CA1110240A - Dibenzo b,d, pyranones useful as intermediates in the production of pharmaceuticals - Google Patents

Abstract

A B S T R A C T
Intermediates useful in the production of novel 9-hydroxydibenzo[b,d]pyrans which have analgesic, by potensive immuno suppresant and tranquilizing anti-secre-tory and anti-anxiety properties and having the formula:

wherein R1 is hydrogen, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken in-dividually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group;
each of R4 and R5 is hydrogen, methyl or ethyl;
Z is (a) alkylene having from one to nine carbon atoms; (b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than 9;
each of m and n is 0 or 1;
X is O, S, SO and SO2; and W is methyl, phenyl, p-chlorophenyl, p-flourophenyl, pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substi-tuent is phenyl, p-chlorophenyl or p-fluorophenyl;
with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-;
may be obtained by reaction of

Description

~$1~!Z~

This application is divided out of Application No.
263,717 which relates to novel dibenzopyrans and more parti-cularly to l,9-dihydroxy-hexahydrodibenzopyrans having in the 3-position (1) an aryl or cycloalkyl group (W) linked to said position by an alkylene group; or (2) a methyl, aryl or cycloalkyl group linked to said position vla (a) O, S, SO or S2 groups; or (b) an alkylene group interrupted by an O, S, SO or SO2 group; or tc) an alkylene group attached to said 3-position or to said methyl, aryl or cycloalkyl groups by O, S, SO or SO2; and to the use of such dibenzopyrans and derivatives thereof as analgesic, hypotensive, antisecretory and anti-anxiety agents, as immuno~suppressants and tranquil-izers in mammals, including man.
The present application is directed to dibenzo-[b,d]pyran-9(8H)ones of use as intermediates in the produc-tion of such active compounds.
Despite the current availability of a number of ` analgesic agents, the search for new and improved agents con-tinues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other more potent analgesic agents such as d-propoxyphene, codeine and morphine, possess addictive liability. The need for im-proved and potent analgesic agen~s is, therefore, evident.
The analgesic properties of 9-nor-9B-hydroxyhexa-hydrocannabinol and of other cannabinoid structures, such as ~8-tetrahydrocannabinol (~8-THC) and its primary metabolite, --2~
ll-hydroxy-~-THC have been reported by Wilson and May, Absts, Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), and J. Med. Chem., 17, 475-476 (1974).
- U.S. Patents 3,507,885 and 3,636,058, issued 5 April 21, 1970 and January 18, 1972, respectively, describe various l-hydroxy-3-alkyl-6H-dibenzo-[b,d]pyrans having at the 9-position substituents such as oxo, hydrocarbyl and hydroxy or chloro, hydrocarbylidene, and intermediates there-- for.
U.S. Patent 3,649,650, issued March 14, 1972, dis-- closes a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo~b,d]-~- - pyran derivatives having at the l-position an ~-dialkylamino-alkoxy group active as psychotherapeutic agents.
~: German Specification 2,451,934, published May 7, 1975, describes l,9-dihydroxy-hexa~ydrodibenzo[b,d]pyrans and certain l-acyl derivatives thereof having at the 3-posi--; tion an alkyl or alkenyl group, as hypotensive, psycotropic, sedative and analgesic agents. The precursor hexahydro-9H-; dibenzo[b,dJpyran-9-ones used in their preparation, and which - 20 are reported to have the same utility as the corresponding 9-hydroxy compounds, are described in German Specification

2,451,932, published May 7, 1975.
German Specification 2,415,697, published October 17, 1974, describes 1-hydroxy-6,6,9-trimethyl-hexa-hydrodibenzo[b,d]pyran derivatives, and intermediates there-for, having at the 3-position an aralkyl, ~substituted aralk-yl) or pyridylalkyl group. They ar~ useful as analgesic ; agents and as mild tranquilizers.
U.S. 3,856,821, issued December 24, 1974, describes ~; 30 a series of 3-alkoxy substituted dibenzo[b,dJpyrans having antiarthritic, antiinflammatory and oentral nervous system activity.
A stereospecific synthesis of (-)trans-6a,7,8,10a-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-l-ol, more commonly known as (-)-Ql-tetrahydrocannabinol, has been reported by Razdan et al. (J. Am. Chem. Soc., 96, 5860-5, 1974). The process, a one-step synthesis, comprises the re-Z~

--3--action of c /trans-(+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of 1% boron trifluoride etherate and an-hydrous magnesium sulfate in methylene chloride at 0C. The ` tetrahydro compound thus produced is converted to the corre-sponding 9-keto hexahydro compound by the procedure of Wildes et al., J. Org. Chem., 36, 721-3 (1971). The procedure in-volves methylation of the l-hydroxy-tetrahydro compound to its methyl ether and thence to the hydrogen chloride adduct by reaction with zinc chloride and HCl at 0CO in chloroform.
The adduct is then dehydrohalogenated by reaction with potassium tricyclopentylcarbinolate to give the corresponding 6a,7,8,9,10,10a-hexahydro-3-pentyl-6,6-dimethyl-9-methylene-6H-dibenzo[b,d]pyran-l-ol methyl ether. Oxidation of the 9-methylene group with potassium permanganate-periodate affords the 9-ketone. Demethylation of the methyl ether with pyridinium chloride or other acid reagent affords the alcohol.
Bergel et al., J. Chem. Soc., 286-7 ~1943) investig-ated the replacement of the pentyl group at the 3-position of 7,8,9,10-tetrahy~ro-3-pentyl-6,6,9-trimethyl-6H-dibenzo-[b,d]pyran-l-ol by alkoxy ~butoxy, pentoxy, hexoxy and oct-oxy) and found that it led to biological inactivity. The hexoxy derivative was reported to exhibit feeble hashish activity at 10 to 20 mg./kg. The remaining ethers showed no activity in doses up to 20 mg./kg.
In a more recent study, Loev et al., J. Med. Chem., 16, 1200-6 (1973) report a comparison of 7,8,9,10-tetrahydro-

3-substituted-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-l-ols in which the 3-substituent is -OCH(CH3)C5Hll; -CH2CH(CH3)C5H
- or CH~CH3)C5Hll. The ether side chain containing compound ` 30 was 50% less active in central nervous system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as the com-pound in which oxygen is replaced by methylene.
As described in Application No. 263,717 there has been found a class of compounds effective as analgesic, hypotensive, antisecretory and antianxiety agents and as immuno-suppressants and tranquiliæers; namely, l,9-dihydroxy-dibenzo[b,d]pyrans ~Formula I) which are non-narcotic and free of addiction liability. Compounds of Formula II also `- possess such activity and are furthermore useful in the pro-duction of compounds of Formula I. The present invention provides intermediates ~Formula III) for the preparation of said compounds. ~he compounds have the formulae:

~Z-W ~Z-W
~ ... I ......................... II

-. IRo and "^~

R ~ W ...III
wherein R is selected from the group consisting of hydrogen and alkanoyl having from one to five carbon atoms;
Rl is selected from the group consisting of hydro-:; gen, alkanoyl having from one to five carbon atoms and -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4;
each of R2 and R3 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino, and N-alkyl-piperazino having from one to four carbon atoms in the alkyl group;
each of R4 and R5 is selected from the group con-. .

l~lQ2'~0 -5~
sisting of hydrogen, methyl and ethyl;
Ro is selected from the group consisting of oxo and alkylenedioxy having from two to four carbon atoms;
Z is selected from the group consisting of ~a) alkylene having from one to nine carbon atoms; tb~ -(alkllm-X-(alk2)n~ wherein each of (alkl~ and (alk2~ has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alkl) plus (alk2~ is not greater than 9;
each of m and n is 0 or 1;
X is selected from the group consisting of O, S, SO and SO2; and W is selected from the group consisting of methyl, pyridyl, piperidyl, ~ Wl wherein Wl is selected from the group consisting of hydrogen, fluoro and chloro; and tCH2 ) - ~ H-W2 wherein W2 is selected from the group ~ CH2 ) bJ
consisting of hydrogen and ~ Wl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5, with the pro-viso that the sum of a and b is not greater than 5;
with the proviso that when W is methyl, Z is -talkl) -X-(alk2) -.
Compounds having the above formulae contain asym-- metric centers at the 6a- and/or lOa-positions. There may be additional asymmetric centers in the 3-position substi-tuent (-Z-W), the 6-position and the 9-position. Diastereo-mers with the 9~-configuration are generally favored over the 9a-isomers because of greater (quantitatively) biological activity. Similarly, the trans ~6a,10a) diastereomers are favored over the cis (6a,10a) diastereomers~
In the above formulae, the wavy lines are intended to depict the diastereomers at the 9- and the 6a,10a-positions.
- In general, the optically active enantiomers con-taining the same absolute configuration at both the 6a- and lOa-positions as the natural cannabinols are favored because ~o of greater ~quantitatively) biological activity. ~he racemic modifications of these compounds can be used as such because they contain 50% of the more active enantiomer. The utility of the racemic mixtures, the diastereomeric mixtures as well as of the pure enantiomers and diastereomers is determined by the biological evaluations described below.
~ Although compounds of Formula II are described herein as intermediates for compounds of Formula I, many, particularly those wherein the C-9 substituent is oxo (=O), also exhibit analgesic and tranquilizer activity.
The preferred compounds of Formula I are those wherein the OR group at the C-9 position has the B-configura-tion. Such compounds are of greateX potency and efficacy than are the corresponding ~-compounds.
15 Of special interest are c,ompounds of Formula I
wherein the several variables have the significapce shown below in Table A:
TABLE A ~ ~
OR 1 Z m n W
B-OH OH alkylene having 1 to 6 carbon atoms - - phenyl, pyridyl B_OH OH -~alkl~m~X~~alk2)n pyridyl B-OH OH -~ alk ~ -X- 1 - phenyl, 1 m pyridyl B-OH OH -X- ~alk ) - - 1 phenyl, 2 n pyridyl Particularly favored because of their potency are those compounds of Formula I, Table A, wherein Z-W, the C-3 substituent, has the values shown in Table B below:
TABLE B
(a) (CH2)q 6 5 (b) -CH(CH3) -(CH2)t C6H5 [ 2 q]m [(CH2)t]- C6H5 (d) ~[CH(CH3)~(CH2)q] O-[CH(CH3) ~CH2)t]n 6 5 (e) - [(CH2)q¦-O~[(CH2)t] CH3 (f) ~[CH(CH3)~(CH2)q] -O-[CH(CH3) (CH2)t]n 3 - 1~102~0 In the above Table, each of q and t is an integer from 1 to 4; and each of m and n is 0 or 1; with the proviso that only one of m and n is 0.
Additionally, the intermediates for the above men-tioned compounds of interest ~Tables A and B) and, in parti-cular, the 6a,7-dihydro-6H-dibenzo[b,d]pyran-9(8H)-ones and the 6a,7,10,10a-tetrahydro-6H-dibenzo~b,d~pyran-9(8H)-ones of Formulae II and III are the preferred classes of inter-mediates by reason of their precursor relationship to the compounds of Tables A and B above.
The compounds of this invention of Formula III are readily prepared by ring annelation of the appropriate 5-ORl-3-hydroxymethylene-2-R4R5-7-(Z-W)-4-chromanone with methyl vinyl ketone in the presence of a base; for example, an alkali metal hydroxide or alkoxide or a tertiary organic base such as triethylamine, to effect Michael addition, followed by treatment with a base, e.g., an alkali metal hydroxide or alkoxide (sodium or potassium hydroxide, ethox-ide or methoxide) to complete aldol cyclizationO
The resulting 6a,7-dihydro-1-ORl-6,6-R4R5-3-~Z-W)-6H-dibenzo[b,d]pyran-9~8H)-one is then converted via Birch reduction to the corresponding 6aB,7,10,10a~-tetrahydro com-pound (Formula II, Ro = oxo). As described in Application No. 263,717 the reduction is conveniently carried out using lithium as the metal. Sodium or potassium can also be used.
The reaction is conducted at a temperature of from about -35C. to -80C. The Birch reduction is favored because it offers stereoselectivity resulting in formation of the desir-- ed trans-ketone of Formula II.
Treatment of the compounds of Formulae II and III
wherein Ro is oxo with the appropriate alkylene glycol having from two to four carbon atoms in the presence of a dehydrat-ing agent such as p-toluenesulfonic acid, or other acid used in ketalization (oxalic, adipic), affords the corresponding ketals.
Reduction of the 9-oxo groups of Formulae II and - III compounds ~Ro = oxo) via metal hydride reduction affords -compounds of Formula I (R = H~. Representatlve of the metal `~ hydrides useful for such conversion are lithium aluminum hydride, lithium borohydride and sodium borohydride. Sodium borohydride is favored as reducing agent in this step since it not only affords satisfactory yields of desired product, but reacts slowly enough with hydroxylic solvents (.nethanol, ethanol, water) to permit their use as solvents. A tempera-ture of from about 0C. to 30C. is generally used. Lower temperatures, even down to about -70C., can be used to in-crease selectivity of the reduction. Higher temperaturescause reaction of the sodium borohydride with the hydroxylic solvent. If higher temperatures are desired or required for a given reduction, isopropyl alcohol or the dimethyl ether ;~ of diethylene glycol are used as solvents.
Agents such as lithium borohydride or lithium aluminum hydride require anhydrous conditions and non-hydroxylic solvents ~1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of diethylene glycol~.
The isomeric 9~- and 9B-hydroxy compounds are pro-duced in this step. The above described reaction sequence is summarized below.
IH~ CH3COCH-CH~ [~

R5 z-W 4 ~
IV R ~ Z-W
Ll III

~-W R~ Z-W
I ~+ cis isomer~
: :

z40 g The required 5-ORl-3-hydroxymethylene-2-R4R5-7-(Z-W)~4-chromanones ~IV) are prepared from 3,5-dihydroxy-benzoic acid by the following abbreviated sequence:

HJ~ COOH YlO~\CO 2 V / VI

lH ~ 1Yl 5HO ~ Z-W Yl ~ -Z'-W
VIII VII

R4 R5C=CH-COOEI
3 ( 2 5~2 fH

4~ NaH~ V

IX
The starting material, 3,5-dihydroxybenzoic acid (V) is converted to a compound of Formula (VI) wherein Y2 represents an alkoxy group, desirably methoxy o~ ethoxy for ease of preparation, or an amino group; and Yl is a hydroxy protecting group, by methods described in the literature.
When Z is alkylene, Yl is desirably alkyl having from one to four carbon atoms or benzyl. The function of group Yl is to protect the hydroxy groups during subsequent reactions. It is its ability to perform a specific function;
' "` l~l~Z~(~

i.e., protection of the hydroxy groups, rather than its structure which is important. The selection and identifica-tion of appropriate protecting groups can easily and readily be made by one skilled in the art. The suitability and effectiveness of a group as a hydroxy protecting group are ` determined by employing such a group in the above illustrat-ed reaction sequence. It should, therefore, be a group which is easily removed to permit restoration of the hydroxy groups.
Methyl is favored as a protecting alkyl group since it is easily removed by treatment with pyridine hydrochloride. The - benzyl group, if used as a protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.
When Z is -(alkl)m~X~(alk2)n~' Yl is preferablY
benzyl or a substituted benzyl group since it can subsequent-ly be removed without detriment to the Z group.
The diprotected benzoic acid derivative (VI) isthen converted to a compound of Formula VIII by known tech-nology. In one procedure VI is hydrolyzed to the correspond-ing acid (Y2 = OH), or lithium salt, and reacted with the appropriate alkyl lithium to produce an alkyl disubstituted phenyl ketone (Y2 = alkyl). When methyl lithium is used, the resulting acetophenone derivative is treated with a Grignard Reagent (W-Z'-MgBr). The intermediate adduct is hydrolyzed to the corresponding alcohol which is then hydro-genolyzed to replace the hydroxy group with hydrogen. Thisprocedure is especially useful for those compounds wherein Z is alkyle~e.
The ether groups are deblocked by s~itable means:
treatment vith pyridine hydrochloride (Yl = methyl) or cata-lytic hydrogenolysis (Yl = benzyl), or by treatment with anacid such as trifluoroacetic acid, hydrochloric, hydrobromic or sulfuric acids, or pyridine hydrochloride. Acid debenzyl-ation is, of course, used when the group -Z-W contains sulfur.
A further method for converting compounds of Formula VI to those of Formula VIII comprises reaction of a - ketone of Formula VI (Y2 = alkyl) with the appropriate tri-phenyl phosphonium bromide derivative [(C6H5)3P-Z-W]Br in 2'~0 the presence of a base le~gO, sodium hydride). The reaction proceeds vla an alkene which is ~ubsequently catalytically hydrogenated to the corresponding alkane ~Z-W) and deblocked to the dihydroxy compound (VIII). Of course, when -Z- is (alkl~m-X-~alk2~n and Yl is benzyl, the catalytic hydrogena-tion al~o results in cleavage of the benzyl ethers.
Alternatively, conversion of structure VI compounds to those of structure VIII can be achieved by the ~equence VI ~ VII ~ VIIIo In this ~equence, the diprotected benzamide (VI, Y2 = NH2) is converted to the ketone (VII, Z' = Z less one CH2 group) by reaction with the appropriate Grignard re-agent (BrMg-2'-W) followed by reaction with methyl- or ethyl-magnesium halide to form the corresponding carbinol. De-hydration of the carbinol, e.g., with p-toluenesulfonic acid, ;15 affords the corresponding alkene which is then catalytically hydrogenated ~Pd/C) to the alkane ~VIII). The ether groups are deblocked (converted to hydroxy) as described above.
-The conver~ion of VIII to the 4-chromanone ~IX) i8 achieved by the reaction of VIII with crotonic acid or an acid of the formula R4R5-C-CH-COOH in the presence of boron trifluoride etherate at from about 20 to about 125C. In addition to structure IX products, a second product, isomeric to IX t7-hydroxy-2~2-R~R5-s-z-w-4-chromanone)~ i9 also pro-duced.
The 4-chromanones of Formula IX are then converted to hydroxymethylQne derivative~ of Formula IY by reaction with ethyl formate and ~odium hydride.
Compounds of Formula VIII wherein -Z-W iB -alkyl-ene-W or -~alkl)-X'-(alk2~n-W wherein ~alk~ alk~), W and n are a~ defined above and X' i~ O or S, are obtained by the following seguenae:

2~0 ; Yl Yl C6H5) 3P=CHCOOC2 5 ~, ~

, C~ Y10~ ~COOC2H5 ~R ' - H, alkyl) o 1 k~/

YlO~ H~ 2~CH OH
C5H5N/ R' Tosyl \PBr3 6s, Chloride Y

OJ~H 2 CH2-0~= Yl~H 2~CH2Hr 1 ~ 6H 5 ~ 3 l~H 2 CH2-X '--W YlO~:H CH -P ~C6H5~ 3 1RI~ (CH2)V-W
OH 1Yl H~VIII l(~H2~H2=C-tCH2)V--W

