CA1099269A - Process for the production of 9-hydroxydibenzo ¬b, d| pyrans and intermediates therefor - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
9-Hydroxydibenzo[b,d]pyrans useful as analgesics, hypotansives, immunosuppressants, tranquilizers; as anti-secretory and anti-anxiety drugs; having the formulae:

I

and II
wherein R is hydrogen or alkanoyl having from one to five carbon atoms;
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 individually 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;
R0 is oxo or alkylenedioxy having from two to four carbon atoms;
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 or SO2; and W is methyl, phenyl, p-chlorophenyl, p-fluoro-phenyl, pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluoro-phenyl;
with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-.

Description

`- --This invention relates to no~el dibenzopyrans and more partic-ularly to 1,~ 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 cycloQlkyl group llnked to said position Vi& (a) O, S, SO or S02 groups; or (b) an alkylene group interrup~ed by an 0~ S, SO
or S02 group; or (c) an alkylene group aktached to said 3-position or to said methyl, aryl or cycloalkyl groups by 0, S, SO or S02; to intermediates therefore and derivatives thereo~, a~d to the use of such dibenzopyrans and derivat,ives thereof as analgesic, hypotenslve, antisecretory and anti-anxiety agents, as immuno-suppressants~and tranquilizers 1~ mammal~, including man~.
Descri~tion o~ the Prior Art . . ~
Despite the current availability of a n~ber o~ analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control o~ broad levels of pain ~nd accompanied by a minimum o~ side-e~fectsO The most commonly used agent, aspirin, i~ of no : , :

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. . :

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~; w` ~
practical value ~or the control of severe pain and i9 known to exhibit various undesirable side-effects. Other, more potent analgesic agents such as d-pro-poxyphene, codeine, and morphine, posseRs addictive liability. The need for improved and potent analgesic agents is, therefore, evident.
I~he analgesic properties Or 9-nor-9~-hydroxyhexahydrocannabinol and of other cannabinoid structures, such as ~8-tetrahydrocannabinol~ a-THC) and its primary metaboli~e, ll-hydroxy-~3-THC have been reported by Wilson and May, Absts, ~ , Am. Chem. Soc., 168 Meet., MEDI 11 tl974), and J Med. Chem., 17, 475-476 (1974)- ;
U S. Pat~nts 3,507,885 and 3,636,058, issued April 21, 1970 and January 18, 1972, respectively, describe various 1-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~r.
U.S. Patent 3,649,650, i3sued March 14, 1972, discloses a serie~ of 15 tetrahydro-6,6,9-trialkyl-6H-dibenzo[b,d]pyran derivatives having at the 1-position an ~-dialkylaminoalkoxy group active as psychotherapeutic agents.
German SpeciPication 2,451,934, published May 7, 1975, describes 1,9-dihydroxy-hexahydrodibenzo[b,d]pyrans and certain l-acyl derivatives thereof having at the 3-position an alkyl or alkenyl group, a~ hypotensive, psycho-tropic, sedative and analeesic agents. ~he precursor hexahydro-9H-dibenzotb,d]
pyran-9-ones used in their preparation, and which are reported to have the same utility as the corresponding 9-hydroxy compounds, are described in German Specification 2,~51,932, published May 7, 19750 German Specification 2~415~697~ published October 17a 1974, describes 1-hydroxy-6,6,9-trimethyl-hexahydrodibenzo~b,d]pyran derivatives, and interme-diates therefor, having at the 3-position an aralkyl, (substltuted aralkyl) or pyridylalkyl group. They are useful as analgesio agents and as mild tranquil-izers.

..

. . :

2~
U.S, 3~856,821, isgued ~ecember 2~ ~974~ describ~s a serie~ o~ 3-alkoxy substituted dibenzo~b,d]pyran~ hQving ~ntiarthritic9 antiinflamm~tory and centrPl nervous system activity.
A stereospeci~ic synthesis of (-)trans-6a,7,8,10a-tetrahydro-3-pentyl-6,6,9-tri~ethyl-6H-dibenzo[b,d]pyran-l-ol,more commonly known as (-)-~ -tetrahydrocannabinol, has been reported by Razdan ot al. ~J, Am Chem. SocO, 96, 5860-5, 1974). The process, a one-step synthesis, comprise~ the reaction of cis/trans-(~)-p_menth~2,8-dien-1-o1 with olivetol in the presence o~ 1%
boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0CO The tetrahydro compound thus produced i5 converted to the corresponding 9-keto hexahydro compound by the procedure of Wildes et al., J.
. Chem., 36, 721-3 (1971). The procedure involves methylation of the 1-hydroxy-tetrahydro compound to its methyl ether and thence to the hydrogen chloride adduct by reaction with zinc chloride and HCl at oec. in chloro-~orm. The adduct is then dehydrohalogen~ted by reaction with pota~ium tri-cyclopentylcarbinolate to give the corresponding 6a,7,899,10,10a-hexahydro-

3-pentyl-6,6-dimethyl-9-methylene-6X-dibenæo[b,d]pyran-l-ol methyl etherO
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) investigated the replace-ment of the psntyl group at the 3-position of 7,8,9,10-tetrahydro-3-pentyl 6,6,9-trimethyl-6H-dibenzo~b,d]pyran-l-ol by alkoxy (buto w9 pentoxy, hexoxy and octoxy) and found that it led to biological inactivity. ~he hexoxy deri-vative was reported to exhibit feeble hashish activity a~ 10 to 20 mg./~gOThe remaining ethers showed no activity in doses up to 20 mg /kgo In a more recent study, Loev et al.7 J Med. Chem , 16, 1200-6 (1973) report a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-~ --4--!`~```

