, (NDGA), expensively derived from Larrea divaricata or Larrea tridentata, the creosote bush, or synthesized from phenyl S. ethers, has been used as a food additive and anti-oxidant.

Optically active NDGA and racemic mixtures thereof are 15 also useful for this purpose. The d,l form, as distin- S* guished from the meso form, gives a pleasant, rather medicinal odor to soaps, lotions, ointments and toilet articles in general; and is more soluble than its meso isomer. The optically active NDGA (and racemic mixture thereof) of this invention is distinguished from the meso form by its melting point of 157*C ;to 160 0 C, as opposed to the 185°C to 186°C melting point of the meso form.

S

L Racemic 2,3-dimethyl,1,4-bis(3,4-dimethoxyphenyl)-1,4t.t butanedione has served as an intermediary in the synthesis t 25 of meso-NDGA in prior art processes, but the optical 1t ~orientation of the 2,3-dimethyl bonds has been lost in subsequent processing steps. This invention involves the preservation of the optical orientation of these bonds thrqugh reduction, methylation and cleavage steps to produce optically active molecules, or a racemic mixture of NDGA, as well as the diols and ethers intermediate to the synthesis. Insofar as the optically active isomers and racemic mixture of NDGA may be utilized in place of the meso form thereof, the synthesis of d,l-NDGA provided herein fulfills the need for an easier, less expensive method of production, providing product in higher yields -2than prior art processes, without the use of high pressure hydrogenation equipment and expensive catalysts.

Relevant Art U.S. Patent No. 2,456,443 to Mueller et al., provides a synthesis of an NDGA of melting point 185*-186 0 C (the melting point of the meso form) by bromination of safrole (3,4-methylenedioxy-alkylbenzene), coupling the resultant molecules to form 2,3-bis(3,4-methylenedioxybenzyl)butane, chlorinating this compound to form 2,3-bis(3,4dichloromethylenedioxybenzyl)-butane, and hydrolyzing this compound to form NDGA. The intermediates of the S present process are not involved.

U.S. Patent No. 2,644,822 to Pearl discloses proc- 15 esses for reacting benzaldehydes having a hydroxy group r or a potential hydroxy (oxy) group at the 4-position (para to the aldehyde group) and at least another hydroxy or potential hydroxy group at the 3-position to produce ketone and diol intermediaries, and a final nordihydroxybutanediol product. Where the examples provide melting points for this product, they are given as 165°-186.5°C, corresponding with the meso form of the product. In each Scase, the diols are formed from ketones by means of bimolecular reductions. The process of the present 25 invention does not utilize bimolecular reduction, but ,J rather the reduction of a diketone.

C. W. Perry, M. V. Kalnins and K. H. Deitcher, "Synthesis of Lignans, I. Nordihydroguaiaretic Acid," J.

Org. Chem. 37, 4371 (1972) discloses the synthesis of meso-NDGA by alkylation of the sodium enolate of propioveratrone (3,4-dimethoxypropiophenone) with alpha-bromopropioveratone (alpha-bromo-3,4-dimethoxypropiophenone) to form racemic 2,3-dimethyl,1,4-bis(3,4-dimethoxyphenyl)l,4-butanedione. Cyclodehydration of this racemic diketone produces all-cia 3,4-dimethyl, 2,5-bis 3,4dimethoxyphenyl)tetrahydrofuran which is hydrogenated at '1 -3high pressure to produce the tetramethyl ether of NDGA, this composition being further dealkyla ed to form the meso product.

U.S. Patent No. 3,769,350 to Perry discloses a method for synthesizing meso-NDGA from a protected ortho dihydroxybenzene. The claims of this patent are drawn to the synthesis of racemic 2,3-dimethyl-l,4-bis(3,4dialkoxyphenyl)l,4-butanedione, the starting material of the present process. This racemic composition is an intermediary in the process described in the patent for synthesizing meso-NDGA; however, unlike the present i process, the patent discloses the conversion of this diketone i-termediary to 3,4-dimethyl-2,5-bis(3,4dialkoxyphenyl)-furan, and from thence through several 15 routes to the final product. As in the above-described article, hydrogenation of the furan is conducted under pressure. Unlike the present invention, the process disclosed in the Perry patent and article does not produce optically active NDGA, nor a racemic mixture thereof. Further, the Perry process requires the use of expensive and potentially dangerous high-pressure hydrogenation equipment which is not required to produce the S' isomer produced by the present invention.