The first step in the above sequence ~the Wittig reaction) provides opportunity, by choice of appropriate re-actants, to produce compounds having straight or branched alkylene groups. In the given illustration, the value of R' as methyl or ethyl permits formation of a compound having alkyl substitution on the carbon atom (~) adjacent to the phenyl group. Substitution of a methyl or ethyl group at other sites, e.g., the B-carbon atom of the alkylene group, is achieved by choioe of the appropriate carboalkoxy alkyl-idene triphenylphosphorane, e.g., ~C6H5)3P-C~R')-COOC2~5.
The unsaturated ester thus produced is reduced to the corre-sponding saturated alcohol by reaction with lithium aluminum hydride, generally in the presence of a small amount of aluminum chloride. Alternatively, when Yl is other than benzyl (e.g., methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium-carbon, followed by treatment of the saturated ester thus produced with lithium aluminum hydride. Conversion of the alcohol - to the corresponding tosylate or mesylate followed by alkyl-ation of the tosylate or mesylate with an alkali metal salt of the appropriate ~X'-(alk2)-W reactant, and finally re-moval of the protecting groups (Yl) affords the desired resorcinol. When X' is sulfur, the protecting group is ~- methyl.
A variation of the above sequence comprlses bromin-ation of the alcohol rather than converting it to a tosylate or mesylate. Phosphorous tribromide is a convenient bromin-; ating agent. The bromo derivative is then reacted with the appropriate ~X'-(alk2)-W in the presence of a suitable base ~Williamson reaction).
The bromo compounds also serve as valuable inter-mediates for increasing the chain length of the alkylene moiety in the above sequence to give compounds wherein Z is -alkylene-W. The prooess comprises treating the bromo derivative with triphenyl phosphine to produce the correspond-ing triphenylphosphonium bromide. Reaction of the triphenyl-phosphonium bromide with the appropriate aldehyde or ketone 1~ %~0 in the presence of a base such as sodium hydride or n-butyl lithium affords an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.
In this variation, the value of the protecting group (Yl) selected depends upon the particular sequence followed. When the vertical sequence on the right is used, benzyl is the preferred protecting group by reason of the catalytic hydrogenation step. Methyl is the preferred pro~
tecting group when the left vertical sequence is followed, since it is conveniently removed by treatment with acid as described herein.
Alternatively, the compounds of this invention can be prepared according to the procedure described by Fahrenholtz, et al., ~. Am. Chem. Soc., 89, 5934-5941 ~1967).
This process comprises Von Pechmann condensation of the appropriate -Z-W substituted 3,5-dihydroxybenzene with di-ethyl-~-acetoglutarate in the presence of phosphorous oxy-chloride. The ethyl-5-hydroxy-4-methyl-7-~Z-W)-coumarin-3-propionate thus produced is then cyclized to 7,10-dihydro-1-hydroxy-3-(Z-W)-6H-dibenzo~b,d]pyran-6,9(8H~-dione by reac-tion with sodium hydride in dimethylsulfoxide. The dibenzo-[b,d]pyran thus produced is converted to the corresponding 9-ketal derivative by reaction with ethylene glycol and p-toluenesulfonic acid. Treatment of the ketal with the appro-priate alkyl magnesium iodide followed by acid hydrolysis affords dl-6a,7-dihydro-1-hydroxy-6,6-dialkyl 3-(Z-W)-6H-di-benzo~b,d]pyran-9(8H)-one.
A further method for making compounds of Formula VIII wherein Z-W is (alkl)-X-~alk2)-W comprises reaction of the appropriate 3,5-~di-protected hydroxy~styrene oxide with an alcohol or thioalcohol ~HX-(alk2)-W) as its alkali metal ~preferably sodium or potassium) salt. Methyl is a favored protecting group for the 3,5-dihydroxy styrene oxides because of its ease of removal. The resulting 3,5-~di-protected hydroxy)phenyl hydroxyalkyl ether compound (Formula VIIIA~ is converted to the corresponding alkyl ether (Formula VIIIB) by treatment with phosphorous oxychloride followed by dehalo-genation of the thus produced chloro derivative by means of hydrogen over palladium. Removal of the protecting groups as described above affords the desired compound. The reac-tion sequence is presented below (Yl = benzyl, alkyl havingone to four carbon atoms; X' is O, S; R' = H, CH3, C2H5 and - may be alike or different~.
Yl loyl ~ ~ Na ~ ~ IX'H
Yl R' RHl 1 -CH-X'-(alk )-W
VIIIA

H2/Pd-C

. Y1 / CIH-CIH-X (alk2) ,:
VIIIB
H
.

~J~A~ X'-talk2)-W
VIII
- Esters of compounds of Formulae II and III wherein Rl is alkanoyl or -CO-(CH2)pNR2R3 are readily prepared by re-acting Formula II or III compounds with the appropriate alkanoic acid or acid of formula HQOC-(CH2)pNR2R3 in the presence of a condensing agent such as dicyclohexylcarbodi-imide. Alternatively, they are prepared by reaction of a Formula II or III compound with the appropriate alkanoic acid chloride or anhydride, e.g., acetyl chloride or acetic an-hydride, in the presence of a base such as pyridine dl-5-Hydroxy-2,2-dimethyl-7-~1-methyl-4-phenylbutyl~-- 4-chromanone A mixture of 2-t3,5-dihydroxyphenyl)-5-phenyl-pentane (9.6 g.) and 3-methylcrotonic acid ~4.5 g.) is heat-ed to 125C. under nitrogen, and boron trifluoride etherate ~8.7 ml.) is added. After refluxing for one hour, the re-action is cooled and water ~10 ml.) is added followed by 6N
` sodium hydroxide (40 ml.). The reaction mixture is heated for 5 minutes on a steam bath, cooled and acidified with 6N
- 15 hydrochloric acid. The aqueous layer is extracted with ether (3 x 100 ml.) and the combined ether extracts washed with 10% sodium bicarbonate ~1 x 25 ml.) and water ~1 x 25 ml.).
The organic phase is dried over sodium sulfate and concentrat-ed under vacuum to afford 12.7 g. of a crude oil which is purified by silica gel chromatography to yield S.0 g. of dl-

5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanone as a colorless oil.

IR: (CHC13) C=O 1635 cm NMR: -~CDCl 1-1.7 (M,7,~-methyl, ethylene), 1O5 (S,6,gem dimethyl), 2.3-2.9 ~M,3,benzylic-methylene, methinyll, 2.65 (S,2,a-methylene), 6.1-6.35 ~M,2,aromatic), 6.9-7.4 (M,5,aromatic~, 11.53, 11.63 ~d,l, hydroxyl~.
Similarly, 2-(3,5-dihydroxyphenyl)-6-phenylhexane is converted to dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-5-phenylpentyl)-4-chromanone (an oil):
CDC13 1.2 ~d,3,~-methyl, J = 7 cps) 1 4 (S,6,gem dimethyl), 1.0-1.9 [M,6,~-CH2-(CH2)3-C~CH3)-Ar~, 2.3-2.8 (M,3,benzylic-methylene, methinyl), 2.7 (S,2,~-methyl-ene), 6.2-6.4 (M,2,aromatic), 7.1-7.3 (M,5,aromatic~, 11.6 (S,l,hydroxyl);
1-(3,5-Dihydroxyphenyl)-2-phenylethane is converted .

`` 1~1C~240 to 5-hydroxy-2,2-dimethyl-7-~2-phenylethyl~-4-chromanone ~an oil):
- IR: (CHC13~ C=O 1645 cm 1 NMR: ~CDCl 1.45 (S,6,gem dimethyl), 2 65 (S,2,~-methylene), 2.85 (S,4,ethylene), 6.25, 6.3 (2d,2,aromatic~,7.2 (S,5,aromatic), 11.6 (S,l,hydroxyl-D2O overlay).
MS: (molion) 296.
2-(3,5-Dihydroxyphenyl)-4-phenylbutane is converted to dl-5-hydroxy-2,2-dimethyl-7-~1-methyl-3-phenylpropyl)-4-chromanone (an oil):
NMR: ~CDCl 1.3 (d,3,methyl), 1.45 (S,6,gem di-3methyl~, 1.55-2.1 (M,2,methylene), 2.25-2.75 (M,3,benzylic-methylene, methinyl), 6.15 (d,2,aromatic), 7.1 (S,5,aromatic), ! 11. 6 (S,l,hydroxyl-D2O overlay)~
MS: (mol-ion) 324.
; 2-(3,5-Dihydroxyphenyl)-5-phenylpentane (5.27 g.) is converted by reaction with boron trifluoride etherate (4.81 ml.) and crotonic acid ~2.08 g. of freshly distilled) in place of 3-methylcrotonic acid to dl-5-hydroxy-2-methyl-7-~1-methyl-4-phenylbutyl)-4-chromanone:
NMR ~CDCl 1.1 ~D,3~-methyl, J = 7 Hz~, i 4 ~D,3,2-methyl, J = 7 Hz), 1.3-1.8 ~M,4-ethylene), 2.2-2.9 (M,5,~-methylene, benzylic methylene, methinyl), 4.5 ~M,1,-methinyl ether), 6.1, 602 ~2D,2,aromatic, J = 1 Hz~, 6.9-7.4 (M,5,aromatic), 11.7 (S,l,phenolic OH) 4-(3,5-Dihydroxyphenyl)-1-phenoxypentane is convert-ed to dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenoxybutyl)-4-chromanone, a light yellow oil:
MS: ~mol-ion) 354.
Rf = 0.61 (silica gel, 18-benzene:l-ethyl acetate~
Analysis:
Calc d for C22H264 C, 74-55; H~ 7.39~
Found: C, 74 56; H, 7.36%.
4-(3,5-Dihydroxyphenyl)-1-(4-pyridyl)pentane is converted to dl-5-hydroxy-2,2-dimethyl-7-[1-methyl-4-~4-111~2~

pyridyl)butyl]-4-chromanone, an oil:
- Rf = 0O39 (silica gel, l-benzene:l-ethyl acetate) CDC13 1 1.90 (M,13-H,methylene, methyl doublet at 1.20, J = 7 Hz, and gem dimethyl singlet at 1.5);
2.43-2.86 ~M,5-H,methylene, methinyl, including singlet (two C;3 H's at 2,71); 6.26 (bOd.S,l-H,aromatic); 6.33 (b.d.S,l-H, aromatic); 7~00-7O20 ~b.d.D,2-H,pyridine aromatic); 7.25 (b.d.S,l-H,hydroxyl); 8041-8.61 (b.d D,2-H,pyridine aromatic).
dl-5-Hydroxy-2,2-dimethyl-7-(1-methyl-3-phenoxy-propyl)-4-chromanone is prepared from 3-(3,5-dihydroxyphenyl~-l-phenoxybutane as an oil.
Rf = 0.7 (silica gel, 18-benzene:l-ethyl acetate) MS: (mol-ion) 340 ;~ ~nalysis:
15 Calc d for C21H24 4 C, 74.09; H~ 7-11%
Found: C, 74.04; H, 7.19%.
dl-2-(3,5-Dihydroxyphenyl)-1-(2-phenylethoxy)pro-pane is converted to dl-2,2-dimethyl-5-hydroxy-7-[1-methyl-2-(2-phenylethoxy)ethyl]-4-chromanone (an oil).
NMR: ~CDCl 1,21 ~d; J = 7 Hz, methyl), 1.48 (s, gem dimethyl), 2.73 (s, C-3 methylene), 2.86 (+, J = 7 Hz, CH2Ph), 2.9 ~m, me~hine), 3.50 (d, J = 7 Hz, -CH2O-), 3,65 ~t, J = 7 Hz, -OCH2-), 6.31 ~d, J = 1 Hz, ArH), 6~38 (d, J =
1 Hz, ArH), 7.26 (s, Ph) and 13.33 ~s, phenol).

dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanone To sodium hydride obtained by washing 50~ sodium hydride in mineral oil dispersion ~6.67 g.) with pentane is added dropwise, over a 30 minute period, a solution of dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanone (4.7 g.) and ethyl formate (23.1 g.). The reaction mixture is then cooled to room temperature and ether (350 ml.) added.
The resulting mixture is refluxed for 18 hours, cooled to room temperature and acidified with lN hydrochloric acid The ether layer is separated and the water layer extracted ~ith ether t3 x 100 ml.~. The cornbined ether extracts are dried over sodium sulfate and concentrated under vacuum to yield 5.7 g. of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4~chromanone as an oil.
NMR: ~CDCl 1.05-1.8 (M,13,gem dimethyl, ~-m~thyl, ethylene~, 2.45 (m,3,benzylic-methylene, methi~yl), 6.2-6.5 (M,2,aromatic), 7.0-7.6 (M,6,aromatic, met~inyl ether), 11.3, 11.36 (2bd.S, l,phenolic hydroxyl), 13.3, i~3.5 (2bd.S, l,hydroxyl).
` 10 IR: (CHC13) C=O 1625 cm 1 - In like manner, the products of Example 1 are con-verted to:
dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-methyl-5-phenylpentyl)-4-chromanone:
NMR ~CDCl 1.2 (D,3,~-methyl, J = 7 cps), 1.6 (S,6,gem dimethyl), 1.0-2.0 [M,6,~CH2-(CH2)3-CH(CH3)Ar], 2.3-2.8 (M,3,benzylic-methylene, methinyl), 6.2-6.4 (M,2,aromatic), 7.1-7.4 (M,6,aromatic, vinylic), 11.4 (bd.S,l phenolic-hydroxyl);
5-hydroxy-3-hydroxymethylene 2,2-dimethyl-7-(2-phenylethyl)-4-chromanone (an oil):
IR: (CHC13) C = O 1625 cm NMR ~CDC13 1-5 (S,6,gem dimethyl)~ 2.85 (S,4,-ethylene), 6.2, 6.3 ~d,2,aromatic), 7.0-7.5 (M,6,aromatic, methinyl), 11.35 (S,l,hydroxyl-D2O overlay), 13.4, 13.6 (d,l,-hydroxyl-D2O overlay).
MS: (mol-ion) 324.
dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-; methyl-3-phenylpropyl)-4-chromanone ~an oil):
NMR: ~CDCl 1.15 (d,3,methyl), 1.5 (S,6,gem di-methyl), 1.65-2.1 (M,2,methylene), 2.25-2.75 (M,3,benzylic-methylene, methinyl), 6.15, 6.3 (2d,2,aromatic), 7.1 (M,6,-aromatic, olefinic proton), 11.3 (S,l,hydroxyl-D2O overlay), 13.3, 13.8 (d,l,hydroxyl-D2O overlay~.
MS: (mol-ion) 352.

.

dl-5-Hydroxy-3-hydroxymethylene-2-methyl-7-~1-methyl-4-phenylbutyl?-4-chromanone:
NMR: ~TcDcl 1.1 (D,3,~-methyl, J = 7 ~z), 1.5 (D,3,2-methyl, J = 7 ~z), 1.3-1 8 ~M,4-ethylene), 2.3-2.9 ~M,3,benzylic), 4.9 ~M,l,methinyl ether, J = 5 Hz), 6.2, 6.3 (2D,2,aromatic, J = 1 Hz), 6.9-7.4 ~M,6,aromatic, vinylic~, 11.2 (bd.S, l,phenolic OHI.
- dl-5-Hydroxy-2,2-dimethyl-7-~1-methyl-4-phenoxy butyl)-4-chromanone is converted to d,l-5-hydroxy-3-hydroxy-methylene-2,2-dimethyl-7-~1-methyl-4-phenoxybutyl)-4-chroma-none: Rf = 0.44 [silica gel, 18-benzene:l-ethyl acetate].
MS: (mol-ion) 382.
dl-5-Hydroxy-2,2-dimethyl-7-[1-methyl-4-~4-pyridyl)-butyl~-4-chromanone is converted to d~-5-hydroxy-3-hydroxy-methylene-2,2-dimethyl-7-[1-methyl-4-(4-pyridyl)butyl]-4-chromanone, a viscous oil:
Rf = 0.15 (silica gel, l-benzene:l-ethyl acetate).
dl-2,2-Dimethyl-5-hydroxy-7-[1-methyl-2-~2-phenyl-ethoxy)ethyl]-4-chromanone is converted to dl-2,2-dimethyl-3-hydroxymethylene-5-hydroxy-7-[1-methyl-2-(2-phenylethoxy~-ethyl]-4-chromanone (an oil).
Rf = 0.35 (silica gel, 1:1 pentane:ether).

dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo-[b,d~pyran-9(8~)-one To a solution of 5-hydroxy-3-hydroxymethylene-2~2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanone (0 916 gO) in methanol (4 ml.) and methyl vinyl ketone (0.037 ml.) is added triethylamine (0.09 ml.). The reaction is stirred for 16 hours at room temperature and then diluted with ether (50 ml.). The resulting ether solution is extracted with 10%
sodium carbonate solution (4 x 5 ml.), dried over sodium sulfate and concentrated under vacuum to yield 1.09 g~ of an oil. The residue is refluxed with ethanol (7.3 ml.) and 2N
- 35 potassium hydroxide (7.3 ml.) for 16 hours. Thereafter, the ~eaction solution is cooled, acidified with 6N hydrochloric acid and extracted with dichloromethane (3 x 20 mlO). The 2~

organic phase is dried over sodium sulfate and evaporated to yield 0.99 g. of an oil which crystallizes from ether:-hexane ~1:1) to yield 0.49 g. of dl-6a,7-dihydro-1-hydroxy-

6,6-dimethyl-3-(1-methyl-4-phenylhutyl)-6H-dibenzo~b,d~pyran-9(8H)-one, m.p. 145Q148C. after crystallization from iso-propyl ether.
NMR: ~CDCl 1-2.35 (M,10,~-methylene, ethylene, i remaining protons), 1.355 ~S,6,gem dimethyl), 2.35-3.0 ~M,5,~-methylene, benzylic-methylene, methinyl), 6.1-6.7 ~M,2,-aromatic), 7-7.35 (M,5,aromatic), 7.9-8.2 (bd.S,l,olefinic proton), 10.8 (S,l,phenolic OH).
IR: ~CHC13) C = O 1600 cm 1.
Analysis:
Calc d C26 30 3 C, 79.97; H, Found: C, 79.91; H, 7.78%.
MS: (mol-ion) 390.
Similarly, dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-5-phenylpentyl)-6H-dibenzo[b,d]pyran-9(8H)-one is prepared from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-

7-(1-methyl-5-phenylpentyl)-4-chromanone, m.p. 204-208C.
NMR: ~CDCl 1.1, 1.5 (2S,6,gem dimethyl), 1.0-3.0 [M,17,~-methyl, ~CH2(CH2)3-CH(CH3)-Ar, benzylic, remaining protons], 6.2, 6.5 (2D,2,aromatic protons, J = 2 cps~, 7.0-7.4 (M,5,aromatic), 8.05 (D.l.vinylic, J = 2 cps), 10.8 (S,l,phenolic hydroxyl).
I~: (KBr) C = O 1613 cm A ~ :
Calc'd for C27H323 C~ 80-16; H~ 7-97%
Found: C, 80.00; ~, 8.29%.
dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-(2-phenyl-ethyl)-6H-dibenzo[b,d]pyran-9(8H)-one is prepared from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(2-phenylethyl~-4-chromanone, m.p. 233-235C.
NMR: ~CDCl 1.0-1.4 (M,3,6a-methinyl, 7-methylene~, 35 1.5 (S,6,gem dimethyl), 2.35-2.85 ~M,2,8-~-methylene~, 2.9 (S,4,ethylene), 6.3, 6.55 (2d,2,aromatic), 7.3 ~S,5,aromatic~, . .
-2~-7.95 (d,1,10-olefinic proton3, 10.5 ~S,l,hydroxyl-D2O over-lay)-- MS: ~mol-ion) 348; and dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylpropyl)-6H-dibenzo[b,d]pyran-9~8H)-one from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-methyl-3-phenylpropyl)-4-chromanone, m.p. 181C~
NMR: ~CDCl 1.2, 1.3 ~d,2,methyl), 1.55 (S,6,gem-dimethyl~, 1.6-3.1 (M,8,remaining protons), 6.3, 6.55 (2d,2,-aromatic), 7.2, 7.25 (2S,6,aromatic, hydroxyl-D2O overlay),

8.05 (d,l,olefinic proton).
MS: (mol-ion) 376.
dl-6a~-7-Dihydro-l-hydroxy-6d-methyl-3-~1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-9(8H)-one is prepared from dl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(1-methyl-4-phenylbutyl)-4-chromanone; m.p. 195-197C.
NMR ~CDCl 1-2 ~D~3,~-methyl, J = 7 Hz), 1.4 (D,3,6-methyl, J = 7 ~z), 1~3-1.8 (M,6,7-methylene, allylic), 3-8 (M,l,methinyl ether Jvicinal - 20 aromatic), 7.9 (D,l,vinylic, J = 1 Hz), 9.6 (S,l,phenolic OH).
IR: (KBr) C - O 1639 cm 1.
Analysis:
Calc d for C25H283 C~ 79-75; H~ 7-50%
Found: C, 79.76; H, 8.33%.