,.
,, . : :.
.

f~

trimethyl-6H-dibenzo~b9d]pyran-l-ols in which the 3-~ubstituent i3 OCH(CH )C H -CH2cH(cH3)c5Hll or CH(CH3)C5 11 taining compound was 50~ less active in central nervous sy~tem actlvity than the corresponding compound in which the alXyl si~e chain is directly attached to the aroma~ic ring, rather than through an interreni~g oxygen atomj and 5 times as active as the compoun~ in which oxygPn is replaced by methylene, There has now been found a class of compound effective as analgesic, hypotensive, anti-secretory and anti-anxiety agents and as immunosuppre~sants and tranquilizersj namely, l,9-dihydroxydiben~o[b3d]pyrans (Formula I) which are non-narcotia and free of addiction liabilityO Further3 valuable inter-mediates (Formulae II and III) for the preparation of ~aid compounds and derivatives of ~aid compounds useful as dosage forms (Formula I, R ~ hydrogen) have also been foundO The com~tounds have the formulae H ~OR
~ H ~ ORl 8 ~ ~ 10 OR1 B ~ R, ~ ; Z-W
I II

and Ro ~ III

wherein R i8 selected from the group consi~ting of hydrogen and alkanoyl having from one to five carbon atoms;

;' ' t ~

Rl i5 selected from the group consisting o~ hyd~ogen, alkanoyl having from one to five carbon ~toms and -CO-(CH2) -~2R3 uherein p is O or an integer from 1 to 4; each of R2 a~d R3 when taken indi-vidually is selected from the gro~p con3i~ting of hydrogen and alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitro-gen to uhich they are attached form a 5- or 6-membered heterocyclic ring selected from the group consi~ting of piperidino, pyrrolo, pyrrolidino, morpholino, and N-~lkylpiperazino haring from one to four carbon atom~ in the alkyl group, each of R4 and R5 is ~elected ~rom the group consisting of hydrogen, methyl and ethyl;
R i3 selected from the group consisting of oxo and alXylenedioxy having from two to four carbon atoms, Z is selected from the group consisting of (a) alkylene having from one to nine carbon atoms;
(b) -(alkl)m-X-~alk2)n-wherein each of (alkl) and ~alk2) has from 1 to 9 carbon atom~, with the proviso that the summation of carbon atoms in (alkl~ plus (alk2) is not greater than 9, each of m and n is O or l;
.X is selected from the group consi~ting of O~ S, SO and SO2; and W is selected from the group consistlng of methyl? pyridyl, piperidyl, ~ Wl wherein Wl is selected from the group consisting of f--( CH2 ) hydrogen, fluoro and chloro, and -CH ~ H-W2 ~herein W2 i9 ~elected from the group consisting of hydrogen and ~ Wl ; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5, uith the pro~iso that the sum of a and b is not greater than 5;
with the proviso that when W is methyl, Z is -(alkl) -X-¢alk2)n-,; . ~ .

:: : - .~:

r 1~ 6g Compouds havin~ the above ~ormulae conta~n a~ymmetrio center at the 6a- and/or lOa positionsO l~ere may be ~dditional asymmetric centers in the 3-position substituent (-Z-W), the 6-position and the 9-position Dias-tereomers with the 9~-configuration are generally favored over the 9~-isomers because of greater (quantitatively) biological actiVityO Similarly~ the trans (6a,10a) diastereomers are favored over the cia ~6a,10~) diaatereomers, In the above f~rmulae, the wavy lines are intended to depict the diastereomers at the 9- and the 6a~10a-positons.
In general, the optically active enantiomers containing the same absolute configura-tion at both the 6a~ and lOa-positions a~ the natural can-nabinols are favored because of greater (guantitatively) biological activityO
The racemic modifications of these compounds can be u~ed as such because they cont~in 50% of the more active en~ntiomer~ The utility o~ the racemic mix-tures, the diastereomeric mixtures as well as o~ the pure enantlomers and diastereomers is determined by the biological evaluations describPd below.

,:: -7-' ~Q~9%~9~

Although compounds of Formula II are descri~ed herein as lntermedi-ates for compounds of Formula I, many, particularly tho~e wherein the C-9 substituent is oxo (=0) 7 also exh~bit a~alge~ic and tranquilizer activityO
The preferred compounds of Formula I are tho~e wherein the OR group at the C-9 position has the ~-configuration. Such compound~ are of ~reat,er potency and efficacy than are the correspondlng a-compoundsO
Of spqcial interest are compounds of Formula I wherein the several v~riables have the significance shown below in Table A:
TABLE A

0~ ~1 Z _ m n W_ ~-OH OH alkylene having 1 to 6 - - phenyl, carbon atoms pyridyl ~-OH OH -(alkl)m-X-(alk2) - 1 1phenyl~

~-OH OH ( l)m 1 phenyl, ~-OH OH -X-(alk2)n~ ~ 1phenyl, Particularly favored because o~ their potency are tho~e compounds of Formula I, Table A, wherein Z-W, the C-3 sub~tituent, has the values ~hown in Table B below:
TABLE B:
~a) ( H2)q 6 5 (b) -CHtCH3)-~CH2)t C~ 5 (c) -[(CH2) ]_o-[(CH2)t~n-C6H5 (d) -[CH(CH )~(CX ) ] -O-[CH(CH3)-(CH2)t] -C6H5 (e) -[(CH2) ] -0-[(CX2)t~n-CH3 (f) ~[C~(CH3)~(CH2)q]m~0-[CH(CH3)~CX2)t]n 3 In the above t&ble, each of q and t is an integer from 1 to ~; and each of m and n is O or l; with the proviso that only one of m and n i5 Oo . .