U.S. Patent No. 3,843,728, a division of the above 1 25 Patent No. 3,769,350, discloses the same process and iL' claims racemic 2,3-dimethyl,1,4-bis(3,4-dialkoxyphenyl)1,4-butanedione compounds.

U.S. Patent No. 3,906,004, also a division of the above Patent No. 3,769,350, discloses the same process and claims the synthesis of meso-2,3-dimethyl-1,4bis(3,4-dialkoxyphenyl)-butanedione from 3,4-dimethyl- The d,l form of the tetramethylether intermediate of d,1-NDGA (1,4-bis(3,4-dimethoxyphenyl)2,3-dimethyl butane) has been described by A. W. Schrecker, "Meso- Dihydroguaiaretic Acid and its Derivatives," J. Amer.

-4- Chem. Soc., 79, 3823 (1957), along with an optically active isomer thereof.

Three d,l-diketone intermediates of the present process (1,4-bis(3,4-dimethoxyphenyl),2,3-dimethylbutanone, 2,3-bis(3,4-methylenedioxy benzoyl)butane, and 2-(4-benzyloxy-C-methoxybenzoy) ,3-(3,4-methylenedioxy butane) have been described in T, Biftu, B. G. Hazra, R. Stevenson and J. R. Williams, J.C.S. Perkin I, 1147 (1978). The article describes the reduction of the S" 10 racemic diketone by lithium aluminum hydride to a racemic diol. It also describes the direct hydrogenation of the d,l-diketone, using large amounts of palladium-carbon catalyst, to the d,1-tetramethyl ether.

In another article, T. Biftu, B. G. Hazra, and R. Stevenson, J.C.S. Perkin I, 2276 (1979), another d,l-diketone related to the diketone of the present process (1,4-bis(3,4,5-trimethoxyphenyl),2-3-dimethyl butane) is described. The diketone is reduced with Sets. lithium aluminum hydride to a racemic diol, which is :'12 0 hydrogenated with a palladium-carbon catalyst to the d,l-tetramethyl ether.

1 c, The use of a 48 percent solution of hydrogen bromide t to dealkylate a solution of a desmethyl tetramethyl ether (1,4-bis(3,4-dimethoxyphenyl)-butane) in glacial acetic c acid, to form desmethyl NDGA (1,4-bis(3,4-dihydroxyphenyl)butane) is described in O. Gisvold, D. Buelow, and E. H. Carlson, J. Am. Pharm. Assoc. 35, 188-91 (1946).

None of the foregoing prior art discloses the synthetic method of this invention, nor the optically active isomers of NDGA.

Summary of the Invention This invention is directed to the synthesis of compositions composed of optically active molecules of the formula:

R

SR

R1 0

CH

3

R

2 0 R 6

/,CH

3

OR

3

OR

4 wherein R 1

R

2

R

3 and R 4 are independently H, lower 10 alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups, t r. and/or R 1 and R 2 taken together, and/or R 3 and R4 taken t: together, may form lower alkylene radicals; and, RS and S'1 R 6 are independently H, OH, O, lower alkoxy and lower aralkoxy groups. In the structural formulae given 15 throughout this application, the substituents which are attached to the molecule above the plane of the molecule are designated by T and those below the plane are designated by 5. Where no stereo-orientation is indicated, the substituents in the compound designated thereby can be either in their R or S orientation, and the compound can be a mixture of R and S isomers. Where the term S "optical activity" is used herein it pertains only to bonds depicted by V and/or 5. The optical orientation or asymmetry resulting from other bonds not so depicted is irrelevant. Unless otherwise specified, where only one optically active compound is depicted, its antipode, as well as racemic mixtures of both antipodes, are intended, it being understood that the orientation of these bonds is not altered throughout the process of this invention, so that the specific form of the starting material will determine the specific form of the intermediate compositions and final product.

A stereo-selective synthesis of d,l-nordihydroguaiaretic acid (d,1-2,3-dimethyl,1,4-bis(3,4-dihydroxyphenyl)butane) is provided in which the starting material -6is a diketone of optically active molecules of the formula: CH 3 I OR 4 where R 1 R 2

R

3 and R4are as above described.

Formula I is reduced to form optically active molecules of a diol of the formula:

C.