25 U.V.: AmaX = 226 (~ = 14,400), 324 (~ = 26,600) MS: (mol-ion) 376.
dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenoxybutyl)-6H-dibenzo[b,d]pyran-9~8H)-one is prepared from the corresponding 3-hydroxy-methylene derivative; m.p.
165-175C.
MS: (mol-ion) 406.
Rf = 0.31 ~silica gel, 18-benzene:3-ethyl acetate~.
Analysis:
Calc'd for C26H30O4: C, 76.82; H, 7.44%
Found: C, 76.80; H, 7.57%.

dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-~1-methyl 4-(4-pyridyl)butyl]-6H-dibenzo[b,d]pyran-918H)-one is pre-pared from the corresponding 3-hydroxymethylene derivative as a glassy solid.
MS: (mol-ion) 391 Analysis:
Cald'd for C25H29NO3-H2O: C, 73.32; H, 7.62; N, 3.42~
Found: C, 73.22; H, 7.47; N, 3.25%.
dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-[1-methyl-2-(2-phenylethoxy)ethyl]-6H-dibenzo-[b,d]pyran-9(8H)-one is prepared from dl-2,2-dimethyl-3-hydroxymethylene-5-hydroxy-7-[1-methyl-2-(2-phenylethoxy)ethyl]-4-chromanone, m.p~ 185-187C.
IR: (CHC13) C = O 1613 cm 1.
NMR: ~CDCl 1.15 ~s, one methyl of gem dimethyl), 1.20 ~d, J = 7 Hz, methyl), 1.48 (s, one methyl of gem di-methyl), 2.0-3.1 (m), 2.85 ~t, J = 7 Hz, CH2Ph), 3.4-3.8 (m, -CH2OCH2-), 6.35 (bs, ArH), 6.63 tbs, ArH), 7~30 (s, Ph~, 8.10 (d, J = 2 Hz, C-10 H) and 12.3 (s, phenol).
MS: m/e 406 (M~), 391, 376, 363, 315, 302 ~100%), 287, 285 and 272.
ExAMæLE 4 dl-6aB~7~lo~loa~-Tetrahydro-l-hydroxy-6~6-dimethyl-3-(l-methyl-4-phenylbutyl)-6H-dibenzo~b,d]pyran-9~8H)-one A solution of dl-6a,7-dihydro-1-hydroxy-6,6-dimeth-yl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo~b,d]pyran-9~8H)-one (0.976 g.) in tetrahydrofuran (7 ml.) is added to a rapidly stirred solution of lithium (0.1 g.) in liquid ammonia (35 ml.) (distilled through potassium hydroxide pellets). The reaction is stirred for 15 minutes and then solid ammonium chloride is added to discharge the blue color. The excess ammonia is allowed to evaporate and the residue is diluted with water (35 ml.) and acidified with concentrated hydro-chloric acid. The water solution is extracted with dichloro-methane (3 x 25 ml.) and the dichloromethane extracts driedover sodium sulfate and evaporated to yield 0.98 g. of a ; mixture of trans- and cis-6a,10a-diastereomers as a crude .~

; -24-oil which is purified vla column chromatography on silica gel to yield the trans-diastereomer followed in later frac-tions by the cis-diastereomer. The following are thus ob-tained:
dl-6a~,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d~pyran-9~8H)-one, 0.393 g., m.p. 200-205C.
NMR: ~CDCl 1-2.35 ~M,ll,a-methyl, ethylene, re-maining protons), 1.55 (S,6,gem dimethyl), 2.35-3.0 ~M,7,a-methylenes, benzylic-methylene, methinyl), 6.2-6.45 (M,2,-aromatic), 7-7.35 ~M,5,aromatic), 7.8.(bd.S,l,hydroxyl-D2O
overlay).
IR: (CHC13) C = O 1600 cm 1; and dl-6a~,7,10,10aB-tetrahydro-l-hydroxy-6,6-dimethyl-3~(1-methyl-4-phenylbutyl)-6H-dibe~zo[b,d]pyran-9(8H)-one as a solid foam.
IR: (CHC13) C = O 1690 cm 1, OH 3275 cm 1.
NMR: ~CDCl 0.95-2.12 (M,ll,a-methyl, ethylene, re-- maining protons), 1.35, 1.4 ~2S,6,gem dimethyl), 2.25-2.95 (M,7,a-methylenes, benzylic-methylene, methinyl), 6.1-6.35 (M,2,aromatic), 7.1 (bd.S.,l,hydroxyl), 7.25 (S,5,aromatic).
Repetition of the above procedure but using the products of Example 3 as reactants affords:
dl-6a~ 7,10,10a~tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-5-phenylpentyl)-6H-dibenzo[b,d]pyran-9(8H)-one, m.p. 159-163C.:
NMR: ~CDCl 1.1, 1.5 (2S,6,gem dimethyl), 0.9-3.1 [M,l9,a-methyl, ~-CH2-(CH2)3-CH~CH3)-Ar, benzylics, remain-ing protons], 3.9-4.4 (bd.D,l,a-carbonyl), 6.2 (M,2,aromatic), 7.0-7.4 (M,5,aromatic), 7.8 ~S,l,phenolic hydroxyl).
IR: (KBr) C = O 1695 cm 1.
: Analysis:
Calc d o C27 34 3 C, Found: C, 79.49; H, 8.43%
and the corresponding cis-diastereomer:

24(~

dl-6a~,7,10,10a3-tetrahydro-1-hydroxy-6,6-dlmethyl-3-(1-methyl-5-phenylpentyl)-6H-dibenzo[b,d]pyran-9(8H)-one;
m.p. 91-130C.
IR: (KBr) C - O 1709 cm MS: ~mol-ion~ 406.
- dl-6a~,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3-~2-phenylethyl)-6H-dibenzo[b,d]pyran-9~8H)-one, m.p. 206-; 209C.:
IR: (KBr) OH 3260 cm 1, C = 0 1710 cm 1.
NMR: ~CDC13 1.05-1.45 (2S,6,gem dimethyl), 2.75 (bs,4,ethylene), 1.1-3.1 (M,7,remaining protons), 3.75, 4.0 (2d,1,10aa proton), 6.2 (d,2,aromatic), 7.15 (S,5,aromatic), 8.8 ts~l~hydroxyl-D2o overlay).
. MS (mol-ion) 350.
dl-6a~,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3-~1-methyl-3-phenylpropyl)-6H-dibenzo[b,d]pyran-9(8H)-one, - m.p. 165C.:
IR ~KBr) OH 3175 cm 1, C = O 1695 cm 1; and dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylpropyl)-6H-dibenzo[b,d]pyran-9(8H)-one as a solid foam:
IR: ~CHC13) C = O 1685 cm 1, OH 3250 cm 1.
NMR: ~CDC13 1.35, 1.45 (2S,6,gem dimethyl), 2~8 ~bd,s,4,ethylene), 1.75-3.6 ~M,8,remaining protons), 6.3 (M,2,aromatic), 7.25 (M,6,aromatic,hydroxyl).
dl-6a~,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenoxybutyl)-6~-dibenzolb,d]pyran-9(8H)-one:
M.P. 160-175C.
MS: ~mol-ion) 408 Rf = 0.53 (silica gel, 8-benzene:2-ethyl acetate~
NMR; ~CDCl 7.41-6.67 (multiplet,6,phenoli~ OH, C6H5~; 6.3 ~S,2,aromatic H2 + H4); 4.33-1.50 (Ms, 15, re-maining methylene and methine protons); 1.47 (S,3,CH3); 1727 and 1.17 ~D,3,Me); 1.12 ~S,3,CH3).
Analysis:
Cal~'d for C26H324 C~ 76-44; H~ 7-89%
Found: C, 76.61; H, 7.90%.

' ' ' dl-6a~,7,10,10a~i-tetrahydro-1-hydroxy-6,6-dimethyl-3-[1-methyl-4-(4-pyridyl~butyl]-6H-dibenæo[b,d]pyran-9(8H)-one:
M.P. 60-70~C.
Rf = 0.4 ~silica gel, ethyl acetate) MS: (mol-ion) 393 NMR: ~CDCl 0.83-1.73 (M,15,methyl,methylene), - 1.73-3.0 (M,8,1-methine, remaining protons), 3.97-4.2 (bd.D,-l,aliphatic), 6.27 (S,2,aromatic), 7.03, 7.13 (D,2,pyridine aromatic~, 7.55 ~S,l,hydroxyl), 8.42 (M,2,pyridine aromatic).
dl-6a ,7,10,10a~-tetrahydro-1-hydroxy-6~-methyl-3-(l-methyl-4-phenylbutyl~-6H-di~en~lb,d]pyran-9~8H~-one, m.p.
~ ~ .
163-167C. ~pre-softening at 140C ).
IR: (KBr) C = O 1709 cm Analysis:
C lc 25 30 3 ~ ; , Found: C, 79.43; H, 8.03%.
MS: lmol ion) 378.
dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-[1-methyl-2-(2-phenylethoxy)ethyl~-6H-dibenzo~b,d~pyran-

9(8H)-one (a solid glass):
NMR: ~CDCl 1.13 ~s,one methyl of gem dimethyl~, 1.24 (d, J = 7 Hz,methyl), 1.50 ~s,one methyl of gem dimethyl), 1.6-3.2 ~M), 3.2-3.8 ~M), 4.05 ~M,one proton), 4.30 (M,one proton), 6.33 ~s, two ArH), 7.30 ts,Ph) and 7.70 (s,phenol).
~ MS: (mol-ion) 408 ~M~ , 100%), 392, 375, 304, 287 : 286, 274 and 273.
Rf = 0.57 (silica gel, ether) and the corresponding cis-isomer:
~. _ dl-6aB,7,10,10aB-tetrahydro-l-hydroxy-6,6-dimethyl-3-[1-methyl-2-(2-phenylethoxy)ethyl]-6H-dibenzo[b,d]pyran-9~8H)-one, m.p. 127130C.:
NMR: ~CDCl 1-20 (d,J = 7 Hz, methyl), 1.32 and 1.39 (s,gem dimethyl), 1.6-3.8 (M), 6.25 (s, two ArH), 7.07 (s, phenol) and 7.28 ~s,Ph).
.

-` ~il13240 MS: ~mol-lon) 4~8 ~M(--, 100%~ 393, 391, 325, 316, 304, 287, 286, 274, 273 and 245.
Rf = 0.50 ~silica gel, ether~.

dl-6aa,7,8,9,10,10aa-Hexahydro-l-hydroxy-6,6-dlmethyl-3-(l-methyl-4-phenylbutyl)-6H-dibenzo~b~dlpyran-9B
To a solution of dl-6a~ 7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl~-6H-dibenzo-[b,d]pyran-9(8H)-one (0.25 g.~ in ethanol (200 ml.~ stirred at room temperature under nitrogen is added sodium borohydr-ide (0.5 g.). The reaction is stirred for 30 minutes and acidified with 6N hydrochloric acid, then diluted with water (50 ml.) and extracted with ether ~3 x 50 ml.). The combin-ed ether extracts are dried over sodium sulfate and concen-trated under vacuum to yield 0.25 g. of a mixture of 9-OH a-- and B-isomers. Column chromatography (silica gel) yields 0.087 g. of dl-6aB,7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-di-methyl-3-(l-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-9B
m.p. 156-158C. after crystallization from ether:hexane (1:2).
: MS: (mol-ion) 394.
Analysis:
- Calc'd for C26H34O3: C, 79.15; ~, 8.69%
- Found: C, 78.94; H, 8.79%.
The following compounds are prepared by means of the above procedure from appropriate reactants of Example 4:
dl-6a~,7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-di-methyl-3-(l-methyl-5-phenylpentyl)-6H-dibenzo[b~d]pyran-9B-ol:
NMR: ~CDCl 1.0, 1.4 (2S,6,gem dimethyl), 1.2 - 30 (D,3,a-methyl, J = 7 cps), 0.8-4.0 ~M,18,remaining protons), 4.1-4.7 (M,2,phenolic-OH and alcoholic OH), 6.1, 6.2 t2D,--- aromatic, J = 3 cps), 7.0-7.3 ~M,5,aromatic~.
Analysis:
Calc d for C27 36 3 ; 35 Found: C, 79.58; H, 8.92~.
dl-6a ,7,8,9,10,1Oa -hexahydro-l-hydroxy-6,6-di-methyl-3-(2-phenylethyl)-6H-dibenzo[b,d~pyran-9 -ol; m~p~
213-215C.:

Z9~

IR: (KBr) OH 3367 cm 1.
NMR: ~CDCl 1.0, 1.35 (2S,6,gem dimethyl), 2.85 (S,4,ethylene~, 3.85 (bs,l,hydroxyl-D2O overlay), 3.6 (M,l,-10a~-proton), 0.8-3.6 (M,8,remaining protons), 6.2 (2d,2,-aromatic), 7.2 ~S,5,aromatic), 8.75 (S,l,hydroxyl-D2O overlay).
MS: (mol-ion~ 352.
dl-6a~,7,8,9,10,10a~-Hexahydro-l-hydroxy-6,6-di-methyl-3-(1-methyl-3-phenylpropyl)-6H-dibenzo~b,d]pyran-9B-ol, m.p. 171-172C.:
NMR: ~CDCl 1~15, 1.25 ~d,3,methyl), 1.35 (S,6,-gem dimethyl), 1.6-1.95 ~M,2,methylene), 2.15-2.7 (M,3,-benzylic-methinyl and methylene), 1.0-3.8 (M,10,remaining protons and hydroxyl), 6.1, 6.25 (2d,2,aromatic), 7.2 (S,5,-` atomatic).
Analysis:Calc'd for C25H323 C~ 78-91; H~ 8-47%
Found: C, 78.57; H, 8.50%.
dl-6a~-7,8,9,10,10a-hexahydro-1-hydroxy-6~-methyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo~b,d]pyran-9~ol.
This product is obtained as a mixture of the di-astereomeric alcohols. The mixture, a foam, is separated into two components by preparative layer chromatography on silica gel plates using 5% methanol in chloroform as eluting solvent.
T~e diastereomeric mixture exhibits maxima in the infrared region ~in chloroform) at 3827 and 3333 cm 1 (OH).
From 60 mg. of the foam, 10 mg. of component A
is isolated; Rf = 0.65. Its NMR spectrum is provided below.
CDC13 7 0 7.5 ~M,5,aromatic), 6.2, 6 3 3n ~2D,2,aromatic), 1.2 ~D,3,~-methyl, ~ = 7 Hz), 0.8-4.5 (M,-22,remaining protons).
Component B, 42 mg., Rf = 0.75, is similarly isol-ated. Its NMR spectrum is provided below.
NMR: ~CDCl 7 0-7 5 (M,5,aromatic), 6.1, 6.3 (2D,-2,aromatic), 1.2 (D,3,~-methyl, J = 7 Hz), 0.8-4.5 (M,22,re-maining protons).

dl-6a~,7,8,9,10,10a~-Hexahydro-l-hydroxy-6,6-di-methyl-3-~l-methyl-4-phenoxybutyl)-6H-dibenzo[b~d]pyran-9B
m.p. 144-146C.
Rf = 0.31 (silica gel, 9-ether:l-hexane).
Analysis:
C lc d C26 34 4 C, 6.06; H, 8.35%
Found: C, 75.85; H, 8.22~.
NMR: ~CDCl 6.75 (M,6,phenolic OH + C6H5~; 7.95 and 7.80 ~DS,2,aromatic H2 + H4); 4.17-1.00 (M,26,non-