, . , ., . -. .
. . . ..
, 326~g Additionally, the inte~media~e~ ~or the above-mentioned compound o~
interest ~Tables A and B) and, in particular, 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(8~)-ones of Formul~ II and III are the preferred clas~es of intermediates by reason of their precursor relationship to the compounds o~ Tables A and B
above.

The compounds of this invention of Formula III are readily prepared by ring annelation ofthe 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 tri~
ethylamine, to effect Michael addition, followed by ~rea~ment; with a base, e.e., an alkali metal hydroxide or alkoxide (sodium or potassium hydroxide, ethoxide or methoxide) to complete aldol cyclization.
The resulting 6a,7-dihydro-1-OR~-6,6-R4,R5-3-(Z-W)-6H-dibenzo~b,d]-pyran-9(8H)-one is then converted via Birch reduction to the corresponding 6a~,7,10,10aa-tetrahydro compound (Formula II, Ro = oxo) The reduction ls conveniently carried out using lithium as the metal~ Sodium or potassium can also be used~ T~e reaction is conducted ~t a temperature of from about -35C~
to -80C. The Birch reduction is favored because ~t of~ers skareoselectivity resulting in formation of the desired trans-ketone ~f Formula II.
Treatment of the compounds of~ormulae II and III wherein Ro is 020 wlth the appropriate alkylene glycol h~ving from two to four carbon ~toms in the presence o~ a dehydrating agent such as p-toluenesulfonic acid, or other acid used in ketalization (oxalic, adipic), affords the corre3ponding ketalsO

_9_ X~ 6~
Reduction of the 9-oxo groups 0~ ~or~ul~e II ~na III compounds ~Ro -o~o) via metal hydride reduction af~ord~ compounAs o~ Formula I ~R = H)o Representative of the metal hydrides useful for such ~onver~ion are lithium aluminum hydride, lithium borohydride and 30di~m borohydride. Sodiun boro-hydride is favored as reducing agent in this step since it not only afford3satisfactory yields o~ desired product, but reacts 510wly enough with hydroxy-lic solvents (methanol, ethanol, water) to permittheir use as solvants. A
temperat~e of ~rom about 0C0 to 30C. is generally usedO Lower tempera-tures, even down to about -70C., can be used to increase 3electivity o~ the reduction. Higher temperatures cause reaction o~ the sodium borohydride with the hydroxylic solvent. I~ higher temperature3 are desired or required ~or a given reductiona isopropyl alcohol or the dimethyl ether o~ diethylene glycol ~re used as sol~ents.
Agents such a6 lithium borohydride or lithium aluminum hydride re-quire anhydrous conditions and non-hydroxylic ~olvents (1,2-dimethox~ethane, tetrahydro~uran, ether, dimethyl ether o~ diethylene glycol)0 The isomeric 9~- and 9~-hydroxy compounds are produced in this ~tep.
The above-described reaction sequence i9 gummari~ed belOWJ

1~1 ~j, 1 1 ~ ae~ OR
R5 Z-W 4 ~

R5 o Z-W
~ 0~

~ ~ 1 NH3 R5 I Z-W ~ Z_W

cis isomer) :.' ~ ' : : , :

The required 5-ORl-3-hydroxymethylene-2-R4R5-7-~-W)-4-chromanones (IV) are prepared from 3,5-dihydroxyben~oic acid by the following abbreviated sequences:
OH Y

~O'~coo~ Y o)~~Y2 1, J~

HO~lZ~-W ~ z t -W
VJI
VIII
R4R5C=CH-COOH

BF3 (C2H5)2 1~ OH
4 ~ ~CO ~ ~ IV

Z-W
IX
The starting material, 3,5-dihydroxybenzoic acid (V) i~ convarted to a compound of Formula (VI) wherein Y2 represents an alkoxy group1 de3irabl~
methoxy or ethoxy for ease of preparation~ or an amino group; and Yl is a hydroxy protecting group, by methods described in the literature.

,~ -11-' ' ~ .

' . ~ ~ Q ~ ~ ~ g When Z is alkylene, ~1 is de~irably alkyl having from one to four carbon atoms or benzylO Ihe ~unction o~ group Yl is to protect the ~droxy groups ~uringsubsequent reaction~O It i~ it3 ability to per~orm a 8peci~ic function; i.eO~ protection of the hydro~y groups, rathar than its structure which is importantO The selectlon and identl~ication of appropriate protect-ing groups can easily and readily be made by one skilled in the art, The suitabllity and effectiveness of a group as a hydroxy protecting group are determined by employing ~uch a group in the above-illustrQted reaction sequence, It should, therefore, be a group which i9 easily removed to permit restoration o~ the hydroxy groupsO Methyl is favored as a protecting alkyl group since it is easily removed by treatment with p~ridine hydrochloride, The ~enzyl group, if used as a pro~ecting grol~p, is removed by catalytic hydrogenolysis or acid hydrolysi3, When Z is -(alkl)m-X-(alk2)n-, Yl i8 preferably benzyl or a sub-stituted benzyl group since it can subsequently be removed without detrimentto the Z groupO
The diprotected be~zoic acid derivative ~VI) iæ then converted to a compound o~ Formula ~III by ~no~a technologyO In oae procedure VI is hydro lyzed to the corresponding acid (Y~ = OH)~ or lithium salt, and reacted with the appropriate alkyl lithium to produce an alkyl disub~tituted phenyl ketone (Y2 = alkyl)O When methyl lithium is used, the resulting acetopheone deriva-tive is treated with a Grignard Reagent (W-Z'-MgBr), The intermediate adduct is hydrolyzed to the correspo~ding alcohol which i9 then hydrogenolyzed to replace the hydroxy group with hydrogen, ~his ~rocedure i~ especially use-ful for those compounds wherei~ Z is alkyla~e, ~ he ether groups ar~ deblocked by suit~ble means: trea~ment withpyridine hydrochloride (Y1 = methyl) or catalytic hydrog~nolysis ~Yl = benzyl)9 .,' : :. ~ . .
~: : , :':
', . :. , ' ,: :
, ..