C'

C t

OR

4 Formula II is alkylated to form optically active molecules of the formula: CH 3 OR 3 OR 4

III.

where Rand R, are independently lower alkyl, alkenyl, aryl., aralkyl or aralkenyl, or uilyl, or substituted -I N FMW- ~Liii~ i i i i i t~; -7silyl with from one to three substituents which are, independently, lower alkyl, alkenyl, aryl, aralkyl or aralkenyl groups.

Formula III is then cleaved to form optically active molecules of the formula:

R

1 0 CH 3

R

2 0 CH 3 00

OR

3

IV.

0.o0

OR

4 *o o 15 Compound IV is then cealkylated to form optically oeo"e active molecules of NDGA: o 0 00 HO CH 3 HO C H 4000 3 3 OH v.

H V.

25

OH

0o Detailed Description of the Preferred Embodiments: i 0' As used throughout this application, the term "lo'w.'r alkyl" refers to both straight and branched chain hydrocarbon groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, etc., and the term "lower alkoxy" refers to the corresponding methoxy, ethoxy, etc.

groups. The term "lower alkylene" includes both straight and branched chain alkylene radicals containing from 2 to 6 carbon atoms such as methylene, ethylene, propylene, butylene, isobutylene, etc. The term "lower aralkyl" or

J

-8- "lower aralkenyl" refers to aralkyl or aralkenyl groups containing from 7 to 14 carbon atoms, such as phenyl lower alkyl, benzyl, phenylethyl, etc., and the term "lower aralkoxy" refers to the corresponding aralkoxy groups. The term "halogen" includes all four halogens, iodine, bromine, chlorine and fluorine.

In accordance with this invention, the starting material is a compound described by Formula I above obtained by means of syntheses known to the prior art, such as that described in U.S. Patent No. 3,769,350.

In the specific embodiments described below, R 1

-R

6 are methyl groups. Although it is understood that other substituents, as above defined may also be used.

So Molecules of optically active 1-4-bis(3,4-dimethoxyphenyl),2,3-dimethylbutane-1,4-dione (Formula I) are 40 converted to molecules of optically active 1-4-bis(3,4v* dimethoxyphenyl),2,3-dimethyl-butane-1,4-diol (Formula II) by reduction. Standard reducing agents such as sodium borohydride and lithium aluminum hydride may be used to carry out this reaction, and preferably the reducing agent is lithium aluminum hydride. The reaction is carried out in an inert organic solvent, preferably tetrahydrofuran, although any conventional solvent may be used, including water, methanol, ethanol or diethyl 25 ether. The reaction may be carried out at a temperature of between about 0°C and about 100°C, and preferably the 'e" 1 materials are mixed at about 0°C and slowly warmed to reflux temperatures. Product yields of between about and about 100 weight percent are obtained. Critical to obtaining such yields are the maintenance of an excess of the reducing agent and neutral to basic conditions.

Optically active molecules of 1-4 bis(3,4-dimethoxyphenyl)2,3-dimthyl-butane-l,4-diol (Formula II) are then methylated to form optically active molecules of 1,4bis(3,4-dimethoxyphenyl),2,3-dimethyl 1,4-dimethoxy-butane (Formula III). An alkali metal hydride, preferably -9sodium hydride, and a dry dialkyl formamide, preferably dimethylformamide, or other suitable solvent such as tetrahydrofuran or dimethyl sulfoxide, are mixed with the diol, the hydride being added in excess amounts, namely at a molar ratio of reagent to starting compound of greater than about 2 and less than about 5. Methyl iodide (or other suitable alkyl halogen such as methyl bromide or ethyl iodide is then added to the mixture, also in excess, at a molar ratio of alkyl halogen to S 10 starting compound of greater than about 2 and less than about 5. The reaction is preferably carried out at "ambient temperature, for a period of between about and about 1 hour. Yields of between about 90 and about I 100 weight percent are obtained when excess reagents over starting compounds are used, and the reaction is kept free of water and hydroxylic solvents.