10 aromatics including 1.42 [S,Me], 1.28 and 1.17 ~D,Me], 1.10 [S,CH33, methylene, methine and hydroxyl).
dl-6a3,7,8,9,10,10a~-hexahydro-1-hydroxy-6,6-di-methyl-3-(1-methyl-4-phenoxybutyl)-6H-dibenzo[b,d]pyran-9~-ol, an oil.
Rf = 0.37 (silica gel, 9-ether:l-hexane).
- MS: (mol-ion) 410 - dl-6aB,7,8,9,10,10a~-hexahydro-1-hydroxy-6,6-di-.?~ methyl-3-[1-methyl~4-(4-pyridyl)butyl]-6H-dibenzo[b,d~pyran-9B-ol:
~; 20 M.P. 170-190C.
- Rf = 0.19 ~silica gel, 9-benzene:l-methanol).
. NMR: ~CDCl 8.50-8.45 tD,2,pyridine aromatic~;
7.32 (S,l,phenolic hydroxyl); 7.12-7.07 (D,2,pyridine aromatic);
` 6.26 (BS,l,benzene aromatic); 6.10 (BS,l,benzene aromatic);
25 4.60-3.30 (M,3,methine ~ OH [singlet 3.83~); 2.80-0.80 ~M,26,-alkyl, including singlet at 1.44 [Me], doublet 1.24-1.17 [CH3], singlet 1.12 [CH3] and remaining methylene and methine absorptions).
dl-6aB,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-30 3-~1-methyl-2-(2-phenylethoxy~ethyl3-6H-dibenzo[b,d]pyran-9(8H)-one is converted to dl-6aB,7,8,9,10,10a~-hexahydro-1-hydroxy-6,6-dimethyl-3-[1-methyl-2-(2-phenylethoxy)ethyl]-6H-dibenzo[b,d]pyran-9B-ol (a solid):
IR: (CHC13) OH 3597 and 3333 cm 1.
NMR: ~CDCl 1.02 (s, one methyl o~ gem dimethyl), ' 1.20 (d,J = 7 Hz,methyl), 1.37 ~s, one methyl of gem di-methyl), 1.6-4.2 (M~, 6,19 (bs, ArH), 6.30 (bs, ArH) and 7^27 (s,Ph).
dl,6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-[1-methyl-2-~2-phenylethoxy)ethyl]-6H-dibenzo~b,d]pyran-9-(8H)-one is converted to dl-6a~,7,8,9,10,1Oa~-hexahydro-1- hydroxy ~6,6-dimethyl- 3- [l-meth ~ 2-~2-phenylethoxy)-ethyl~-6H-dibenzo[b,d]pyran-9~-ol, m.p. 90~-105C.
IR: (CHC13) OH 3534 and 3279 cm NMR: ~CDCl 1.12 (M,three methyls~, 1.73 (M), 2.32 ~M), 2.82 (t,J = 7 Hz, CH2Ph), 3.0-4.1 (M), 6.13 ~d,J = 2 Hz, ArH), 6.30 (d,J = 2 Hz, ArH), 6.90 (bs,phenol) and 7.25 (s,PH).
MS: (mol-ion) 410 (M~ ) and 105.

dl-5-Hydroxy-2,2-dimethyl-7-(2-heptyloxy)-4-chromanone To a solution of 5,7-dihydroxy-2,2-dimethyl-4-chromanone (18.5 g., 87.1 mM) and potassium hydroxide ~2.44 g., 43.5 mM) in N,N-dimethylformamide (58 ml.~ is added with stirring 2-bromoheptane (15.77 g., 88,0 mM~. The mixture is heated for four days at 100C., cooled to room temperature and then added to a mixture of aqueous sodium hydroxide (110 ml. of lN), water ¢45 ml.) and chloroform (150 ml ~.
The mixture is agitated and the chloroform layer separated.
The aqueous layer is extracted with more chloroform (150 ml.)O
The combined chloroform layers are washed with lN sodium hydroxide (2 x 100 ml.) dried over sodium sulfate and concen-trated to an oil. The unreacted 2-bromoheptane is removed by distillation and the residue purified by silica gel chroma-tography to give 5.90 g. (22.1%) of the title product as an oil.
NMR (CDC13) ~ - 12.4 (one proton singlet, hydroxyl-ic), 5.7 and 6.0 (two one proton doublets, J = 3 Hz., aromatic protons), 4.1-4.7 tone proton multiplet, ether methine), 2.7 (2 proton singlet, C-3 methylene), 0.7-2,0 (22 proton multiplet for the remaining protons, gem dimethyl appearing as a singlet at 1.5).

O

In liXe manner, dl 5-hy ~ ~-2,2-dimethyl-7-[2~(5-pherlyl)-pentylo~y]-4-o11roma~one is prepcli-e~ ~y-.ubstituting 2-bromo-5-phenyl--pen ~ e for 2-bromohep~e~ m~p~ 83-84C.~ KBr) C = 0 1639 cm 1.
NMR ~CDCl 1-3 ~D,3,~-methyl, J = 7 Hz~, 1.3-2.0 ~M,4,ethylene), 1.5 (S,6,gem dimethyl), 2.7 (S,2,~-methylene), 2.5-2.9 (M,2,benzylic methylene~, 4.1-4.7 ~M,l,methine~, 5.9-6.1 ~M,2,aromatic), 7.1-7.5 ~M,5,aromatic), 12.2 ~S,l,phenolic).
MS: ~mol-ion~ 354.
Analysis:
. .
Calc'd for C22H26O4: C, 74.55; H, 7.39%
Found: C, 74.68; H, 7.46%.
- dl-5-Hydroxy-2,2-dimethyl-7-(1-methyl-3-phenylprop-oxy)-4-chromanone is prepared from 2-bromo-4-phenylbutane as . an oil:
NMR: ~CDCl ~1.25, 1.35 (d,3,methyl), 1.4 (S,6,gem dimethyl), 1.6-2.4 ~M,2,methylene), 2.6 (S,2,benzylic methyl-ene), 2.85 (S,2,3,~-methylene), 4.05-4.7 (M,l,methinyl), 5.9 ~6d,2,aromatic), 7.25 (S,5,aromatic~.
- dl-5-hydroxy-2,2-dimethyl-7-cyclohexyloxy-4-; 20 chromanone is prepared from bromocyclohexane:
M.P. 729-75Co IR ~KBr) C = O 1626 cm 1; OH 3390 cm 1.
MS: ~mol-ion) 290 CDC13 1 2-1 (M~lo~c5Hlo-cyclohexyl)~ 1.4 ~S,6,gem dimethyl~, 2.65 ~S,2,~-methylene), 4.0-4.45 ~M,l,-cyclohexyl methinyl~, 5.85-6.05 (M,2,aromatic), 11.9 ~S,hydr-oxyl, D2O overlay).

dl-5-Hydroxy-3-Hydroxymethylene-2,2-Dimethyl-7-~2-~eptyloxy)-4-Chromanone To the sodium hydride obtained by washing 9.23 g.
(192 mM~ of 50% sodium hydride in mineral oil dispersion with pentane is added dropwise, over a 30 minute period, a solu-tion of dl-5-hydroxy-2,2-dimethyl-7-~2-heptyloxy)-4-chromanone 35 (5.90 g., 19.2 mM) and ethyl formate (34.9 ml., 432 mM).
After the addition is complete, ether (475 ml~ is added and `` ~ Z40 the resulting mixture refluxed. After 18 hours, the reaction mixture is cooled to room temperature and acidified with lN
hydrochloric acid. The organic layer is separated and the aqueous layer is further extracted with ether (3 x 125 ml.)~
The combined ether extracts are dried over sodium sulfate and concentrated under vacuum to yield 6.41 g. (~100%) of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-~2-heptyloxy)-4-chromanone as an oil.
NMR: ~CDC1 13.4 (one broad singlet proton, hydr-oxylic), 11.8 (one proton singlet, phenolic hydroxylic), 7.4 (one broad proton singlet, vinyl), 6.1, 6.0 (2 one proton doublets, J = 3 Hz, aromatic), 4.8-4.2 (one proton multiplet, methine), 2.1-0.7 (20 proton multiplet for the remaining : protons).
In like manner, appropriate reactants of Example 6 are converted to: dl-5-hydroxy-3-methylene-2,2-dimethyl-7-[2-(5-phenyl)pentyloxy]-4-chromanone, an oil.
NMR: ~CDMCl 1-3 (D,3,~-methyl, J = 7 ~z), 1.3-2.0 (M,4,ethylene), 1.4 (S,6,gem dimethyl), 2.3-2.8 (bd.,T,2-20 benzylic methylene), 4.1-4.7 (M,l,methine), 5.8-6.0 ~M,2,-aromatic), 7.0-7.4 (M,6,aromatic and vinylic), 10.0 (S,l,-phenolic), 13.3 (bd,S,l,hydroxylic);
dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-~2-(4-phenyl)butyloxy]-4-chromanone, an oil;
dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-cyclohexyloxy-4-chromanone;
IR (KBr) C = O 1620 cm 1; OH 3420 cm 1 MS: (mol-ion) 318 CDC13 1-1 2-3 (M~l~csHl0-cyclohexyl)~ 1 55 30 (S,6,gem dimethyl), 4.1-4.5 (M,l-cyclohexyl-methinyl), 5.9-6.1 (M,2,aromatic), 7.1-7.5 (d,l,methinyl~, 11.6 ~S,l,hydr-oxyl, D2O overlay).
dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-~1-methyl-3-phenoxypropyl)-4-chromanone, an oil (from reactant of Example 1~:

3Z~) Rf = 0.42 (silLca gel, L8-benzene:l-ethyl acetate~
MS: (mol-ion) 368.

dl-6a,7-Dihydro-l-Hydroxy-6,6-Dimethyl-3-(2-Heptyl-oxy~-6H-Dibenzo-[b,d]pyran-9(8H~-One To a solution of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(2-heptyloxy)-4-chromanone (5.17 g., 15O4 mM~
and methylvinyl ketone (2.27 ml., 27.9 mM) in methanol (23 ml.) is added triethylamine (0.54 ml.). The reaction is - 10 stirred for 16 hours at room temperature and then diluted with ether (250 ml.). The resulting ether solution is ex-tracted with 10% sodium carbonate (6 x 30 ml.~, dried over sodium sulfate, and concentrated under vacuum to yield 6.11 g. of an oil. The residue is refluxed with ethanol (45 ml.) 15 and 2N potassium hydroxide (45 ml.) for 16 hours. Thereafter the reaction solution is cooled, acidified with 6N hydro-chloric acid and extracted with dichloromethane (3 x 100 ml.).
The organic phase is dried over sodium sulfate and evaporated to yield 6.3 g. of a dark solid. The solid is triturated in 20 hot ether to yield 1.00 g. of the title compound, m.p. 185-189C.; 1.26 g. of further material is obtained vla silica gel chromatography of the mother liquor. The total yield is 42.3%.
NMR (CDC13) ~ - 11.2 (one broad proton singlet, 25 phenolic OH), 7.9 (one broad proton singlet, vinyl), 6.2, 5.9 (two one proton doublets, J ~ 3 Hz, aromatic protons~, 4.6-4.0 (one proton multiplet, methine ether), 3.0-0.6 (25 proton multiplet, remaining protons).
IR (KBr) C = 0 1600 cm 1.
Analysis:
Calc'd for C22H304 C~ 73-71; H~ 8-44%
Found: C, 73.41; H, 8.37%.
W CH3CH2H = 342 m~ ~= 26,800)-max The following compounds are similarly prepared from appropriate reactants of Example 7:
dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutoxy)-6H-dibenzo[b,d]pyran-9~8H)-one; m.p. 140-168C;

.

NMR: ~CDCl 1.3 (D,2,~-methyl, J = 7 Hz), 1.1-2 3 ~M,15,remaining protons), 2.3-3.0 (bd,T,2,benzylic-methylene), 4.1-4.7 lM,l,methine), 5.95 (D,l,aromatic, J = 2 Hz), 6.3 (D,l,aromatic, ~ = 2 Hz), 7.2-7.4 (M,5,aromatic), 8.0 (D,l,-vinylic, J = 2 Hz).
IR: (KBr) C = O 1563 cm Analysis:
Calc'd for C26H304 C, 76-82; H~ 7-44%
Found: C, 76.74; H, 7.48%
MS: (mol-ion) 406.
dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylbutoxy)-6H-dibenzolb,d]pyran-9(8H)-one;
M.P. 163C.
~ NMR: ~CDCl 1.2, 1.3 (d,3,methyl), 1.45 ~S,6,gem ; 15 dimethyl), 1.65-2.2 (M,2,methylene), 2.3-2.95 (M,4,methylene,-benzylic methylene), 4.1-4.6 (M,l,methinyl), 5.9, 6.15 (2d,2,-aromatic), 7.15 (S,6,aromatic, hydroxyl-D2O overlay), 7.95 (6S,l,olefinic proton).
MS: (mol-ion) 392 dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-cyclo-hexyloxy-6H-dibenzo-[b,d]pyran-9(8H)-one;

IR (KBr) C = O 1590 cm 1; OH 3390 cm 1 NMR: ~DMSO 1.05-3.0 (M,15,c5Hlo-cyclohexyl~ 6a 25 methinyl, 7-methylene, 8-~-methylene), 1.45 (S,6,gem dimeth-yl), 4.0-4.4 (M,l,methinyl) 5.8-6.1 (2d,2,aromatic), 7.1-7.25 (d,l,olefinic proton), 7.3 (S,l,hydroxyl-D2O overlay).
dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenoxypropyl)-6H-dibenzolb,d~pyran-9(8H)-one, a light yellow solid:
M.P. 203-206C.
MS: (mol-ion) 392 Analysis:
Calc'd for C25H284 C, 76-50; H~ 7-19%
35 Found: C, 76.33; H, 7.12~.

dl-6aB~7~lo~loa~-Tetrahydro-l-Hydroxy-6~6-Dimeth 3-(2-Heptyloxy)-6H-Dibenzo~b,d]pyran-9(8H)-One A solution of dl-6aB,7-dihydro-1-hydroxy-6,6-di-- 5 methyl-3-(2-heptyloxy~-6H-dibenzo[b,d]pyran-9(8H)-one (1.2 ~; g., 3.3 mM) in tetrahydrofuran (9 ml.l is added dropwise to a rapidly stirred solution of lithium (25 mg.) in liquid ammonia (45 ml.) at -78C. During the addition an additional 75 mg. of lithium is added to insure the blue color. After ` 10 an additional 15 minutes of stirring solid ammonium chloride is added to discharge the blue color. The excess ammonia is allowed to evaporate and the residue was diluted with water (45 ml.) and acidified with 10% hydrochloric acid. The aqueous solution is extracted with dichloromethane (3 x 50 ml.) and the dichloromethane extracts dried over sodium sulf-ate and evaporated to yield 1.30 g. of a crude semi-solid which is purified vla silica gel column chromatography to yield 0.614 g. (50.9%) of product, m.p. 155-158C. after recrystallization from chloroform/hexane.
NMR (CDC13) ~ - 8.2 (one proton singlet, phenolic OH), 5.8-6.3 (2 proton multiplet, aromatic), 3.9-4.6 (2 pro-ton multiplet, methine ether and C-10 equatorial), 0.3-3.2 (26 proton multiplet, remaining protons).
IR (KBr) C = O 1737 cm 1.
MS (m/e) 360 (M+), 261 (M-99).
Analysis:
Calc d or C22 32 4 C, 73.30; H, 8.95%
Found: C, 73.05; H, 8.82%
and the corresponding cis-isomer:
dl-6aB,7,10,10aB-tetrahydro-l-hydroxy-6,6-dimethyl-3-t2-heptyloxy)-6H-dibenzo[b~d]pyran-9(8H)-one~ m.p. 141-146C. (from ether/hexane).
IR: (KBr) C = O 1718 cm 1.
MS ~m/e) 360 (M ), 261 (M-99).
Similarly, the following compounds are prepared from products of Example 8:
dl-6aB,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-.

111~240 .

3~ methyl-4-phenylbutoxy)-6H-dibenzo[b,d]pyran-9(8H)-one;
M.P. 122-125C.
NMR: ~CDCl 1.3 (D,3,~-methyl, J = 7 Hz), 1.1-3~0 (M,16,remaining protons), 2.3-3.0 (bd.T,2,benzylic methylene), 4.1 (bd.D,l,C-10 equatorial, J = 14 Hz), 4.1-4.7 ~M,l,-methine), 5.95 (D,l,aromatic, J = 2 Hz), 6.1 (D,l,aromatic, J = 2 Hz), 7.2-7.4 (M,5,aromatic), 7.9 (S,l,phenolic~.
IR: (KBr) C = O 1709 cm 1 Analysis:
Calc'd for C26H32O4: C, 76.44; H, 7.90%
Found: C, 76.22; H, 7.79%
and the corresponding cls-isomer:
dl-6aB,7,10,10aB-tetrahydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutoxy)-6H-dibenzo~b,d]pyran-9(8H)-one, m.p. 141-142C.
IR: (KBr) C = O 1707 cm 1 MS: (mol ion) 408 Analysis:
Calc'd for C26H324 C~ 76-44; H~ 7-90%
Found: C, 76.58; H, 7.92%.
dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylpropoxy)-6H-dibenzo~b,d~pyran-9(8H)-one, m.p. 160C.
NMR: ~CDCl 1.2, 1.3 (d,2, -methyl), 1-4 (S,6,gem dimethyl), 1.65-2.9 (M,ll,remaining protons), 3.9-4.5 (M,2,-10a~-proton,methinyl), 5.9-6.1 (2d,2,aromatic), 7.2 (S,5,-aromatic), 7.9 (S,l,hydroxyl-D2O overlay).
MS: (mol ion) 394.
dl-6a~,7,10,10a~-Tetrahydro-l-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo[b,d]pyran-9(8H)-one, m.p. 215-218C.
IR (KBr) C = O 1695 cm 1; OH 3225 cm 1 MS: (mol-ion) 344 CDC13 1.0 3.2 (M,18,c5Hlo-cyclohexyl~ 6aB~-7,8,10,10a~-protons), 1.5 (S,6,gem dimethyl), 3.9-4.3 (M,l,-l~ D
:

cyclohexyl-methinyl), 5.9, 6.05 (2d,2,aromatic~, 8.9 (bs,l,-hydxoxyl-D2O overlay~.
dl-6a~,7,10,10a~-Tetrahydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenoxypropyl)-6H-dibenzo[b,d]pyran-9(8H)-one:
- 5 M.P. 167-170C.
MS: (mol-ion~ 394 Analysis:
Calc'd for C25H304 C~ 76-11; H~ 7-66%
Found: C, 75.93; H, 7.63%
NMR: ~CDCl 7.87 (S,l,phenolic proton), 7.42-6.67 ` (M,5,C6H5), 6.33 (S,2,aromatic H2 + H5), 4.42-1.00 (M,22,non-aromatics - including triplet centered at 3.90 for -CH2-O-, singlet at 1.48 for CH3, doublet centered at 1~27 for CH3, ~ singlet at 1.13 for CH3 and 11 other methylene, methine pro-; 15 tons).
`: EXAMPLE 10 dl-6a~,7,8,9,10,1Oa~-Hexahydro-l-Hydroxy-6,6-Dimeth-yl-3-(2-Heptyloxy)-6H-Dibenzo[b,~]pyran-9B-ol To a solution of dl-6aB,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(2-heptyloxy)-6H-dibenzo~b,d]pyran-- 9(8H)-one (0.60 g., 1.66 mM) in ethanol (18 ml.), stirred at room temperature under nitrogen is added sodium borohydride (275 mg.). The reaction is stirred for 30 minutes and poured onto a mixture of ice (35 ml.), 10% hydrochloric acid (35 ml.) and ether (200 ml.). The ether layer is separated and the aqueous layer extracted with additional ether (2 x 100 ml.). The combined ether extracts are dried over sodium sulfate and evaporated to an oil. Crystallization from hexane yielded 305 mg. (50.3%) of product, m.p. 102-104C.
NMR: ~CDCl 7.9-6.7 (one broad proton singlet, hydroxylic), 6.1-5.8 (two broad proton single~, aromatic), 4.5-0.5 (31 proton multiplet, remaining protons).
IR (KBr) OH 3390 cm Analysis:
Calc'd for C22H34O4: C, 72.89; H, 9.45%
Found: C, 72.52; H, 9.18%.
`"