or by tre~tment with an ~Cid such as trifluoroacetic acid, hydro~hloric, hydrobro~ic or sul~uric aclds, or p~ridin~ hydrochloride, Acid d~benzyla-tion is, o~ course, used ~hen the gro~p -Z~W contains sulfurO
A further me~hod for converting compounds o~ Formula VI to those of Formula VIII comprises reaction of a ~etone of Formula VI ~Y2 ~ aIkyl) with the appropriate triphenyl phosphonium bromlde derivative t~c6H5)3p-z-w]Br in the pre~ence of a base ~e.g., sodium hydride) ~he reaction proceed~ via an alkene which is subsequently catalytically hydrogenatRd to the corresponding alkane ~Z-W) and deblocked to the dihydro~y compound ~VIII). Of course, when -Z- is ~alkl)m-X-(alk2)n and Yl i9 ben~yl, the catalytic hydrogenation also results in cleaYage of the benzyl eth~rs Alternatively, conversion of ~tructure VI com~ounds to those of ~trUcture VIII can be achieved by the 3equence VI ~ VII -) VIII. In thi~
se~uence, the diprotected benzsmide (VI, Y2 = NH23 is conv~rted to the ketone (VII, Z' = Z less one CH2 erouP) by reaction w~th th~ appropriate Grignard reagent (~rMg-Z'-W) followed by reaction with methyl or ethyl-ma~nesium halide to form the corresponding carbinol Dehydration o~ the carbinol, eOg with p-toluenesulfonic acid, a~ords the corre~ponding alkene which i~ then catalytically hydrogenated (Pd/C) to the alkane (VIII)O The ether groups are deblocked ~converted to hydroxy) a~ de3cribed above The conversion of VIII to the 4-chromanone (IX) i~ achieved by the reaction o~ VIII with crotonic acid or an acid o~ the Fvrrnula R4R5-C~CH-COOH
in the presence o~ boron tri~luoride etherate at ~rom a~out 20 to about 125rC
In addition to structure IX products, a second product, isomeric to IX ~7-hydroxy-2,2-R4R5-5-Z-W-4-chromanone), i3 also producedO
~he 4-chromanones o~ Formula IX are then convPrted to hydroxy-methylene derivative o~ Formula IV by reaction with ethyl ~orrnate and ~odium hydride.

~ -13-" ~

Compounds of Formula VIII wherein -Z-W i~ -elkylene-W or -(~lkl)-X'-(alk2)n-W ~herein (alkl), (alk2), W and n are ~8 defined above and X' is O or S, Qre obt~ined ~y the follo~ing ~equence:
Yl (C6H ) P=CHCOOC2H5

5 3 .

Y10 ~\C~ Y10 ~/ C~ COOC2H5 (R~ = H, alkyl) Yl Y10~ CH2X
C H N/ R' 5 5/ ~osyl \ PBr3 Chloride I 1 Yl y o ~ ~CX CH2-0~9~ " jCX~ 2 CH2Br ~¦W-X'H 1(C6H5~3P
oy YlO~ICX~ ~2~CT~2-X'-W ~ /C~2 R' 1 ~. 2 ( 6 5)3 ~acid ~ ~ Br OH Rl_C_(CH2)V_W

llo~Z-W~ i~ /c~
VIII Y10 , H 2~CH2=C_ ( CH2 ) -W
R' ` ` , :. ~.';' . :. . ..

::~ . .:

, `

ffl~6~
The ~irst step in the above sequence (the Wittig reaction) pro~lde3 opportunity, by choice of appropriate reactants, to produce compounds having straight or branched alkylene groupsO In the given illustration, the value o~ R' as methyl or ethyl permits ~ormation of a compound having alkyl substi-tution on the carbon atom (~) adJacent to the phenyl groupO Substitution ofa methyl or ethyl group at other sites, eOg~, the ~-carbon atom o~ the alkyl-ene group, is achieved by choice of the appropriate carboal~oxy alkylidene triphenylphosphorane, e.g., (C6H5)3P=C(R')-COOC2H5~ The unsaturated ester thus produced is reduced to the corresponding saturated alcohol by reaction with lithium aluminum hydride, generally in the presence o~ Q small amount of aluminum chloride. Alternatively~ when Yl is other than benzyl ~eOgO methyl), ~he alcohol is produced by catalytic reduction o~ the ~msaturated eater using palladium-carbon, followed by treatment of the saturated eater thus produced with lithium alt~inum hydride. Conversion of the alcohol to the corresponding tosylate or mesylate followed by alkylation o~ the tosylate or mesylate with an alkali metal salt of the appropriate HX'-(alk2~W reactant, and ~inally removal of the protecting groups ~Yl) affords the desired resorcinol, When X' is sul~ur, the protecting group i9 methyl.
A variation o~ the above ~equence ~omprises bromination of the alcohol rather than converting it to a toqylate or mesylate. Pho~phorous tribromide is a convenient bromin~ting agent. The bromo derivati~e i3 then reacted with the appropriate HX'-(alk2)-W in the pre~ence o~ a suitable base (Williamson reaction).
m e bromo compounds al90 serve as valuable intermediates for in-creasing the chain length of the alkylene moiety in the ~bove sequence to givecompounds wherein Z is -alkylene-W. The process comprises treating the bromo derivative with triphenyl phosphine to produce the correspondln~ triphenyl-phosphonium bromide. Reaction o~ the triphenylphosphonium bromide with the -15~