Optically active molecules of 1,4-bis(3,4-dimethoxyphenyl),2-3-dimethyl-l,4-dimethoxy-butane (Formula III) are then reacted to form 1,4-bis(3,4-dimethoxyphenyl),2-3-dimethyl-butane (Formula IV) utilizing a Smixture of sodium and ammonia in an inert organic solvent such as, preferably, tetrahydrofuran. Preferably, an Sexcess of sodium is used, and the mixture is kept free of Swater or other hydroxylic solvents. Other reagents known to the art may be used to effect the cleavage, including lithium or potassium in lower alkyl amines; and other conventional inert organic solvents such as ethyl ether, and benzene may also be employed. The reaction is carried out at a temperature of between about -80 0 C and about -330C. The mixture is allowed to react for between about 10 and about 20 minutes, after which time the reaction should be stopped with a reagent such as ethanol or methanol. Allowing the reaction to go on for additional lengths of time results in reduction of the rings to a complex mixture. Yields of between about 90 and about 100 weight percent are obtained.

Optically active molecules of 1,4-bis(3,4-dimethoxyphenyl),2,3-dimethyl-butane (Formula IV) are then converted to optically active molecules of nordihydroguaiaretic acid (1,4-bis(3,4-dihydroxyphenyl),2,3dimethyl-butane) (Formula V) by dealkylation. Preferably the dealkylation is carried out utilizing a halogen acid, preferably hydrobromic acid, in a solution of a concentration of about 48 percent plus or minus about 10 pert, cent. The starting material and reagent, preferably at a mole ratio of greater than about 4, are heated in the absence of air, in a vacuum or inert atmosphere such as r E nitrogen or argon, to between about 100°C and about 130°C for at least about 8 to about 10 hours, and preferably about 9 hours. A yield of between about 90 and about 15 100 weight percent is obtained. Critical to obtaining such yields are the use of excess acid and the complete exclusion of oxygen.

O.verall yield of d,l-nordihydroguaiaretic acid for the total synthesis beginning with the Formula I diketone 20 is between about 45 and about 100 weight percent.

It is understood that the orientation of the carbon- 9 methyl bonds in the 2,3-butane position remains unchanged t throughout all the above reactions, and that the orientation of these bonds in the starting diketone determines I 25 the orientation of the:a bonds in the final product.

Further, where the final product is a racemic mixture, the mixture may be separated into its antipodes by means known to the art.

The invention is further illustrated by the following examples: iil-

EXAMPLES

EXAMPLE 1 05 1,4-bis(3,4-dimethoxyphenyl), 2,3-dimethyl butane-1,4-diol To 1 g of lithium aluminum hydride suspended in 100 ml of tetrahydrofuran and cooled to ice temperatures 1 cV 10 under dry nitrogen was added 3.86 g of the starting C diketone, 1,4-bis(3,4-dimethoxyphenyl),2,3-dimethyl r. butane-1,4-dione, in 30 ml of dry THF. The mixture was Sallowed to slowly come to room temperature while stirring j and finally refluxed for 1 hour and then allowed to stand S 15 overnight. One ml of saturated sodium sulfate solution was added dropwise and stirring continued for several hours. Filtration and evaporation gave a colorless oil that crystallized on addition of ether. A yield of 3.93 g was obtained. IR spectra showed no carbonyl.

EXAMPLE 2 1,4-bis(3,4-dimethoxyphenyl),2,3-dimethyl 2 1,4-dimethoxy butane 23 t To 3.9 g of starting diol in 20 ml of dried dimethyl formamide, stirring under nitrogen atmosphere, was added sodium nydride (washed repeatedly with dry hexane) in small portions until a large excess had been added.

Methyl iodide was ten added in excess and stirring continued for 1 hour. Water was added and the mixture was extracted with chloroform, the CHCL 3 evaporated and the residue run through a short silica gel column to remove Mr. Yield was 4.0 g (95 percent theoretically) of colorless goo that showed no carbonyl (DMF) in the IR spectra.

r.

I -12- EXAMPLE 3 1,4-bis(3,4-dimethoxyphenyl),2,3-dimethyl butane To approximately 100 mg of sodium, stirring in 200 ml of dry liquid NH 3 at -80 0 C, was added 1.6 g of starting compound in 20 ml of dry THF. The blue color faded about halfway through the addition and another approximately 100 mg of sodium was added, followed by the S, 10 remainder of the starting material. Additional sodium r t was added and the blue color maintained for 14 minutes at i "t -80 0 C. An additional 20 ml of dry THF was used to wash I l starting material from the syringe. Three ml of ethanol was added quickly to stop the reaction. The NH 3 and THF were evaporated under N 2 100 ml of water was added and the product extracted into chloroform. Evaporation gave 1.4 g of colorless oil.