111~2~0 Similarly, the following are prepared from ap-propriate tetrahydro compound:
dl-6aB,7,8,9,10,10aa-hexahydr~--l-hydroxy-6,6-dimethyl-3-(1-methy -4-phenylbutoxy)-6H-dibenzo[b,d]pyran-9~-ol, an amorphous solid.
! IR: (KBr) O~ 3390 cm 1 MS: (mol.ion) 410 NMR: ~CDCl 1.3 (P,3,~-methyl), 1.0-4 5 (M,24, remaining protons), 5.8-6.0 ~M,2,aromatic), 6.8-7.3 (M,5, aromatic).
dl-6aB,7,8,9,10,10a~-hexahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylpropoxy)-6H-dibenzo[b,d]pyran 9B-ol, an amorphous solid.
MS (mol.ion) 396 dl-6a~,7,8,9,10,10aa-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo[b,d]pyran-9B-ol:
M.P. 214~-216C.
IR (KBr) OH 3365 cm 1; 3125 cm MS: (mol.ion) 346 CDC13 1.0 3.0 (M,23,C5H10-cyclohexyl,gem dimethyl, 7,8,9a,10 protons), 3.5-4.15 (M,2,6a~,10aa pro-tons), 4.35-4.7 (M,l,cyclohexyl-methinyl), 4~85-5 05 (bd, 1,hydroxyl-D2O overlay), 6.1-6.45 (M,2,aromatic), 9.7 (S,l, hydroxyl-D2O overlay).
dl-6aB,7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenoxypropyl)-6H-dibenzo[b,d]
pyran-9B-ol:
M.P. 151-152C.
Rf = 0.25 (silica gel, 9-ether:l-hexane) MS: (mol.ion) 396 Analysis: Calc'd for C25H32O4: C, 75~72; H, 8.14 %
Found: C, 75.79; H, 8.39 %
dl-6aB,7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenoxypropyl)-6H-dibenzo[b,d]
pyran-9a-ol; an oil.

, l~lU240 , Rf = 0.35 (silica gel, 9-ether:l-hexane) MS: (mol.ion) 396 EXAMæLE 11 The following compounds are prepared according to the procedures of Examples 1-5 from appropriate ~3,5-dihydroxy)phenyl compounds of the Formula 3,5-(HO)2C6H3-Z-W and the appropriate acid of Formula R4R5C=CH-COOH, H ~ ~ OH

R4\ 0 R5 ~ 0 ~ Z-W

10 CH3 CH3-(CH2)6- C6H5 H H -(CH2)7- C6H5 CH3 CH3(CH2~8 C6H5 CH3 H -CH(CH3)(CH2)5- C6H5 2 5 C2H5 -CH(CH3)(CH2)6- C6H5 15 CH3 CH3 -CH~CH3)~CH2)7- C6H5 : H H -CH(CH3)(CH2)3- 4-FC6H4 :. 3 C2H5 -C(CH3)2(CH2)3 C6H5 CH3 CH3 -(CH2)3-CH(CH3)- C6H5 CH3 H -cH(cH3)(cH2)2cH(cH3~ C6H5 20 C2H5 H -CH(CH3)(CH2)3- 4-ClC6H4 C2H5 C2H5 -CH(CH3)(CH2)4 4-ClC6H4 CH3 CH3 -CH(CH3)(CH2)2- 4-ClC6H4 H H -CH(CH3)(CH2)- 4-ClC6H4 CH3 CH3 ( 3)( 2) 4-FC6H4 25 CH3 CH3 -CH(CH3)tCH2)2- 4-pyridyl H H -(CH2~3 2-pyridyl C2H5 H -(CH2)3 3-pyridyl CH3 CH3 -(CH2)3 4-pyridyl C2H5 -(CH2)3 2-piperidyl 30 H H -(CH2)3 4-piperidyl 2~o _ CH3 H -(CH2)4 2-pyridyl 2 5 H -(CH2)4 4-pyridyl C2H5 C2H5 -(CH2j4 3-piperidyl 5 CH3 CH3 -(CH2)4 4-piperidyl H H -(CH2)2 C6H5 H H -CH(CH3)(CH2)2- 4-FC6H4 CH3 ( 3)( 2)2 4-ClC6H4 2 5 C2H5 -CH(CH3)(CH2)2- C6H5 H H -CH(CH3)(CH2)3- C6H5 CH3 CH3 -CH2CH(CH3)CH2- 2-pyridyl H H -CH2CH(CH3)CH2- 4-piperidyl 2 5 H -CH(CH3)CH~CH3)CH2- 3-pyridyl C2H5 C2H5 -CH(CH3)CH~CH3)CH2- 4-pyridyl 15 H H -CH(CH3)CH~CH3)CH2- 3-piperidyl CH3 C2H5 -cH(cH3)~cH2)2 2-pyridyl CH3 C2H5 -CH(CH3)~CH2~2- 3-pyridyl CH3 CH3 -CH~CH3)~CH2)2- 4-piperidyl H H -CH(CH3)(CH2)3- 3-pyridyl 20 CH3 CH3 -CH(CH3)(CH2)3- 4-piperidyl CH3 CH3 -CH(CH3)CH~c2Hs)cH2 4-pyridyl 2 5 CH3 -CH(C2H5)~CH2)2 4-pyridyl 2 5 ~ 2 5)~ 2)2 2-piperidyl H ~ 2 5)(C 2)2 4-piperidyl 25 CH3 H -CH2CH~C2H5)CH2- 3-pyridyl CH3 CH3 -CH(C2H5)~CH2)3 3-pyridyl -. CH3 CH3 -CH(C2H5~(CH2)3 4-pyridyl 2H5 C2H5 -CH(C2H5)CH~CH3)CH2- 2-pyridyl H H -CH(C2H5)CH(c2Hs)cH2 4-pyridyl :~ 30 H H -CH(C2H5)CH(C2H5)CH2 2-piperidyl CH3 CH3 -(CH2)3CH(CH3)- C6H5 CH3 CH3 -(CH2)3CH(CH3)- 4-FC6H4 . CH3 CH3 -(CH2)3CH(CH3)- 4-pyridyl H H -(CH2)3CH(CH3)- C6H
35 CH3 CH3 -(CH2)3CH~CH3)- C6H
. 3 CH3 -CH~CH3)~CH2)2CH~CH3) C6H5 R4 5 z W
_ CH3 H -CH(CH3)(CH2)2CH(CH3)- C6Hll C2H5 C2H5 -cH(cH3)(cH2)2cH(cH3)- 4-piperidyl CH3 CH3 -CH(CH3)(CH2)3- C6H
5 H H -cH(cH3)(cH2)2cH(cH3)- C6H
2H5 C2H5 -(CH2)3- C6H
CH3 H -(CH2)4- C6H
CH3 C2H5 -(CH2)8- C6H
CH3 CH3 -(CH2)2- C4H7 10 CH3 CH3 -CH2CH(CH3)CH2- C5H9 H CH3 -CH2CH(CH3)CH2- C5Hg CH3 CH3 -CH(CH3)(CH2)2- C7H13 H H CH(CH~CH(CH3)CH2- C6H
CH3 CH3 -CH(CH3)(CH2)3- C5H9 15 CH3 CH3 -(CH2)4- C6H5 CH3 CH3 -(CH2)2CH(C2H5)- C6H5 ~: CH3 CH3 -C(CH3)2- C6H5 H CH3 -CH(CH3)CH2CH(C2H5)- C6H5 H CH3 -CH(CH3)CH2- C5Hg 20 H CH3 -CH(CH3)CH2- C3H5 C2H5 H -CH(CH3)CH(CH3)- C6H
CH3 CH3 -CH(CH3)(CH2)4- C5Hg CH CH3 -CH(C2H5)~CH2)2- C6H5 25Compounds of the following formula are obtained from appropriate reactants of preparatiQns K and Y and appropriate acids of formula R4R5C=CHCOOH by the pro-. cedures of Examples 1-4 (R4 and R5 = H, CH3 or C2H5~:

:' If 4~- ¦
~ (alkl)-X-(alk ~ -W

2~(~
. , Reduction of th~ keto compounds with sodlum borohydride according to the procedure of Example 5 affords the corresponding 9-hydroxy compounds (both isomers formed; the ~-form predominates) The sulfoxide and sulfone compounds of Examples 15 and 16 are reduced in like manner to the corresponding 9-hydroxy compounds.

dl-5-Hydroxy-2,2-dimethyl-7-(1-methyl-4-phenylbutoxy~-4-chromanone . _ A mixture of 5-phenyl-2-pentanol (16.4 g., 100 nM), triethylamine (28 mlO, 200 mM~ and dry tetra-hydrofuran (80 ml.) under a nitrogen atmosphere is cooled in an ice/water bath. Methanesulfonyl chloride (805 mlO, 110 mM) in dry tetrahydrofuran (20 ml~) is added dropwise at such a rate that the temperature holds essentially con-stant. The mixture is allowed to warm to room temperature and is then filtered to remove triethylamine hydrochloride.
The filter cake is washed with dry tetrahydrofuran and the combined wash and filtrate evaporated under reduced pres-sure to give the product as an oilO The oil is dissolvedin chloroform (100 ml.) and the solution washed with water (2 x 100 ml.) and then with saturated brine (1 x 20 ml ~.
Evaporation of the solvent affords 21.7 gO (8907%) yield of 5-phenyl-2-pentanol mesylate which is used in the next step without further purification.
A mixture of 2,2-dimethyl-5,7-dihydroxy-4-chro-manone ~2.08 g., 10 mM), potassium carbonate (2.76 gO, 20 ! mM), N,N-dimethylformamide ~10 ml~) and 5-phenyl-2-pentanol mesylate (2.64 g., 11 mM), under a nitrogen atmosphere, is heated to 80-82~C. in an oil bath for 1.75 hours. The mixture is cooled to room temperature and then poured into ice/water (100 ml.). The aqueous solution is extracted with ethyl acetate (2 x 25 ml.) and the combined extracts washed successively with water (3 x 25 ml.~ and saturated brine ~1 x 25 ml.). The extract is then dried (MgSO4), decolorized with charcoal and evaporated to give the pro-duct as an oil which crystallizes upon seeding with pure . .

: -43--product; m.p. 83-84C. Yield = quantltatlve.
In like manner, the folLowing compounds are pre-- pared from appropriate 2,2-R4R5-5,7-dihydroxy-4-chromanones and appropriate alkanols. The necessary alkanol reactants not previously described in the literature are prepared from appropriate aldehydes or ketones via the Wittig re-action of Preparation Go ;~ R5 ~ 0 ~O-~alk~)-w Z4~

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r~ mU~ ~ ~ ~ ~ m ~ ~ ~ ~ ~ ~ ~ ~ s ~rl m u uN uN ~: u ~ u u uN u ~ u u u u u u u EXAMPLE l.4 The products of Example 13 are converted to compounds having the formula below by the procedures of Example 1-5.
OH

R ~ ~ O-(alk2)-w dl-6aB,7,10,10a~-Tetrahydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-3-phe~ylsulfinylpropyl)-6H-dibenzo[b~d]pyran-9~8H)-one Equimolar amounts of m-chloroperbenzoic acid and dl-6aB,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylthiopropyl)-6H-dibenzo-[b,d]pyran-9 (8H)-one are reacted together in a mixture of chloroform and acetic acid (2:1) at room temperature for one hour.
The organic phase i5 washed with water, dried (MgSO4~ and evaporated to dryness to give the product.
In like manner the thio ethers of Example 12 are oxidized to the corresponding sulfoxides of formula OH

~\(alkl) -~- ~alk2) -W

dl-6aB,7,10,10aa-Tetrahydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-3-phenylsulfonylpropyl)-6H-dibenzo~b,d]pyran-9~8H~-one The procedure of Example 15 is repeated but using two equivalents of m-chloroperbenzoic acid as oxidizing agent per mole of thio ether reactant.

?240 : `

Similarly, the thio ethers of Example 12 are converted to their corresponding sulfonyl derivatives to give compounds of the formula:

OH

R ~ k~ alk2)-W

EXAME~E 17 (-)-Trans 3-(1-methyl-4-phenylbutyl)-6a,7,8,10a-tetrahydro-6,ff,9-trimethyl-6H-dibenzo[b,d]pyran-l-~ -ol To a stirred solution of (+) p-mentha-2,8-dien-l-ol (4.9 g., 0.0322 mole) and 5-(1-methyl-4-phenylbutyl)-resorcinol (8.2 g., 0.032 mole) in dry methylene chloride~200 ml~) is added anhydrous magnesium sulfate (4 g., 0.332 mole). The mixture is stirred under a nitrogen atmo-sphere and cooled to 0C. Freshly distilled boron tri-fluoride etherate (2 ml., 0.016 mole) is then added drop-wise over a 5 minute period. The reaction mixture isstirred for 1.5 hours at 0C. and anhydrous æodium bicar-bonate (10 g., 0.119 mole) is added. Stirring is continued until the dark color fades, The reaction mixture is fil-tered and evaporated to give 11.7 g. (93.6%) of a resinous product. The product i8 purified via column chromatography on an activated magnesium silicate, available from M C & B
Manuacturing Chemists, 2909 Highland Avenue, Cincinnati, Ohio, under the trademark "Florisil", to give 3.4 g~ ~27%) of the desired product as a mixture of optically active diasteriomers.
NMR ~CMDSl 1.1 (S~3~Cl-methyl)~ 1.3, 1.45 (2S,6, gem dimethyls), 1.7~ (S,3,Cg-methyl), 0.7-3.0 (M,12,remain-ing protons), 3.0-3.6 (M,l,Cloa proton), 5.05 (S,l,hydroxyl, D2O overlay), 6.1 (S,l,C4-proton, aromatic), 6.4 (M,2,C2-proton, aromatic, C10-proton), 7.1-7 t5 (M,5,aromatic protons).
MS: (mol.ion) 390 It is converted to the optically active 6a~,7,10, 10a~-tetrahydro-1-hydroxy-3-(1-methyl-4-phenylbutyl)-6,6-dimethyl-6H-dibenzo[b,d]pyran-9(8H)-one diasteriomers according to the procedure of Wildes et al,, J. ~. Chem.
36, 721-3 (1971) ~ r !' ' i`. ' ' " :. ,. j *[~]d (C = 1.0, CHC13) = -100.8.

dl-6a~,7,10,10a~-tetrahydro-1-(4-morpholinobutyryloxy)-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-9(8H)-one h~drochloride ., To a stirred solution of dl -6a~,7,10,10a~-tetra-hydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,dlpyran-9(8H)-one (0.52 g., 1.28 mM) in dry - methylene chloride (25 ml.) is added 4-morpholinobutyric acid hydrochloride (0.268 g., 128 mM).i The mixture is stirred at room temperature under a nitrogen atmosphere.
A O.l M solution of dicyclohexylcarbodiimide in methylene chloride (12.8 ml., 1.28 mM) is added dropwise and the mixture stirred for 24 hours. It i5 filtered and evap-orated to give the title product, which is purified by - column chromatography on silica gel.
EXA~LE 19 - The procedure of Example 18 is repeated but using the appropriate dl-6a~,7,10,10a~-tetrahydro-6,6-R4R5-3-(Z-W)-6H-dibenzo[b,d]pyran-9~8H)-ones of Example 4, 9 and those produced as penultimate products in the pro-3G cedures of Examples 11, 12 and 14; and the appropriate alkanoic acid or acid of formula HOOC-(CH2)p-NR2R3.HCl to produce esters of the formula . ~ R

4 ~

wherein R4, R5, z and W are as defined in Example 4, 9, 11, . 12 and 14 and Rl is Rl* Rl*
:~ 5 -COCH3 -CO(CH 2 ) 3NHC4Hg-COCH2CH3 -C(cH2)2N(c4H9)2 -CO(CH2)3CH3 -COCH2-piperidino -COCH2NH2 -COCH2-pyrrolo ~ -CO(CH2)2NH2 -COCH2-(N-methyl)piperidino i -CO(CH2)4NH2 -CO(CH2)2-morpholino -COCH2N(CH3)2 -CO tCH2 ) 2-(N-butyl)piperidino -CO(CH2)2N(C2Hs)2 -CO(CH2)3-pyrrolidino -CO(CH2)4NHCH3 -CO(C2H4)-(N-ethyl)piperidino -CON~2 -CO-piperidino : 15 -CON(CH3) 2 -CO- (N-methyl)piperidino -CON(C4Hg)2 -CO-morpholino -CON(C2H5)2 -CO-pyrrolo *Basic esters are obtained as their hydroahloride salts. Careful neutralization with sodium hydroxide affords the free ester.

.
: dl-6a~,7,8,9,10,10a~-hexahydro-1-(4-morpholinobutyryloxy)- 6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo~b,d]
pyran-9~-ol hydrochloride . 25 The title product of Example 5 is esterified - according to the procedure of Example 18 to produce the above-named ester salt.