6~

appropriate aldehyde or ketone in the presence of a base such ag ~odium hy-dride or n-butyl lithium afford~ an unsaturated derivative which is then catalytically hydrogenated to the corre3ponding saturated compound~
In this variation, the value o~ the ~rotecting 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 protecting group when the left vertical sequence is followed, since it is conveniently removed by treatment with acid as described hereinO

`~:

. .

Compounds of Formula II ~her~ln -Z W is -(alkl)m-X-(alk2)m-W and X
is -SO- or -S02- are obtained by oxidation of correspon~i~g compounds in which X is -S-. Hydrogen peroxide is a convenient agent for oxidation of the thio ethers to sul~oxides. Oxidation o~ the thio ethers to corr~sponding sulfones is conveniently accomplished by maans of a peracid such ~s perbenzoic, per-phthalic or m-chloroperbenzoic acid. This latter peracid i especially useful since tbe by-product m~chlorobenzoic acid is easily removed.
Alternatively, the compounds of this invention can be prepared according to the procedure descri~ed by Fahrenholt~, et al., J. Am. ChemO SocO, 89, 5934-5941 (1967). This process compri3es Von Pechmann condensation of the appropriate -Z-W substituted 3,5-dihydroxybenzene with diethyl-a-aceto-glutarate in the presence of phosphorous oxychloridç. The ethyl-5-hydroxy-4-methyl-7-(Z-W)-cou~arin-3-propionate thus produced is then cyclized to 7,10-dihydro-l-hydroxy-3-(Z-W)-6~-dibenzo[b,d]pyran-6,9(8H)-dione by reaction with sodium hydride in dime~hylsul~oxide. The dibenzo~b,d]pyran thu~ produced is converted to the corresponding 9-ketal derivative by reaction with ethylene glycol and p-toluenesulfonic acidO Trea~ment of the ketal with the appropri-&te alkyl magnesium iodide followed by acid hy~rolysis affords dl-6a,7-dihydro-l-hydroxy-6,6-dialkyl-3-~Z-W)-6H-dibenzo~b,d~pyran-9(8~)-oneO Birch reduction 2Q of the thus-produced dihydro oompound provides the corresponding tetrahydro compo~md, which is converted to the l,9-dihydroxY compound having Formula I
by reduction with sodium boronydride as described above.

. .: . .

A further method fo~ making compounds of Formula VIII whereln Z-W

is (alkl)-X-(alk2)-W comprises reactlon of th~ ~p~ropri~te 3,5-(di-prot0cted hydroxy)styrene oxide with ~n ~lcohol or ~hio alcohol ~HX-(alk2)-W) as it9 alkali metal (pre~erably sodium or potassium) salt, Methyl i6 a favored protecting group for th~ 3,5-dihydroxy styrene oxides because of it3 eQse Of r~oval. The resulting 3,5-(d~-protected:h~roxy)phen~l hydroxyalkyl ether compound (Formul~ VIII-A) is converted to the correspondln~ alkyl ether (Formula YIII-B) by treatment with pho9phorous oxychloride followed by dehalo-genation of the thus produced chloro derivative by means o~ hydrogen over palladium. Removal of the protecting groups as d~scribed above af~ords the desired compound. The reaction sequence is presented below (Yl - benzyl, ~lkyl having one to ~our carbon atoms; X~ is O, S; R' ~ X, CH3, C2H5 and may be alike or different).

Yl Y
HX'-~alk )-W
~ ~ T O X'H

YlO ~ C ~pH YlO ~ I~lH~X ~alk2) R' R' VIII-A

~ H2/Pd-C
qYl Y0~
c~-x ~ k2 ) -W

HO ~ C~H-CH-X'-~alk2)-W

VIII .

A ~ 18 : : ' - , . ~ .
'' : ' . , :

: . ;
-, ~Q~2~i~

Esters o~ compound o~ Formulae II and III wherain Rl i3 alkanoyl or -CO-~CH2)p-~R2R3 are readily prepared by reacting Formula II or III compound3 with the appropriate alkanoic acid or acid o~ Formula ~OOC-~C~2)p-~R2R3 in the presenCe o~ a condensi~ ~gent such ~s dicyclohexyloarbodiimide. A].ternatively, they are prepared by reaction of a Formula II or III compound with the appro-priste alkanoic aQid chloride or anhydride, e.gO, acetYl chloride or acetic anhydride, in the presence of a base uch as pyridine.
Eaters of Formula I compounds in which ea~h o~ the R and Rl groups is este~ified are prepared by acylation according to the above-described pro-cedures Compounds in which o~ly the 9-hyd~oxy group i~ acylated are obtained by mild hydrolysis of the cQrresponding l,9-diacyl deri~ative, a~vantage bei~g taken o~ the gre~ter eQse o~ hvdrolysis o~ the phenolic acyl group. Formula I
compounds in which only ~he l-hYdroxY group i~ esterified ar~ obkained by boro-h~dride reduation of the correaponding Formula II ketone esteri~ied ~t the l-position. Th~ thus-produced Formula I co~pounda bearin~ l-acYl~9-hy~roXY
substitution or l-hydroxy-9-acyl ~ubstitution ca~ then b~ acylated ~urther with a different acylating agenb to produce a diesteri~ied compound o~
Formula I in which the e~ter group at the 1- and the 9-position are di~erent.