S t C. EXAMPLE 4 cet d-l NDGA Sr c f l To 100 mg of the starting tetramethyl ether in a heavy walled glass tube under nitrogen was added 1 ml of Ite t 25 48 percent hydrobromic acid. The tube was frozen in a liquid nitrogen bath and sealed in a vacuum. The tube was heated to 126 0 C and stirred magnetically for 9 hours.

After cooling overnight the tube was opened and water added and the solid product 82.6 mg (98 percent theoretically) filtered off. Gas chromatography mass spectrometry testing of the trimethyl silyl derivative showed this product to be about 95 percent racemic NDGA with the major impurity being two isomers of a trimethyl product with methyl at the 1-butane position.

-i -13- Although the foregoing invention has been described in so;,a detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the invention, as limited only by the scope of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

t C t i t t t t St' C C Ah

I;;

Claims (15)

1. A compound selected from the group consisting of optically active nordihydroguaiaretic acid isomer of the formula: Ic I~ I C: 41 It St I *I 1 4 4 its antipode, and racemic mixture thereof. 15 2. A compound selected from the group consisting of isomer of the formula: I C se* 44 1 4, 4411 e t 4e rt t t CH 3 CH 3 OR 3 OR 4 wherein R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl and aralkyl, and R 5 and R 6 are lower alkyl, alkenyl, aryl, aralkyl or aralkenyl groups, or silyl, or substituted silyl with from one to three substituents which are lower alkyl, alkenyl, aryl, aralkyl or aralkenyl groups; its antipode, and racemic mixture thereof.

3. A compound according to claim 2 in which R 1 R 2 R 3 R 4 R 5 and R 6 are methyl. 940914,p:\oper\ee,63867blo.spe,14 mm-

4. A process for preparing optically active nordihydroguaiaretic acid isomer selected from the group consisting of the formula: CH 3 CH 3 its antipode, and racemic mixture thereof comprising: dealkylating a compound selected from compounds of the formula: t 4 4 t t I t 1t 1 4 44 t tt t I,. tit* «14 t I t t 4' I t 44'r ~4 c 44' R1O 2 CH 3 CH 3 OR 3 OR 4 20 where R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl and aralkyl; its antipode and racemic mixture thereof. A process according to claim 4 wherein R 1 R 2 R 3 and R 4 are methyl.

6. A process according to claim 4 or claim 5 wherein the hydrogenation is carried out using a solution of hydrobromic acid refluxing for a period of between about 8 and about 10 hours.

7. A process according to any one of claims 4 to 6 wherein the starting material and final product are racemic mixtures, and the final product is resolved into its d- and 1- antipodes. 940914,p:\oper\ee,63867blo.spc,15 X. -16-

8. A process according to any one of claims 4 to 7 wherein the starting material is obtained by cleaving the 1-4 butane oxy substituents from a compound selected from compounds of the formula: OR OR 4 I; II where R 1 and R2 are lower alkyl and aralkyl, R 3 and R4 are lower alkyl and aralkyl, and R 5 and R 6 are lower alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups, or silyl, or substituted silyl with from one to three substituents which are lower alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups; its antipode, and racemic mixture thereof.

9. A process according to claim 8 wherein R 1 R 2 R 3 R 4 R 5 and R 6 are methyl. A process according to claim 8 or claim 9 wherein the reaction product is a racemic mixture, and is resolved into its d- and 1- antipodes.

11. A process according to any one of claims 8 to 10 in which the starting material is prepared by alkylating a compound selected from compounds of the formula: OH OR 4 940914,p:oper\e,63867bo.spe,16 0 0 0 S 17 where RI and R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl and aralkyl; its antipode and racemic mixture thereof.

12. A process for preparing an optically active compound selected from compounds of the formula: R 1 0 R 2 0 t I OR 4 where RI and R 2 are lower alkyl and aralkyl, and R5and R 6 are lower alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups, or silyl, or substituted silyl with from one to three substituents which are lower alkyl, alkenyl, aryl, arakl or aralkenyl groups; its antipode and racemic mixture thereof, comprising alkylating a compound selected from compounds of the formula: It i t C 4 t t. RO1 R 2 0 OR 4 where RI, R 2 are lower alkyl and aralkyl, and R 3 and R4are lower alkyl and aralkl; its antipode and racemic mixture thereof.