In like manner, the remaining products of Example 5 and those of Examples 10-12 and 14 are converted to esters having the formula shown below wherein R4, R5, Z and W are ;

.

as defined in said Example and Rl has the values given below:

:~, U ~ 1 R4 ~ ¦ O l R ~ ~ Z-W
:
:` Rl R
-COCH COCH2-pyrrolo . -CO(CH2)2CH3 -COCH2-pyrrolidino -CO(CH2)3CH3 -COCH2-morpholino -COCH2NH2 -COCH2-(N-methyl)piperazino -COCH2N(CH3)2 -COCH2-(N-butyl)piperazino -C(cH2)2NHCH3 -CO[CH2)2-piperidino -CO~CH2)2N(i-C3H7)2 piperazi2o C CH2 (C4Hg)2 -CO(CH2)3-pyrrolidino : 15 -CO(CH2)4N~C2H5)2 -CO(CH2)4-(N-ethyl) pipera ino -CONH2 -CO-piperidino -CON(CH3)2 -CO-(N-methyl)piperazino -CONHC2H5 -CO-morpholino -CON(C4Hg)2 -CO-pyrrolo dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenyl-but~l)-6H-dibenzo[b,d]pyran-9~8H)-one H A) dl-Ethyl 5-hydroxy-4-methyl-7-~l-methyl-4-phenylbutyl) coumarin-3-proplonate A mixture of 2-(3,5-dihydroxyphenyl)-5-phenyl-pentane (33 g., 0.13 M), (Preparation C) diethyl ~-aceto-glutarate (32.2 g., 0.14 M) and pho6phorous oxychloride (20 g., 0.13 M), protected from atmospherlc moisture, is - stirred at room temperature. After 10 days, the mixture is dissolved in chloroform, washed three times with water, dried (Na2SO4), and evaporated. The residue is subjected to silica gel chromatography (eluents - 9 benzene:l ether) to yield 22 g. o~ the desired ester, mOp 58~-70~C~ from hexane. Further recrystallization from ethyl acetate/
hexane affords an analytical sample: m.p. 78-85C.
Analysis:
Calc'd for C26H30O5: C, 73.91; H, 7.16%
Found: C, 73~82; H, 7.134 MS: (mol.ion) 422 B) dl-7,10-Dihydro-l-hydroxy-3-~1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]-pyran-6,9~8H)-dlone To the sodium hydride powder obtained by washing 10.0 g. (0.21 mole) of 50~ sodium hydride in mineral oil dispersion with dry hexane is added 20.6 g. ~0c049 mole~
of the ester of part A of this example and the two powders are mixed thouroughly. The reaction flask is cooled to 15-17C. and dimethyl sulfoxide (200 ml.) is added directly into the reaction flask. After stirring for an additional hour at 15-17C., the reaction is kept overnight in the refrigerator. After warming to room temperature the reaction mixture is poured into a rapidly stirred mixture of 600 ml. of ice and water and 40 ml. of concentrated hydrochloric acid, more ice being added as needed to keep the mixture cold. The slurry thus produced is stirred for an additional hour and is then decanteda The residual gum is heated on the steam bath with excess concentrated sodium bicarbonate solution and, while still warm, the resultant solid is filtered. The filter cake is washed with bicarbonate solution and water and recrystallized from ethyl acetate/hexane to give 4.5 g. of cyclized product, m.p. 163-164C. Further purification is achieved by recrystallization from methanol; m.p. 166-167C
Analysis:
Calc'd for C24H244 C, 76-57; H~ 6-43~
Found: C, 76.50; H, 6.56%
MS: (mol.ion) 376 C) dl-7,8,9,10-Tetrahydro-l-hydroxy-3-(1-methyl-4-phenyl-butyl)spiro[6H-dibenzo[b,d]pyran-9,2'-[1',3']dioxolan~-6 one A solution of 0.031 mole of the cyclized product l~ Z~O

of part B of this example in benzene (500 ml). containing ethylene glycol (10 ml.) and p-toluenesulfonic acid (10 mg.) is heated overnight under reflux (Dean-Stark trap). The solution is cooled, poured into water containing excess sodium bicarbonate and the organic phase separated, dried ~Na2S04) and evaporated to yield the desired ketal.
D) dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)6H-dibenzo[brd]pyran-9~8~)-one A slurry of 0.175 mole of the above produced ketal in ether (1.5 liters) is added over 90 minutes to the Grignard reagent prepared from magnesium (44.6 g., 1.84 g-atoms) and methyl iodide ~110 ml., 251 g., 1.77 moles) in ether (1.8 liters). After refluxing for 2 days the re-action is treated carefully with lN hydrochloric acid (200 ml.), and then with 6N hydrochloric acid ~740 ml.) The mixture is stirred vigorously for 1 hour and then the ether layer washed once with water and once with 5% sodium bicarbonate. The ether layer is dried (Na2S04) and con-centrated to yield the desired unsaturated ketone. If desired, it is purified by crystallization and/or column chromatography (see Examples 3 and 8).
In like manner, the remaining l-(Z-W-substituted)-3,3-dihydroxybenzenes of Preparation C and those of Preparations D, E, K, M, Q, R and T are converted to the corresponding dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(Z-W)-6H-dibenzo[b,d]pyran-9~8H)-ones.

dl-6aB,7,10,10a~-Tetrahydro-l-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenylbutyloxy]-6H-dibenzo~b,d]pyran-9(8H)-one, Ethylene_Ketal A solution of dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6~6-dimethyl-3-(l-methyl-4-phenylbutyloxy)-6H-dibenzo[b,d]pyran-9(8H)-one (60 mg., 0.145 mM), ethylene glycol (0.5 ml.), benzene (10 ml.) and a crystal of p-toluenesulfonic acid is heated at reflux for three hours.The reaction mixture is then cooled and concentrated. The concentrate is shaken up in ckloroform and the chloroform phase washed first with sodium bicarbonate and then with '' . .

l~lV29~() water. It is then dried (MgSO4) and concentrated to give the ketal as a light brown oil (63 mg.)~
Repetition of this procedure but using propylene glycol, trimethylene glycol and tetramethylene glycol, in place of ethylene glycol, affords the corresponding ketals.
By means of this procedure the ketone products of Examples 3, 4, 8, 9, 11, 12, 14-16, 18, 19 and 21 are converted to the corresponding ethylene, trimethylene and tetramethylene ketals.

dl-5-Hydroxy-2,2-dimethyl-7-(2-heptylmercapto)-4-chromanone To a solution of 5-hydroxy-7-mercapto-2,2-dimethyl-4-chromanone ~19.7 g., 87.1 mM) and potassium hydroxide (2.44 g., 43.5 mM) in N,N-dimethylformamide (58 ml.) is added with stirring 2-bromoheptane (15.77 g~, 88.0 mM). The mixture is heated for four days 100C., cooled to room temperature and then added to a mixture of aqueous sodium hydroxide (110 ml, of lN), water ~45 ml.) and chloroform (150 ml.). The mixture is agitated, the phases separated and the aqueous layer extracted with more chloroform (150 ml~). The combined chloroform layers are washed with lN sodium hydroxide (2 x 100 ml.) dried over - sodium sulfate and concentrated to an an oil~ The unreacted 2-bromoheptane is removed by distillation and the residue purified by silica gel chromatography to give the title product.
The following o~ounds are similarly prepared - ~rom appropriate reactants of the formula Br-(alk2)n-W
from the appropriate 5-hydroxy-7-mercapto-2,2-R4R5 -sub-stituted-4-chromanone:
R ~0~
4 ~ \ ~ -(alk2) -W

`-` lll~Z40 R4 5 ~ (alk2) W
H CH3 l -CH(CH3)tCH2)4- CH3 2H5 C2H5 l -CH(CH3~(CH2)4- CH3 CH3 CH3 ( 3)( 2~3 C6H5 -5 H CH3 ( 3 ( 2~3 C6H5 CH3 CH3 l -CH(cH3)(cH2)2- C6H5 CH3 CH3 l -CH(CH3)(CH2)3- 4-pyridyl H H l -CH(CH3)(CH2)3 4-pyridyl CH3 CH3 l -CH2- C6H5 . 10 CH3 CH3 l -(CH2)4- C6H5 CH3 C2H5 1 -(CH2)7- C6H5 CH3 CH3 l -C(CH3)2(CH2)5 CH3 CH3 H 1 -C(CH3)2(CH2)5 CH3 CH3 ~H3 l -CH(CH3)CH(CH3)(CH2)4 CH3 H CH3 l -CH(CH3)CH(CH3)(CH2)4 CH3 - CH3 CH3 l -(CH2)3- 3-pyridyl CH3 H l -(CH2)3- 4-pyridyl H CH3 1 -CH~CH3)CH2- 2-pyridyl H H l -~CH2~2- 4-pyridyl C2H5 CH3 1 -CH(CH3)(CH2)2 4-piperidyl - CH3 3 C6Hll ~: H CH3 0 -- 4-FC6H4 C2H5 H 0 -- 4-ClC6H4 C2H5 C2HS ~~ C6H5 CH3 3 C5Hg CH3 3 ( 6 5i 3 4 CH3 C 3 0 2-(C6H5)C5H8 CH3 3 ( 6 5)C6Hlo C 3 0 ( 6 5)C7 12 35 H H 0 -- ( 6 5~ 6 lO
3 3 4-pyridyl CH3 3 4-piperidyl :`
:

dl-6a~,7,10,10a~-Tetrahydro-l-acetoxy-6,6-dimethyl-3-~1-methyl-4-phenylbutoxy)-6H-dibenzo[b,d~pyran-9~8H)-one Pyridine (15 ml.), acet:ic anhydride (15 ml.) and dl-6a~,7,10,10a~-tetrahydro-1--hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutoxy)-6H-dibenzo[b,d]-pyran-9(8H)-one (4.06 g.~ are combined at 0CO and the mixture ~tirred for a half-hour at OC. The reaction mixture is poured onto ice/water and acidified wlth dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2 x 100 ml.), the extraats combined and washed with brine. The extract is then dried ~MgSO4) and evap-orated to give a colorless oil which i9 crystallized from : ether-pentane. Yield = 1.69 g.; m.p. 95-96C.
Analysis:
28 34 5: C, 74.64; H, 7.61%
Found: C, 74.55; H, 7.59%
Evaporation of the mother liquor gives a second crystalline fraction whîch is digested in hexane. Yield 1.74 g.; m.p. 94-96C.
By means of this procedure but using the appro-priate alkanoic acid anhydride and the appropriate dl-6a~, 7,10,10a~-tetrahydro-6,6-R4,R5-3-~Z-W)-6H-dibenzo[b,d]
pyran-9~8H)-ones of Examples 4, 9, 11, 12 and 14 as re-actants, affords the propionyloxy, butyryloxy and valeryloxyesters thereof.
Reduction of the 9-keto group of the thus-pro-duced mono esters according to the procedure of Example 5 affords the corresponding 9-hydroxy derivatives. A mix-ture of the 9~- and 9~-isomers i8 produced.

dl-6a~,7,8,9,10,10a~-Hexahydro-l,9-diacetoxy-6,6-dimethyl-3-(1-methYl-4-PheYlbutYl)-6H-dibenzo[b~d~pvran A solution of dl-6a~,7,8,9,10a~-hexahvdro-1-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenylbutyl)-6H-dibenzo [b,d]pyran-9~-ol ~2.0 gO) in pyridine ~20 ml~) is treated at 10C. with acetic anhydride (20 ml.) and the mixture stirred for 18 hours under nitrogen~ The reaction mixture l~lV2~

is worked up according to the procedure of Example 240 In like manner, the l,9-dihydroxy compounds of Examples 5, 10-12, 14 and 15 are converted to their diacetoxy, dipropionyloxy, dibutyryloxy and divaleryloxy esters.

dl-6aB~7~lo~loa~-Tetrahydro-l-~4-N-piperidyl-butyroxy)-6,6-dimethyl-3-~2-~5-phenyl~ pentyloxy]-6H-dibenzo[b,d]pyran-9~8H)-one hydrochloLlde 10A mixture of dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-[2-~5-phenyl)pentyloxy]-6~-dibenzo [b,d~pyran-9(8H)-one (1.26 g~, 3~08 mmoles), 4-N-piperidyl butyric acid hydrochloride ~0.639 g., 3.08 mmoles) and dicyclohexylcarbodiimide (0.698 g., 3.39 mmoles in dry dichloromethane (3.5 ml ) is stirred at 20C. for 18 -` hours. The reaction is cooled to 0C., stirred for a half-hour and filtered. The filtrate is evaporated to an oil which is washed with ether ~3 x) and evaporated to yield 1.78 g. (97~) of dl-6a~,7,10,10a~-tetrahydro-1-~4-N-piperidyl-butyro~y)-6,6-dimethyl-3-[2-(5-phenyl) pentyloxy]-6H-dibe~nzLb,d]pyran-9t8H)-one hydrochloride as a solid, white foam.
IR: (KBr) N ~ 2667, 2564, C = 0 1779 and 1730 cm 1.
25 MS (mol.ion~: ~-HCl), 407, 262, 247, 154, 98 and 91.
PREPARATION A
:.
2-Bromo-5-phenylpentane To phosphorous pentabromide, prepared by addition of bromine (9.0 g~) in methylene chloride (10 mlO) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0C., is added 5-phenyl-2-pentanol ~8.2 gO~ in `methylene chloride at 0C~ The mixture is stirred for 2.5 hours at 0C. and is then allowed to warm to room temp-erature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts wa~hed with water, saturated sodium bicarbonate solution, brine :

l~lC~

and then dried over magnesium sulfate. Concentration of the dried extracts gives 12O4 g. of title product as a light yellow oilO
NMR ~CDCl 1~6 (D, 3, methyl, J = 7Hz), 1.6-2.0 (M, 4, ethylene), 2.3-3.0 (bd, T, 2, benzylic-meth-ylene), 3.7-4.2 (M, 1, methine), 6.9-7.4 (M, 5, aromatic) PREPARATION B
2-(3,5-Dimethoxyphenyl)-5-phenylpentane A solution of l-bromopropylbenzene (51~7 g.l 1n ether ~234 ml.) is added dropwise over a 2-hour period to a refluxing mixture of magnesium (7.32 g.) in ether (78 ml ) The reaction mixture is refluxed for 30 minutes longer and then a solution of 3,5-dimethoxy-acetophenone (50 g.) in ether (78 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenched by addition of saturated ammonium chloride ~234 ml.), the ether layer is separated and the aqueous phase extracted with ether (3 x 200 mlO)c The combined ether extracts are dried over magnesium sulfate and concentrated under vacuum to yield 81 g. of an oil. Forty grams of the oil i5 hydrogenated in a mixture containing ethanol (300 ml.), concentrated hydrochloric acid (2 ml.) and 5% palladium-on-carbon (5 g.). The catalyst is filtered off and the ethanol removed under vacuum. The residue is dictilled under vacuum yielding 28 g. of 2-t3,5-dimethoxyphenyl)-5-phenyl-pentane (b.p. 0.125 mm., 154-159C.).
CDC13 1.25 td,3,~-CH3), 1.3-2.1 (M,4, ethylene), 2.2-2.9 (M,3,benzylic-methylene, methinyl), 3.45 (S,6,methoxyl), 6.2-6.7 (M,3,aromatic), 7.2 (S,5,aromatic).
PREPARATION C
2-(3,5-Dihydroxyphenyl)-5-phenylpentane A mixture of 2-~3,5-dimethoxyphenyl)-5-phenyl-pentane (22 g.) and pyridine hydrochloride ~94 g.) under nitrogen is heated to 190C. for 2 hours with vigorous stirring, The reaction mixture is cooled, dissolved in 6N
hydrochloric acid (200 ml.) and diluted with water to Z~O

.

600 ml. The aqueous solution is extracted with ethyl acetate (4 x 100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield 24 g. of crude product. The product is purified by silica gel chromatography to yield 1902 g. of 2-(3,5-dihydroxyphenyl~-5-phenylpentane as an oil.
NMR ~CDCl 1.1 (d,3,~-methyl), 1-35-1.65 (M,4,ethylene), 202-2.8 (M,3,benzylic-methylene, methinyl~, 6.1-6.5 (M,3,aromatic), 6.65 ~bd.S.,2,hydroxyl), 7-7.4 (M,5,aromatic).
Following the procedures of Preparation B and C, the compounds listed below are prepared by substituting the appropriate l-bromoalkylbenzene for l-bromopropyl-benzene:
2-(3,5-(dihydroxyphenyl)-6-phenylhexane--NMR: ~CDCl 1.1 (D,3,~-methyl, J-7 cps), loO~
1-9 [M,6,~CH2(CH2)3-CH(CH3)-Ar], 2.2-2.8 (M,3,benzylic methylene, methinyl~, 6.0 (bd.S.,2-phenolic OH~, 602-604 (M,3,aromatic), 7.1-7.4(M,5,aromatic) 1-(3,5-dihydroxyphenyl)-2-phenylethane--mOp~ 76-77C~
2-(3,5-dihydroxyphenyl-4-phenylbutane ~an oil~--; NMR: ~cTMcsl 1.1, 1.25 (d,2,methyl), 1.45-2.0 ~,2,methylene~, 2.15-2.7 (M,3,benzylic-methylene, methinyl~, 6.3 (S,3,aromatic~, 6.85 (S,2,hydroxyl-D20 overlay), 7.1 (S,5,aromatic) The following compounds are prepared in like manner from the appropriate alcohol and 3,5-dimethoxy-benzaldehyde or 3,5-dimethoxyacetophenone by the methods of Preparations A, B and C:

HO ~ Z-W

Z W
CH(CH3)CH2 C5Hg CH(CH3)(CH2)2 C5Hg CH(CH3)CH2 C3H5 CH(CH3)CH(CH3) C6H
3)(CH2)3 C6H
CH(CH3)(CH2)4 C5Hg CH~CH3)(CH2)5 C6H
CH(C2H5)(CH2)2 C6H
(CH2)3 C5Hg CH(C2H5)(CH2)3 C6H5 C(CH3)2 C6H5 , (CH2)4 C6H5 :, (CH2) 2CH (C2H5) C6H5 ; 15 CH(CH3)CH2CH(C2H5) C6H5 PREPARATION D
1-(3,5-Dihydroxyphenyl)-2-methyl-4-phenylbutane - A solution of n-butyl lithium (29 ml. of 2.2M) is added dropwise to 3,5-dimethoxybenzyl triphenyl-phosphonium bromide (31.5 g.) in tetrahydrofuran ~200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone ~9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromato-graphy on silica gel (400 g.) and elution with benzene.
Yield: 10 g. as an oil.
CDC13 1.95 (S,3), 2.3-3.1 (M,4), 3.8 (S 6 6.15-6.6 ~M,3), 7.1-7.5 ~(M,6).
The 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene (9.4 g.) thus prepared is dissolved in ethanol (250 ml.) and catalytically hydrogenated at 45 p~s.i. in the presence of palladium-on-charcoal (1 g. of 10%) and 'Z~() concen~rated hydrochloric acid (1 ml.). Yield: 9~4 g of 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenylbutane as an oil.
NMR: ~cTDcl 0 9 (d,3), 1.35-1~95 (M,3),202-2,9 ~M,4), 3.75 ~S,6), 6.35 ~S,3), 7.25 ~S,5)~
It is demethylated according to the procedure of Preparation C to give 1-~3,5-dihydroxyphenyl)-2-methyl-4-phenylbutane.
The 3,5-dimethoxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 3,5-di-methoxybenzyl bromide ~12 g.) and triphenylphosphine ~14.2 g.) in acetonitrile (200 ml~) for one hour. The reaction mixture is then cooled and the crystalline pro-duct recovered by filtration, washed with ether and dried (20 g.); m.p. 269-270C.
PREPARATION E
2-Methyl-2-(3~5-dihydroxyphenyl)-5-phenylpentane To a solution of the Grignard reagent prepared from 2-phenylbromoethane ~5.5 g.), magnesium (0.8 g ) and dry ether (60 ml.) is added a solution of 2-methyl-2-(3,5-dimethoxyphenyl)propionitrile (2075 g.) in dry ether (20 ml.), The ether is distilled off and replaced by dry - benzene (50 ml.) and the mixture re~luxed eor 48 hours, It is then decomposed by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour The mixture is then extracted with ether, the extract dried (MgSO4) and concentrated to an oil. Distillation of the oil ln vacuo affords 2-methyl-2-(3,5-dimethoxyphen-yl)-5-phenyl-3-pentanone; b.p. 168C./0.2 mm. (Yield:
2.32 g., 6Q%) The thus-produced pentanone (58 g.) is dissolved in ethanol (400 ml.) and treated with sodium borohydride (10 g.) at room temperature The reaction mixture is stirred for 12 hours and is then cooled and neutralized with 6N hydrochloric acid. The ethanol is removed under reduced pressure and the residue extracted with ether.