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The analgesic propert1es of the compoundq o~ this invention are determined by tests using nociceptive stimuli, Test Usin~ Thermal Nociceptive Stimuli a) Mous_ Hot Plate Anal~esic Testin~
The method used is modified after Woolfe and MacDonald, JO
Pharmacol. ~p, Ther., 80~ 300~307 ~1944)~ A controlled heat stimulus is -applied to the feet of mice on a 1/8" thic~ aluminum plat~, A 250 watt re-flector infrared heat lamp is placed under the bottom of the aluminum plate.
A ther~al regulator, connected to thermistors on the plate surface, programs the heat lamp to maint.ain a constant temperature of 57Co Each mouse is dropped into a glass cylinder (6 1/2" diameter) resting on the hot plate, and timing is begun when the animal's feet touch the plate. The mouse is ob~erved at 0~5 and 2 hours after treatment with the test compound for the first "flicking" movements of one or both hind feet, or un~il 10 seco~ds elapse without such mo~ements. Morphine has an MPE50= 4-5,6 mg./kg. ~.c.).
b) M ~
Tail ~lick testing in mice is modified after D'Amour and Smith, J.
Pharmacol. ~. Ther., ~ 74-79 (1941), usin~ controlled high intensity heat applied to the tail. Each mou3e is placed in a snug-fitting metal cylinder, with the tail protruding through one end. This cylinder i3 arranged ~o that the tail lies flat over a concealed heat l~mp. At the on3et of testing, an aluminum flag o~er the lamp is drawn backg allowing the light beam to paas through the slit and focus onto the end of the tail, A tlmer is simultaneously activated, The latency o~ a sudden flick of the tail is ascertained. Untreat- ;~
ed mice usuallyreac~ within 3-4 second3 after exposure to the lamp. The end point for protection is 10 3econds. Each mouse is tested at 0.5 and 2 hour3 after treatment with morphine and the test oompound. Morphine has an MPE50 f 3.2-5.6 mg./kg. (s.c.), ~20-, "- ' . ' ` ` ; `' ':

$~

c) Tail Immersion Procedure The method is a modification of the receptacle procedure developed by Benbasset, et al., Arch. int. ~ ., ~ 434 (1959). Male albino mice (1~-21 g.) of the Charles River CD-l strain are weighed and mar~ed for identification. Five animals are normally used in each drug treatment ~roup with each anima~ serving as it~ own control. For general screening purposes, new test agent~ are first administered at a dose of 56 mg./kg. intraperitone-all~ or subcutaneously, deli~ered ln a volume of 10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post dr~g, each animal i3 placed in the cylinder. Each cylinder i3 provided with hole~ to allow for adeguate ~entila-tion and is closed by a round nylon plug through which the animal~S tail pro-trudes. The cylinder iB held in an upright po~ition &nd the tail i~ completely immersed in the constant temperature waterbath (56C.). The endpoint for each tri~l is an enerKetic Jerk or twitch of the tail coupled with a motor response.
In some cases~ the endpoint may be le~ vigorous posb drug. ~o prevent undue ti3sue dam~ge, the tri~al i3 terminated and the tail r~moved from the waterbath within 10 seconds. The response laten~y i8 reaorded in 3econd~ to the neare~t 0.5 second. A vehicle control and a standard of known potency are te3ted concùrrently with screening candidates. If the activity Or a test ~gent has not returned to baseline value~ at the 2-hour te~ting point, re~ponse latencies are determined at 4 and 6 hour3. A final mea~urement iB m~de at 24 hours i~ ~ctivity is still obRerved at the end of the te~t day.

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Test Usin~ Chemical Noc1ceptive Stimuli Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. Twenty minute~
(if treated subautaneously) or fi~ty minutes ~if treated orally) later, each group is treated with intraperitoneal i~ection o~ phenylbenzoquinone, an irri-tant known to produce abdominal contractions~ The mice are obser~ed for 5 minutes for the presence or absence of writ~ing stQrting 5 minutes af-ter the inJection of the irritantO MPE50's of tbe drug pretrsatments in blocXing writhing are ascertainedO

A modification of the procedure of ~affner, ~ ~
Schmer~stillender, Mitte.~ Deutoh Med. Wschr " 55, 731-732 (1929) is used to ascertQin the effccts of the test compound on aggres~ive attacking responses elicited by a stimulus pinching the tailO M~le albino rat~ (50-60 bo) of the Charles River (Sprague-Da~ley) CD strain are usedO Prior to drug treatment, and again at 0.59 1, 2 and 3 hours after treatment, a Johns Hopkins 205 inch "bulldog" clamp is clamped onto the root of the rat's tailO The endpoint at each trial is clear attacking and biting behavior directed toward the offend-ing stimulus, with the latency for attack recorded in secondsO The elamp is removed in 30 seconds if attacking has not yet occurred, and the latency of respon~e is recorded as 30 secondsO Morphine is active at 1708 mgO/kg~ ~iop~
Test Usin~ ctrical Noci~ptive Stim~li The ~Flinch-Jump'' Test A modif;cation of the flinch Jump procedure of ~enen, P~chopharma-colog~a, ~ 278-285 (1968) is u~ed for determining pain thresholds, Male albino rats (175~200 gO) of the Charles River (Sprag~e-Da~ley) CD strain are used, Prior to receiving the drug, the feet of each rat are dipped lnto a .
r~
- ' ' ',, '"
' ~ ' '; '' - ' 20~ glycerol/saline solution, Th~ animal3 are then placed in a chamber and presented with a series o~ 1-second shock to the fee~ which ar~ d~livered in increasing intensity at 30-second intervalsO ~hese intQsities are oO~6, 0.39, 0052, oO78, 1005, 1031, 1058, 1086, 2013, 2042, 2072 Qnd 3004 mA0 Each animal's behavior is rated for the preaence of (a) flinch, ~b) squeak and ~c) ~ump or rapid ~orward movement at shock onset Single upward ~eries of shoc~
intensities are presented to each rat ~ust prior to., and a-t 005, 2, 4 and 24 hours subsequent to drug treatmentO
Results of the above tests are recorded as percent maximum possible e~fect (% MPE)o The % MPE O~ each group is statistically compared to the % MPE o~ the standard and the predrug control vYluesO The % MPE is calculated ~s ~`ollows:

% MPE = test time - control time x 100 cuto~f time - control time The compounds o~ the present invention are active analgesics via or~l and parenteral administration and are conveniently administred in composi-tion formO Such compositions include a pharmaceutical carrier selected on the basis o~ the chosen route o~ admini3tration and standard pharmaceutical practiceO For example, the~ may be administered in the form of tablets, pills powders or granules containing such excipients as starch, milk sugar, certain types of clay, etcO They may be administered in capsules, in admixture~ with the same or equivalent excipientsO ~hey may also be administered in the form of oral suspensions, solution~, emulsionsg ~yrups and elixirs which may con-tain flavoring and coloring agents For oral admi~istration of the thera-peutic agents of this invention, tablets or capsule~ containing from aboutOoOl to about 100 mgO are suitable for most applicationsO
The physician will determine the dosage which will be most suitable ~or an individual patient and it will vary with the age~ weight and response 2$9 of the particular patient and the route o~ administrationO Generall~, however9 the initial analgesic dosage in adults may range f'rom OoOl to 500 mgO per day in single or divided dose~0 In many instances, it is not necessary to exceed 100 mg. daily. The favored oral dosage range is f'rom about 0.01 to about 300 mg./day; the preferred range i8 from about 0.10 to about 50 mgO/day. The favored parenteral dose i8 from about OoOl to about 100 mg,/day, the preferred range from about 0.01 to about 20 mg./dayO
By means of the above procedures, the analgesic activity of several compounds of this invention and of certain prior art compounds are determinedO
The data are reported in terms of maximum possible ef'f'ect.
The following abbreviations are used in tables:
PBQ = phenylbenzoquinone-induced writhing7 ~F = tail flick; HP = hot plate; RTC = rat tail clamp; FJ = flinch ~ump; and TI - tail immersion assays.

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:: , Their anti~vpertensive utility i3 determined by their ability to lower the blood pressure o~ conscious hypertensive rats and dogs a statistical-ly significant degree ~hen administered orally to sai~ hosts at the above-mentioned dosages.
Their tranquilizer activity is demon~trated by oral administration to rats at doses of from about OoOl to 50 mg /kg with sub~equent decrea3es in spontaneous motor activ~ty. The daily dosage range in mammals is from about 0.01 to about 100 mgO
In addition to their analgesic, hypotensive and tranquilizer acti-vities, compounds o~ Formula I are also use~ul as immunosuppressant~ and anti-secretory agents.
Their gastric antisecretory effects in pouch dogs (Heidenhain) is determined by the following procedureO
Gastric antisecretory activity is studied in overnight fasted, con-scious Heidenhain pouch dogs using pentagastrin, histamine or food to stimul~te acid output. Pentagastrin or histamine is administered as a continuous infu-sion into a superficial leg vein ~t doses earlier determined to stimulate near maximal acid output ~rom the gastric pouch. Food stimulus con~ists of one-half can of Ken-L-Ration (approxO 220 gO) per dog; dogs weighing 9-1205 kgo are used~ Gastric Juice is collected at 30 minute interval3 following the 3tart of a histamine or pentagastrin infusion or the ingestion of a standard food meal. A total of ten collection3 are made for each dog during an experimentO
Drug is administered orally at levels of from 0.01 to 50 mgO/kgO after the third gastric Juice collectionO A11 sample volumes are recorded and acid Gon-centration is determined by titrating sample allquots (loO mlO ) to pH 704 withO.lN NaOH using a pH meter (Radiometer) and autoburetteO The drug is given orally after placing it in gelatin capsule30 . :, , .

~:
., Im~unosuppressant activit~ i~ evaluQted by means of a mixed lympho-cyte culture assay procedure. Thi3 assay measuxe~ the effe~ts of the test compound on antigen-stimulated lymphocyte proliferation, Spleen lymphoid cells from BALB/C and C5l~L!6 mice, 8 x 106 cellg from each strain9 Qre sus-pended in 200 ml. of a serum~free medium containing the test compound and in-cubated at 37Co in a 10% carbon dioxide ~tmosphereO The culture conditions and technique are described by Ro W~ Dutton in J, ~, Med. lZ2 7599 ~1965) and the cellular medium is described by W. ~, Weber in J0 Retic. Soc" 8, 37 (1970), Half of the medium, 1 mlO, is replaced with fresh medium every 24 hours. 3H-TdR incorporatîon (24 hour pulse) into desoxyribonucleic acid is then determined bytrichloroace~c acid precipitation of desoxyribonucleic acid and assessment of radioactivity in a liquid scintillation co~nterO The pèrcent inhibition is determined by comparing each te~t compou~d-~reated mixed culture with the control mixed cultureO