13. A process according to claim 11 or claim 12 wherein all radicals are methyl. 940914,p: \cpr~c,63867b~o.spc, 17 b 0 18

14. A process according to any one of claims 11. to 13 wherein the reaction product is a racemic mixture and is resolved into its d- and 1- antipodes. A process according to any one of claims 11 to 14 wherein the starting material is prepared by reducing a diketone selected from diketones of the formula: R 1 0 H 3 R 0 0 4'CII 10R2 OR 3 04 4 where R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl CC C, tC and aralkyl; its antipode and racemic mixture thereof.

16. A process according to claim 15 wherein the reduction is carried out using a solution of sodium borohydride and lithium aluminum hydride in an inert organic solvent and at a temperature of between about 0 *C and about 100 0 C. A process according to claim 16 wherein the inert organic solvent is selected from the group consisting of tetrahydrofuran, water, methanol, ethanol and diethyl ether.

18. A process according to any one of claims 15 to 17 wherein all radicals are methyl.

19. A process according to any one of claims 15 to 18 wherein the reaction product is a racemic mixture and is resolved into its d- and 1- antipodes. 940914,p:\opcr\oe,63867blo.spe,18 19 A process for preparing optically active nordihydroguaiaretic acid isomer selected from the group consisting of formula V: CH 3 CH 3 its antipode, and racemic mixture thereof comprising: reducing a diketone selected from diketones of formula 1: 4 9 9 9 *ooo 9* *0 9 0 9 99 9. 99 U 9 9 .99 9 9 9 .999 0 *999 9099 9~

999. ~9 .9 .9,9 9 9 99 9', 99 9 .999 9 RO1 R 2 0 its antipode and racemic mixture thereof; where R 1 an~d R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl and aralkyl; alkylating a compound selected from compounds of formula H: RO1 OR 4 its antipode and racemic mixture thereof, e.. 9 4 0914,p~koper\ec,63867blo.spe,19 jl 11 where R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R 4 are lower alkyl and aralkyl; cleaving the 1-4 butane oxy substituents from a compound selected from compounds of formula III: R 1 0 R O 1' (III) CH 3 OR 4 a aa 4r a a a.. 4 4 a a 4a t its antipode and racemic mixture thereof; where R 1 and R 2 are lower alkyl and aralkyl, R 3 and R 4 are lower alkyl and aralkyl, and R 5 and R6 are lower alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups, or silyl, or substituted silyl with from one to three substituents which are lower alkyl, alkenyl, aryl, aralkyl, or aralkenyl groups; and dealkylating a compound selected from compounds of formula IV: R 1 0 R20 0 CH 3 CH 3 OR 3 (IV) OR 4 its antipode and racemic mixture thereof; where R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R4 are lower alkyl and aralkyl. 21. A method of imparting a pleasant, medicinal odor to a composition selected from tke group consisting of soaps, toilet articles, ointments, and lotions comprising 940914,p:\oper\ec,63867blo.spe,20 (2ii skT9 I -21 mixing into said composition, a compound selected from the group consisting of optically active nordihydroguaiaretic acid isomer of the formula: its antipode, and racemic mixture thereof. F~c Cr C AS 22. A method of imparting a pleasant, medicinal odor to a composition selected from the group consisting of soaps; toilet articles, ointments, and lotions comprising 15 mixing into said composition, a compound selected from the group consisting of isomers of the formula: OR5 CH R 2 01 O R CH where R 1 and R 2 are lower alkyl and aralkyl, and R 3 and R4 are lower alkyl and aralkyl, and R 5 and R 6 are lower alkyl, alkenyl, aryl, aralkyl or aralkenyl groups, or silyl, or substituted silyl with from one to three substituents which are lower alkyl, alkenyl, aryl, aralkyl or aralkenyl groups; its antipode and racemic mixture thereof. 23. A method according to claim 22 wherein the compound is one in which R 1 -R 6 are methyl. V3 A4,3 $I r i 24. A compound according to claim 1 or claim 2 substantially as hereinbefore 940914,p:\oper\ee,63867blo.sp.e21 t 4 22 described with reference to any one of the examples. A process according to any one of claims 4 to 20 substantially as hereinbefore desc~lbed with reference to any one of the examples. DATED this 14th day of September, 1994. BLOCK DRUG COMPANY By Its Patent Attorneys DAVIES COLLISON CAVE t I C~ C 4' CC It C C C I IC t ICC *IIC CCC I C It CI I C 'C CCC~ 940914,p:\oper\e,63867bl.spC,22