The extract is dxied (MgSO4) and concentrated to give 2-methyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentanol as an oil ~52 g., 88~ yield~.
The pentanol (16 g~) is taken up in ether (100-ml.) and reacted with powdered potassium ~2.5 g.) in ether ~200 ml ). Carbon disulfide ~equimolar to the potassium3 i8 added and the mixture stirred for a half hour~ Methyl iodide ~9.0 g.) is then added and the reaction mixture stirred for 6 hours. The resulting suspension is filtered and the filtrate concentrated under reduced pressure.
The re~idue is taken up in ethanol ~150 ml.), Raney nickel added ~25 g.) an~ the mixture refluxed for 18 hours Evaporation of the alcohol and distillation of the residue gives 2-methyl-2-~3,5-dimethoxyphenyl)-5-phenyl-3-pentene.
The pentene derivative is catalytically hydro-genated according to the procedure of Preparation D and the resulting 2-methyl-2-~3,5-dimethoxyphenyl)-5-phenyl-- 3-pentane demethylated via the procedure of Preparation C to give the productO
PREPARATION F
- 3,5-Dibenzyloxyacetophenone Over a period of 1.5 hours, methyl lithium ~531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 25 3,5-dibenzyloxybenzoic acid ~175 g., 0.532 M) in ether ~250 ml.)-tetrahydrofuran ~1400 ml.) maintained at 15-20C. After stirring an additional 0.75 hour at 10~-15C., water ~600 ml.) is slowly added keeping the reaction temp-erature below 20C. The aqueous layer is separated and extracted with ether ~3 x 250 ml.). The organic phases are combined, washed with saturated sodium chloride solution (4 x 300 ml.), dried over sodium sulfate, and concentrated under vacuum to give an oil which slowly - crystallized from isopropyl ether~ The crude product is recrystallized from ether-hexane to yield 104.7 g. (59%) of product; m.p. 59-61C.

2~

PREPARATION G
Ethyl 3-(3,5-DlbenzyLo ~ tonate (Wittig Reaction) A mixture of 3,5-dibenzyloxyacetophenone (43,2 g., 0.13 mole) and carbethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heated uncler a nitrogen atmosphere at 170C. for 4 hours. The clear melt is cooled to room '' temperature, triturated with ether and the precipitate of triphenyl phosphine oxide removed by filtration. The filtrate is concentrated under vacuum to an oily residue ' 10 which is chromatographed over silica gel (1500 g.) and eluted with benzene:hexane solutions of increasing benzene concentration beginning with 40:60 and ending with 100~
' benzene. Concentratlon of appropriate fractions gives an oily residue which is crystallized from hexane. Yield:
40.2 g. (77%); m.p. 73-75C.
Analysis:
' Calc'd for C26H26O4: C, 77.58; H, 6.S1%
Found: C, 77.72; H, 6.60%
In like manner, ethyl 3-(3,5-dimethoxyphenyl) ' 20 crotonate i9 prepared from 3,5-dimethoxyacetophenone (51.7 g.) and carbethoxymethylene triphenylphosphorane (200 g.). Yield = 61.8 g., 86%, b.p. 146-162C. at ~' 0.3 mm.
PREPARATION H
3-(3,5-Dibenz~yloxyphenyl)-butanol A solution of ethyl 3-t3,5-dibenzyloxyphenyl) crotonate ~24.1 g,, 60 mM) in ether (250 ml.) is added to ;~ a mixture of lithium aluminum hydride (3.42 g., 90 mM) - and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydrQxide (3.4 ml. of 6N) and water (10 ml.) are then added successively to the reaction mixture. The inorganic salts which precipitate - are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil - 2.4 g. (98~).
' Rf = 0.25 [silica gel: benzene(l8):ethyl acetate(l)].

2~

MS: (mol.ion) 362, ~` Analysis:
Calc'd for C24H263 C, 79.53; H, 7.23%
Found: C, 79.37; H, 7.11%
In like manner, ethyl 3-(3,5-dimethoxyphenyl)-crotonate (60.4 g.) is reduced to 3-(3,5-dimethoxyphenyl)-butanol (48.0 g., 90~).
PREPARATION I
3-(3,5-Dibenzyloxyphenyl)butyl Tosylate Tosyl chloride (ll.l g., 58.1 mM) is added to a solution of 3-(3,5-dibenzyloxyphenyl)-l-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45C. The reaction mix-ture is held at -35C. for 18 hours and is then diluted with cold 2N hydrochloric acid ~1500 ml,) and extracted with ether (5 x 250 ml.). The combined extracts are washed with saturated sodium chloride solution ~4 x 250 ml.) and then dried ~Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexaneO Yield: 24.63 g. (84~). -Analysis:
31H32sS C, 72.06, H, 6.24%
Found: C, 72.05; H, 6.29%
PREPARATION J
3-(3,5 Dibenzyloxyphenyl)-l-phenoxybutane A solution of phenol (4.56 g., 48.6 mM) in di-methylformamide (40 ml.) is added under a nitrogen atmo-sphere to a suspension of sodium hydride (2,32 g., 48.6 mM of 50% previously washed with pentane) in dimethyl-formamide (70 ml.) at 60C. The reaction mixture is stirred for one hour at 60-70C., after which a solution of 3-(3,5-dibenzyloxyphenyl)butyl tosylate (23.93 g., 46.3 mM) is dimethylformamide ~80 ml.) is added. The reaction mixture is stirred at 80C. for a half hour and is then cooled to room temperature, diluted with oold water (2500 ml.) and extracted with ether (4 x 400 mlO).
The combined extracts are washed suocessively with cold 2N hydrochloric acid (2 x 300 ml.) and saturated sodium chloride solution (3 x 300 ml.) and then dried (Na2SO4)0 Removal of the solvent under reduced pressure affords the product as an oil. The oily residue is dissolved in ben-zene and filtered through silica gel (100 g.). Concen-tration of the filtrate under reduced pressure gives theproduct as an oil. Yield: 14.86 g. (73~).
Rf = 0.7 (silica gel, benzene~.
MS: (mol.ion) 438 ; Analysis:
Calc'd for C30H30O3: C, 82,16; H~ 6-89~
Found: C, 82.07; H, 6.84%
Repetition of Procedures G through J, but using the 3,5-dibenzyloxy derivatives of benzaldehyde, aceto-phenone or propiophenone, the appropriate carbethoxy ~or carbomethoxy) alkylidene triphenyl phosphorane; and the appropriate alcohol, phenol, thiophenol, hydroxy-pyridine or hydroxypiperidine as reactants affords the following compounds:
~CH2C6H5 ' ~0~

H5C6CH2C~\~alkl) ~X~ ~alk2) n~W
For convenience, the various values of W for given -~alues of -~alkl)-X-~alk2)n~ are collectively ` tabulated.

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-6~-: PREPARATION K
3-(3,5~Dihydroxyphenyl)-l-phenoxybutane A solution of 3-(3,5 ~ dibenzyloxyphenyl)-l-- phenoxybutane (14.7 g., 133.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (i10 ml.) and concentrated hydrochloric acid (0.7 mlO) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10~ palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration - and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10%
- ethyl acetate. me middle fractions are combined and concentrated to give the title product: 7.8 g. t80%), as an oil.
Rf = 0.25 [silica gel, benzene(4), methanol (1)].
MS: (mol.ion) 258 Analvsis:
16 18 3 ~ ; , Found: C, 74.13; H, 7.00~
In like manner, the remaining ethers ~X = O) of Preparation J are debenzylated to afford the corresponding 3,5-dihydroxy derivatives.
The thio ethers are debenzylated by treatment with trifluoroacetic acid. The procedure comprises stirring a solution of the dibenzyl ether (X = S) in tri-fluoroacetic acid at room temperature for two hours. The reaction mixture is evaporated to dryness and the residue taken up in ether. The ether solution is washed with water, dried (MgSO4) and evaporated to give the deben-zylated compound.
PREPARATION Ll-Bromo-3-(3,5-Dimethoxyphenyl)butane A solution of phosphorous tribromide (5.7 ml,, 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3,5-dimethoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether t20 ml.) at -5C. to -10C. and the reaction mixture stirred at -5C. to -10C. for 2.$ hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice ~200 g.) and the resulting mixture extracted with ether (3 x 50 ml.).
The combined extracts are washed with 5~ sodium hydroxide solution (3 x 50 ml.), saturated sodium chloride solution (1 x 50 ml.) and dried (Na2S04). Removal of the ether and vacuum distillation of the residue afords the title product; 25 g. (55% yield); b.p. 125-132C. at 0.4 mm.
The following compounds are prepared from 3,5-dimethoxybenzaldehyde, 3,5-dimethoxyacetophenone and 3,5-dimethoxypropiophenone and the appropriate carbethoxy-alkylidene triphenylphosphorane by the procedures of Preparations G, H and L.
~CH3 H3CO/[~Z-Br Z
(CH2)3 (CH2)4 C (C2H5) CH2 . PREPARATION M
4-(3,5-Dihydroxyphenyl)-1-~4-Pyridyl~Pentane A mixture of 3-(3,5-dimethoxyphenyl)butyl tri-phenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) i9 added to 4-pyridinecarbox-aldehyde ~3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0-5C. Following completion of addition, the mixture is stirred for one hour at 0-5 an~ then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6N HCl. The aqueous acid solution is extracted with benzene (4 x 50 ml.). It , l~.U240 :' is then made basic and extracted with ethyl acetate (3 x 50 ml.). Evaporation of the combined extracts after drying (~SO4) affords 4-(3,5-dimethoxyphenyl)-1--~ (4-pyridyl)-1-pentene (7~1 g , 70%) as an oil, - 5 Cataytic hydrogenation of the thus-produced pentene derivative according to the procedure given in Preparation D gives 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl)pentane in quantitative yield; m.p. 131-133C.
The pentane derivative thus obtained is demethylated by heating a mixture of the com~ound (7.15 g., 25 mmoles) and pyridine hydrochloride (35 g.) under a nitrogen atmosphere at 210C. for 8 hours. The hot mixture i9 poured into water (40 ml.) and the resulting solution made basic with 6N sodium hydroxide. Water and pyridine are removed by distillation in vacuo. Ethanol (50 ml.) is added to the residue and the inorganic salts which precipitate are filtered off. The filtrate is concentrated in vacuo and the residue chromatographed on silica gel (150 g.) using as eluting agents 5% ethanol/-20 benzene (4 liters), 10% ethanol/benzene (1 liter), 13%
ethanol/benzene (1 liter) and 16% ethanol/benzene (5 liters). The product is isolated as a glassy solid by concentration of appropriate fractions of the eluate.
Yield = 5.0 g. (78%).
The 3-(3,5-dimethoxyphenyl)butyltriphenyl-phosphonium bromide is prepared by refluxing a mixture of l-bromo-3-(3,5-dimethoxyphenyl)butane (21.5 g., 78.5 mmoles) and triphenyl phosphine (20.5 g., 78.5 mmoles) in xylene (60 ml.) for 18 hours. The reaction mixture - 30 is then cooled to room temperature and filtered. The filter cake is washed with ether and dried in a vacuum desicator to give 36.4 g. ~86%) yield of product; m.p.
190-200C.
Repetition of this procedure but using the appropriate bromo-(3,5-dimethoxyphenyl)alkane and the appropriate aldehyde or ketone affords the following compounds.
;

IH

r~o~~` ~Z-W
Z W
.
(CH2)3 2-pyridyl (CH2)3 3-pyridyl (CH2)3 4-pyridyl (CH2)3 2-piperidyl (CH2)3 4-plperidyl (CH2)4 2-pyridyl : (CH2)4 4-pyridyl (CH2)4 3-piperidyl (CH2)4 4-piperidyl CH2CH(CH3)CH2 2-pyridyl CH2CH(CH3)CH2 4-piperidyl CH(cH3)cH(cH3)cH2 3-pyridyl CH(CH3)CH(CH3)CH2 4-pyridyl CH(cH3)cH(cH3)cH2 3-piperidyl CH(CH3)(CH2)2 2-pyridyl CH(CH3)(CH2)2 3-pyridyl CH(CH3)(CH2)2 4-piperidyl - 20 ( 3~( 2)3 3-pyridyl CH(CH3)(CH2)3 4-piperidyl CH(CH3)CH(c2Hs)cH2 4-pyridyl ( 2 5)(CH2)2 4-pyridyl CH(C2H5)tCH2)2 2-piperidyl CH(C2Hs)~CH2)2 4-piperidyl CH2CH(c2Hs)cH2 3-pyridyl CH(C2H5)~CH2)3 3-pyridyl CH(C2H5)(CH2)3 4-piperidyl CH(C2H5)CH(cH3)cH2 2-pyridyl CH(C2H5)C}I(c2Hs)cH2 4-pyridyl CH(C2H5)CH(c2Hs)cH2 2-piperidyl (CH2)3 C6Hll :
Z W
(CH3)(CH2)3 C6H
(CH2)4 C3H5 (CH2)2 C4H7 CH2CH(CH3)CH2 C5Hg CH(CH3)(CH2)2 C7H13 CH(CH3)CH~CH3)CH2 C6H
(CH2)6 C6H5 (CH2)7 C6H5 (CH2)8 C6H5 CH(CH3)(CH2)6 C6H5 CH(CH3)(CH2)7 C6H5 CH(CH3)(CH2)3 4-FC6H4 ( 3)2(CH2)3 C6H5 CH(CH3)(CH2)3 4-ClC6H4 CH(CH3)(CH2)4 4-ClC6H4 CH(CH3)(CH2) 4-ClC6H4 CH(CH3)(CH2) 4-FC6H4 CH(CH3)(CH2)2 4-FC6H4 CH(CH3)(CH2)2 4-ClC6H4 (CH2)3CH(CH3) C6H
CH(cH3)(cH2)2cH(cH3) C6H5 CH(CH3)(CH2)2CH(CH3) C6Hll CH(CH3)(CH2)2CH(CH3) 4-piperidyl CH(CH3)(CH2)3 C6H
CH(CH3)(CH2)2CH(CH3) C6H
(CH2)3 C6H
(CH2)4 C6H
(CH2)8 C6H
PREPARATION N

3,5-Dimethoxy-~-methxlstyrene Oxide ~- To a solution of dimethylsulfoxonium methylide ` (69.4 mM) in dimethyl sulfoxide (65 ml.) at room tem-perature is added solid 3,5-dimethoxyacetophenone (10 g., 55.5 mM). The reaction mixture is stirred for one hour at 25C., for one-half hour at 50C. and is then cooled~
The mixture is diluted with water (50 ml.) and added to 24~) a mixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgSO4) and evaporated to an oil. Fractional distillation of the oil yields 8.0 g. (75%) of 3,5-dimethoxy-a-methylstyrene oxide, b.p. 93-97C., 0.2 mm.
IR (CCL4): 2780, 1595, 1196, 1151, 1058 cm 1 UV (95% ethanol): AmaX = 279 nm ~ = 2068) MS (mol.ion): 194 PMR (CDC13) (60 MHz): ~ (1.70 ~S, CH3-), 2.76 (d, J = 6 Hz, ~ ~ ), 2.95 (d, J = 6 Hz, ~ H), 3.81 (S, CH30-), 6.41 (t, J = 2 Hz, ArH) and 6.58 (d, J = 2 Hz, ArH).
Analysis:
Calc'd for CllH14O3: C, 68.02; H, 7.27%
Found: C, 67.967 H, 7.28%
PREPARATION O
2-(3,5-Dimethoxyphenyl)-2-hydroxypropyl-2-phenylethyl Ether A mixture of dry 2-phenylethanol (30 ml,, 251 mM) and sodium metal (690 mg., 30 mM) is heated at 110C.
for 30 minutes. The resulting IM solution of sodium 2-phenylethoxide is cooled to 60C., 3,5-dimethoxy-a-methyl-styrene oxide (2 g., 10.3mM) added and the reaction heated 15 hours at 60C. The reaction mixture is cooled and added to a mixture of ether and water. The ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenylethanol is removed by vacuum distillation (b.p.
65C., 0.1 mm.) leaving a 3.5 g. residue. The residue is purified via column chromatography on Merck silica gel 60 (300 g.) and eluted in 15 ml. fractions with 60%
ether-pentane. Fractions 52-88 yielded 2.9 g. (89%) of 2-(3,5-dimethoxyphenyl)-2-hydroxypropyl 2-phenvlethyl ether.
IR (CC14): 3534, 1595, 1202, 1153 cm 1.
UV (95% ethanol): ~max = 278 (~ = 1830), 273 5 (~ = 1860).
MS: (mol.ion) 316 PMR (CDC13, 60 MHz): ~ 1.46 (S, CH3-), 2.86 ' (S, OH), 2.86 (t, J = 7 Hz, -CH2-Ph~, 3.53 ~S, ~CH2O), 3.71 (t, J = 7 Hz, -CH2O), 3.80 (S, OCH3), 6~38 (t, J - 2 Hz, ArH), 6061 (d, J = 2 Hz, ArH) and 7.23 (S, PhH).
Analysis:
Calc'd for Cl9H244 C, 72-12; H~ 7-65%
Found: C, 71.92; H, 7.63%
PREPAR~TION P
2-(3,5-Dimethoxyphenyl)propyl 2-Phenylethyl E~ther ; To a OC. solution of 2-(3,5-dimethoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether (550 mg., 1.74 mM) in pyridine (2 ml.) is added dropwise phosphorous oxy-chloride (477 ml., 5 22 mM). The reaction i9 allowed to warm to 20C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20C. and then added to ether (150 ml.) and 15~ sodium carbonate ~100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3 x 50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in ab~olute ethanol (15 ml.), 10~ palladium-on-carbon (100 mg.) added and the mixture stirred under one atmo-sphere of hydrogen gas. When hydrogen uptake ceases (26.5 ml., 20 min.), the reaction is filtered through diatomaceous earth and the filtrate evaporated to an oil. The oil is purified via preparative layer chro-matography on silica gel plates, eluted twice with 6:1 pentane: ether to yield 211 mg. (40%) of 2-(3,5-di-methoxyphenyl)propyl 2-phenylethyl ether.
IR (CC14): 1600, 1205, 1155, 1109 cm 1.
MS: (mol.ion) 300 PMR (CDC13, 60 MHz) ~ 1.22 (d, J - 7 Hz, CH3-), 2.82 (t, J = 7 Hz, CH2Ph), 2.8 (H-C-Me), 3.6 (-CH2-O-CH2-), 3.75 (S, OCH3), 6.35 (m, ArH) and 7.18 (S, PhH).
PREPARATION Q
2-(3,5-Dihydroxyphenyl)propyl 2-Phenylethyl Ether A mixture of 2-(3,5-dimethoxyphenyl)propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine (0.4 ml., 4.96 mM) and dry pyridine hydrochloride (4 g., 34.6 mM) ~lC~Z4~

is heated at 190C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.)O The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of the aqueous phase, is dried over magnesium - sulfate and evaporated to an oil. ~he oil is purified via preparative layer chromatography on silica gel - plates, eluted six times with 30% ether-pentane to yield 65.8 mg. (37%) of 2-(3,5-dihydroxyphenyl)propyl 2-phenylethyl ether.
IR (CHC13): 3559, 3279, 1605, 1147, 1105 cm lo MS: (mol.ion) 272 PMR (CDC13, 60 MHz)~ 1.18 (d, J = 7 Hz, CH3-), 2.80 (t, J = 7 Hz, -CH2Ph), 2.80 (H-C-Me), 3.4-3.8 (-CH2OCH2-), 6.08 (t, J = 2 Hz, ArH), 6.21 (d, J = 2 Hz, ArH) and 7.16 (S, PhH).
The following compounds are prepared from appro-priate alkanols by the methods of Procedures O and P.
.'' ~

HO'J~TH~CH2--O--(alk2) W

(alk2) W
. . _ -(CH2)6- CH3 -(CH2)6 C6H5 -(CH2)4 CH3 -CH(CH3)CH2 H3 ( 3)( 2)4 CH3 -(CH2)- 4-FC6H4 -(CH2)2- 4-pyridyl -(CH2)2 2-piperidyl -cH(cH3)cH2- 4-piperidyl -(CH2)2CH(cH3)(cH2)2 3 -CH(CH3)- CH3 -C(CH3)2- CH3 241~) PREPARATION R
4-(3,5-Dihydroxyphenyl)-l-phenoxypentane Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenone ~50.0 g., 0.15 M) in tetrahydro-furan (175 ml.) and 3-phenoxypropyltriphenylphosphonium bromide (7.18 g., 0.15 M) in dimethylsulfoxide ~450 mlO~
is added dropwise over 1.75 hours to a suspension of 50%
sodium hydride (7.89 g., 0.165 M) ~previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0-5C
After stirring for 4 hours at 0-5C. the reaction is allowed to warm to room temperature and is then carefully stirred into ice water (2000 ml.), acidified with con-centrated hydrochloric acid, and extracted with ethyl acetate (5 x 400 ml ) D The combined organic phases are washed with saturated sodium chloride solution (3 x 300 ;: .
ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine oxide. Filtration, - followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane consisting of 30% to 100%
benzene. From the middle fractions 51 g. (75%) of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene is isolated as an oil: Rf = 0c8 (silica gel, 2-benzene:l-hexane);
MS (mol.ion~: 450.
Analysis:
Calc'd for C31H303 C, 82-63; H, 6.71%
Found: C, 82.90; H, 6.69%
A solution of 4-(3,5-dibenzyloxyphenyl)-1-- 30 phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate ~160 mlO) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presene of 10%
Pd/C. Removal of the catalyst by filtration and con-centration of the filtrate under vacuum yields 30.8 g.
(100%) of product as a viscous oil Analysis:
Calc'd for Cl7H2003: C, 74.97; El, 7 40~
Found: C, 74.54; H, 7.45%
PREPARATION S
3,5-Dimethoxy-~-methylstyrene oxide To a -78C. solution of diphenylsulfonium ethylide ~1.0 mole) in tetrahydrofuran (one liter~ is slowly added 3,5-dimethoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
PREPARATION T
3-~3,5-Dihydroxyphenyl)-2-propylbutyl Ether To a solution of sodium butoxide in butanol (0.5 liters of lM) is added 3,5-dimethoxy-~-methylstyre~e - oxide (6.33 M). The mixture is heated for 18 hours at 2~ 70C. and is then cooled and added to a mixture of ether-waterO The ether solution is separated, dried (MgSO4) and evaporated to give 3-(3,5-dimethoxyphenyl)-3-hydroxy-2-propylbutyl ether. It is purified by column chromato-graphy on silica gel with ether-pentane elution.
By means of the procedure of Preparation P the title product is produced.
Similarly, the following are prepared from appropriate alcohols:

HO \ ~ H2 ~ O-(al~ W

2~0 -7~-(alk2) W _ (alk2) W
CH2 CH3 CH(CH3)CH2 CH3 (CH2)6 CH3 CH(c2H5)-(cH2)2 CH3 (CH2)3 C6H5 CH(CH3)CH2 C6H5 (C 2)2 4 FC6H4 (CH2)2 4-pyridyl PREPARATION U
2-R4R5-5,7-Dihydroxy-4-chromanones :, The procedure of British Patent 1,077,066 is employed to produce the compounds tabulated below. It comprises reacting the appropria~e R4R5C=CH-COO~ with an excess (50~) of 1,3,5-trihydroxybenzene and of polyphos-phoric acid (10 to 20 grams per gram of trihydroxybenzene) on a steam bath for three hours. The mixture is then cooled and poured into water. Thé precipitate is ex-tracted with ether, the ethereal extract washed with sodium hydroxide solution, dried and evaporated to afford the product. Purification is accomplished by distillation of the residue. The following are thus prepared:
~ ~H

R5~o~0H

H H

PREPARATI_N V
(4-Halophenyl)cyclohexanols A. 3- and 4-(4-Fluorophenyl)cyclohexanols A benzene solution containing equimolar amounts of 4-fluorostyrene and 2-methoxybutadiene and hydroquinone (1% by weight based on diene) is heated in a sealed tube at 150C. for 10 hours. The reaction vessel is cooled, - the contents removed and concentrated to give l-methoxy-4(and S)-4-(fluorophenyl)cycloheptene which are separated by distillation in vacuo. Hydrolysis of the ether with 3%
hydrochloric acid affords 3- and 4-(4-fluorophenyl~cyclo-hexanones.
Sodium borohydride reduction of the ketones according to the procedure of Example 5 affords the keto compounds.
In like manner, the corresponding 3- and 4-(4-chlorophenyl)cyclohexanols are prepared from 4-chlorostyrene.
B. 2-(4-Fluorophenyl)cyclohexanol This compound is prepared from cyclohexane oxide and p-fluorophenyl lithium according to the procedure of Huitric et al., J.` Org. Chem., 27, 715-9 (1962), for preparing 2-(4-chlorophenyl)cyclohexanol.
PREPARATION W
(2-Halophenyl)cycloalkanols The procedure of Huitric et al., J. ~. Chem., 27, 715-9 (1962) is employed but using the appropriate cycloalkylene oxide and p-halo (Cl or F) phenyl lithium reactants to produce the following compounds:
H ,OH
\C
( \C)_~X

(CH2)a _ X a X_ 2 Cl 2 F
3 Cl 3 F
5 Cl 5 F
PREPARATION X
5-Hydroxy-7-mercapto-2,2-dimethyl-4-chromanone A mixture of 3,5-dihydroxyphenyl methyl sulfide (5.85 g.) and 3-methylcrotonic acid (4.5 g.) is heated ., , to 125C. under nitrogen and boron trifluoride etherate (8.7 ml,) added. The mixture is refluxed for one hour and is then cooled. Water (10 ml.) i8 added, followed by 6N sodium hydroxide ~40 ml.). The mixture is heated on a s~eam bath for five minutes, then aooled and aaid-ified with 6N hydrochloric acid, It is extracted with ether (3 x 100 ml,) and the oombined extracts washed with 10% sodium bicarbonate (l x 2$ ml.) and water (l x 2$ ml.) and then dried (Na2SO4). Concentration of the extXact under vacuum affords dl-5-hydroxy-2,2-dimethyl-7-methylmercapta-4-chromanone. It i9 purified by silica gel chromatography.
The methyl me~capto compound thus produced is hydrolyzed b~ reluxing overnight with excess 48~ hydro-promic acid, Concentration of the reaction mixtureaffords the title campound. It i~ purified by silica gel chromatography.
Thq following compaunds are similarly prepared but replacing 3-methylcratonic acid with the appropriate acid of the formula R4R5C-CH-COOH:
R

R5 " ~ ~ SH

H H

P~EPARATION Y
Alk ~ ,tion of 3! 5-DihydroXyphellylmercaptan A solutiQn of 3,5-dihydroxyphenylmercaptan (3.5 g., 0~01 mqle) in ab~olute ethanol (50 ml.) is made iUSt al~aline with sodium ethoxide. The appropriate bromide l~ O

of formula Br-(alk2)n~W (0.01 mole) is added and the mix~
ture refluxed for 3 hours. It is then concentrated under reduced pressure and the residue extracted with ether.
Evaporation of the ether affords the product.
The following compounds are thus prepared:
~H
~\
~' ro HO ~ ~ ~ S-(alk2)n-W

( alk2 ) W
n 1 -CH(CH3)~CH2)5 CH3 1 -cH(cH3)cH~cH3)~cB2)4 CH3 10 1 C~CH3)2~CB2)5 CH3 1 ~C 2)8 CH3 : 1 -(CH2)4- CH3 :' 1 -CH2- C6H5 1 -(CH2)- C6H5 15 1 C (cH3)~c 2)3 C6H5 1 -CH2- C5Hg -CH2- C6Hll 1 -(CH2)2- C5Hg 20 1 -(CH2)3- C5Hg 1 -(CH2)5- C6H
1 -(CH2)4- C5H9 .' 1 - (CH2) 3CH~C2H5) C6Hll 1 ~ 2)7 C5Hg 25 1 -~CH2)4- C7H13 1 ~CH2)2 C7H13 1 ~C 2)5 C4H7 1 -~CH2)5- C3H5 ~ CH2)- 2-piperidyl - 30 1 ~C 2)3 4-piperidyl . 1 -~CH2)- 2-pyridyl : 1 -(CH2)3- 3-pyridyl '' `` 1~1~24~
~: - 8 .~-n (alk2) W
1 -(CH2)4- 2-pyridyl 1 -CH(CH~(CH2)2 2-pyridyl 1 -CH(CH3)(CH2)3 4-pyridyl 1 -CH(C2H5)(CH2)2 4-piperidyl 1 ~ 2)4 4-FC6H4 1 -CH(CH3)(cH2)2 4-ClC6H4 ~C 3)(2)3 4-FC6H4 O __ C6H5 O __ 4-ClC6H4 0 __ C5Hg a __ 0 -- 4-pyridyl 0 -- 2-piperidyl o -- 2-pyridyl (C6 5)C3 4 0 -- ( 6 5) 6 10 0 -- 3-(c6H5)c7Hl2 0 __ CH3 PREPARATION Z
dl-2-t3,5-Dibenzyloxyphenyl)-2-hydroxy-1-~2-phenylethoxy)-propane To a 20C. solution of dimethylsulfoxoniummethylide (0.184 mole) in dimethylsulfoxide (185 ml.) is added 3,5-dibenzyloxyacetophenone (51.0 g., 0.153 mole).
After stirring 1.5 hours at 20C., the reaction is diluted with 200 ml. of ice water and added to 500 ml. ether and 200 ml. ice water. The organio phase is washed with cold water (2 x 200 ml.), dried over magnesium sulfate and evaporated to an oil. A solution of the thus produced crude 1-(3,5-dibenzyloxyphenyl)-1-methyloxirane ~0.153 mole) in dimethylsulfoxide (100 ml.) is rapidly added to a 20C. solution of sodium phenethoxide (0.306 mole) in Z4~) dimethylsulfoxide (150 ml., made by the slow addition of 36.5 ml. [0.306 mole] of phenethanol to a slurry of 7,34 g. [0.306 mole] sodium hydride in 150 ml. dimethyl-sulfoxide). The reaction is slowly heated over a half-hour period to 70C., stirred 30 minutes and cooled to 20C. The reaction is diluted with 200 ml. ice water and added to ether (2 l.)and ice water (1 liter). The organic phase is washed with cold water (2 x 1 1.), dried over magnesium sulfate and evaporated to an oil. This crude oil is purified via column chromatography on 1.5 kg. of silica gel, and eluted with 60% ether-pentane to yield 30.0 g. (42%) of dl-2-(3,5-dibenzyloxyphenyl)-2-hydroxy-1-(2-phenylethoxy)propane, as an oil.
; IR: (CHC13) OH 3534 cm NMR: ~CDCl 1.46 ~s, methyl), 2.85 (t, J=7Hz, -CH2Ph), 2.81 (s, hydroxyl), 3.55 (s, -CH2O-), 3.68 (+, J=7Hz, -OCH2-), 5.06 (g, PhCH2O-), 6.56 (t, J=2Hz, C-4 ArH), 6.76 (d, J=2Hz, C-2,6 ArH), 7.25 (s, ArH) and 7.43 (s, ArH).
MS: m/e 468 (~), 453, 377 and 335 ~100%) PREPARATION Q~
dl-2-(3,5-Dihydroxyphenyl)-1-(2-phenylethoxy)propane To a OC. solution of dl-2-(3,5-dibenzyloxy-phenyl)-2-hydroxy-1-(2-phenylethoxy)propane (29.0 g , 25 61.9 mmole) in pyridine (50 ml., 0.619 mole) is slowly added phosphorousoxy chloride (5.65 ml., 61.9 mmoles)~
The reaction is allowed to warm to 20C. and is stirred at 20C. for 20 hours. The reaction is added to a OC.
solution of 3.3N NaOH (300 ml.) and the resultant mixture extracted with ether (3 x 500 ml.). Each extract i~
washed with saturated potassium carbonate (1 x 500 ml.) and water (3 x 500 ml.). The combined organic extract is dried over magnesium sulfate, silica gel and then decolorized (carbon) and evaporated to an oil This oil is purified via column chromatography on silica gel (200 g.) eluted with 60~ ether-pentane to yield 17 g.

. .

' ~

(61%) of an oil (mixture of olefins) To a solution of this mixture of olefins ~3.62 g.) in ethanol ~10 ml.) and ethyl acetate (10 ml.) is added solid sodium bicarbonate ~300 mg.) and 10~ Pd/C (1.2 g.). This mix-ture is stlrred 6 hours under one atmosphere of hydrogen.The reaction is diluted with ethyl acetate and filtered through diatomaceous earth. The evaporated filtrate i8 purified via column chromatography on silica gel (200 g.) eluted with 80% ether-pentane to yield 2.0 gO (92%) of dl-2-(3,5-dihydroxyphenyl)-1-(2-phenylethoxy)propane as an oil.
IR: (CHC13) OH 3571, 3279 cm NMR: ~CDCl 1.10 (d, 7=7Hz, methyl), 2.80 (t, J=7Hz, -CH2Ph), 2.90 (M, methine), 3.5 ~m, -CH2O-CH2-), 6.10 (t, J=2Hz, C-4 ArH)I 6.20 (d, J=2Hz, C-2l6 ArH) 6.5 (broad ml hydroxyl) and 7.19 (sl ArH).
MS: m/e 272 ( ~)l 181l 168, 151, 138, 137, 123~105 (100~) and 91.

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

wherein R1 is hydrogen, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken in-dividually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group;
each of R4 and R5 is hydrogen, methyl or ethyl;
Z is (a) alkylene having from one to nine carbon atoms;
(b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than 9;
each of m and n is 0 or 1;
X is O, S, SO and SO2; and W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl.

pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl;
with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-;
which comprises reacting a compound of the formula:

wherein R1, R4, R5, Z and W are as herein defined with methyl vinyl ketone.

2. A process according to claim 1 for the pro-duction of a compound of the formula:

wherein R5 is hydrogen or methyl; Z is CH(CH3)-(CH2)3 or CH(CH3)-(CH2)4 and W is phenyl or 4-pyridyl wherein a compound of the formula:

wherein R5, Z and W are as defined above is reacted with methyl vinyl ketone.

3. A process according to claim 1 for the product-ion of a compound of the formula:

wherein Z is O-CH(CH3)-(CH2)3 or CH(CH3)-(CH2)2 and W is methyl, phenyl or 4-pyridyl which comprises reacting a compound of the formula:

wherein Z and W are as defined above with methyl vinyl ketone.

4. A process for preparing:

which comprises reacting with methyl vinyl ketone.

5. A process for preparing:

which comprises reacting with methyl vinyl ketone.

6. A process for preparing:

which comprises reacting with methyl vinyl ketone.

7. A process for preparing:

which comprises reacting with methyl vinyl ketone.

8. A compound of the formula:

wherein R1, R4, R5, Z and W are as defined in claim 1 whenever obtained by the process of claim 1 or an obvious equivalent thereof.

9. A compound of the formula:

wherein R5, Z and W are as defined in claim 2 whenever obtained by the process of claim 2 or an obvious equivalent thereof.

10. A compound of the formula:

wherein W and Z are as defined in claim 3 whenever obtained by the process of claim 3 or an obvious equivalent thereof.

11. A compound of the formula:

whenever obtained by the process of claim 4 or an obvious equivalent thereof.

12. A compound of the formula:

whenever obtained by the process of claim 5 or an obvious equivalent thereof.

13. A compound of the formula:

whenever obtained by the process of claim 6 or an obvious equivalent thereof.

14. A compound of the formula:

whenever obtained by the process of claim 7 or an obvious equivalent thereof.