.. . . . .

dl-5-~ydroxy-232-dimethyl-7~ methyl-4-phenylbutyl)-4 chrom~Y A~
A mixture of 2-(3,5-dihydroxyphenyl)-5-phenylpentane (9 6 gO) and 3-methylcrotonic acid (4.5 g.) i9 he~ted to 125Co und~r nitrogen, and boron trifluoride etherate (8.7 mlO) is added. Af~er refluxi~ for one hour, the reaction is cooled and water (10 n~0) is added ~ollowed by 6~ sodium hydrox-ide (40 ml.). The resction mixture is heated for 5 minutes on a steam bathg cooled and acidi~ied with 6N hydrochloric acid. The agueous layer is extrac-ted with ether (3 x 100 mlO) and the combined ether e~tract~ waihed with 10%
sodium bicarbonate (1 x 25 mlO) and water (1 x 25 mlO). The organic phase is dried over sodium sul~at0 and concentrated under vacuum to a~ford 12 7 gO of a crude oil which is puri~ied by silic~ gel chromatography to yield 5.0 gO of dl-5-hydroxy-2,2-dimethyl-7-(1--methyl-4 - phenylbutyl)-4-chromanone a3 a colorless oil.
IR: (CHC13) C=0 1635 cm 0 ~MR: ~CDCl 1-107 (M,7,~-methylg ethylene), 105 (S,6,gem dimethyl)~
203-209 (M,3,benzylic-methylene, methi~yl), 2,65 (S,2,~-methylene), 601-6035 (M,2,aromatic), 609-7~4 (M,5,aromatic), 11053, 11063 (d,l, hydroxyl)0 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):
NMR: ~cDScl 102 (d,3,a-methyl, J = 7 cps), 1 4 (S,6,gem dimet~yl), loO~l~g ~M~6~-CH2-(CH2)3-C(CH3)-Ar~ 2.3-208 (M,3,benzylic-methylene, methinyl), 2.7 (S,2,a-methylene), 602-604 (M,2,aromatic), 7.1-703 (M,5, aromatic), 11.6 (S,l,hydrox~1);

., . ' , ; , .. - , .

1-~3,5-Dihydroxyphenyl)-2-phenylethane is converted to 5-hydroxy-2,2-dimethy].-7-(2-phenylethyl) 4-chromanone ~an oil), IR: (CHC13 C-0 1645 cm 1 N~ cDScl 1.45 ~S,6,gem dimethyl), 2065 ~S,2,~-methylene), 2~85 (S,4,ethylene), 6025~ 603 ~2d,2,arom~tlc), 7.2 ~S,5,aromatic), 11,6 ~S,1, hydroxyl-D20 overlay)0 MS: (molOion) 296 2-~3,5-Dihydroxyphenyl~-4-phenylbutane i~ converted to dl-5~hydro~y-2,2-dimeth~1-7-(1-methyl-3-phenylpropyl)~4-chrom~none (an oil):
~MR: ~C~Cl 103 (d33,methyl), 1045 (S,6gem dimethyl), 1055-201 (M~2,methylene), 2025~2075 (M,3,benzylic-methylene, methinyl), 6.15 (d, 2, aromatic), 701 (5,5,arom~tic), 1106 (5,1,hydroxyl-D20 overlay)~
MS: (mol~ion) 324 2-~3,5-dihydroxyphenyl)-5-phenylpentane (5027 g ) is converted by reaction with boron trifluoride ~therate (4081 mlO) and crotonic acid (2008 gO
o~ freshly distilled) in place of 3-methylcrotonic acid to dl 5-hydroxy-2-methyl-7-(1~ methyl-4~ phenylbutyl)-4-chromanone ~MR: ~CDCl lol (D,3,a-methyl, J = 7 Xz), 104 (D,3,2-methyl9 J =

7 Hz), 103-108 (M74--ethylene), 202-209 (M,5,~-methylene, benzylic-methylene, methinyl)~ 405 (M,l,methinyl ether), 601, 6~2 (2D,2,arom~tic, J ~ 1 Xz~, 6.9-7.4 (M,5,aromatic), 1107 (S,l,phenolic OH)o ~ 30-i , -, ` ` ' ' ' ~i2~

4-(3,5-dihydroxyphenyl)-1-phenoxypentane i8 converted to dl-5-hydroxy-2,2-dimethyl-7~1-methyl-4-phenoxybutyl~-4-chromanone, a 1ight yello~
oil r MS: (mol.ion) 354 Rf = 0061 (silica gel, 18-benzene:l-ethyl acetate) Analysis: Calc'd for C22H26040 C, 74 55; X, 7039 %
FoundO C, 74c56; H, 7036 %
4-(3,5-dihydroxyphenyl)-1-(4-pyridyl)pentane i~ converted to dl-5-hydroxy-2,2-dimethyl-7-~1-methyl-4-(4-pyridyl)butyl]-4-chromanone, an oilO
R~ = OD39 (silica gel, l-benzene:l-ethyl acetate) ~MS
NMR: ~CDCl 1-1090 (M,13-H,methylene, methyl doublet at 1020,J = 7 Hz, and gem dimethyl singlet a~ 105); 2043-2086 (M,5-H,methylene, methinyl, including sin~let (two C-3 H's at 2 71); 6 26 (b d.S,l-H,aromatic); 6033 (b.d.S,l-H,aromatic); 7000-7~20 ~bOd D,2-H,pyridine arom~tic); 7025 (bodoS, l-H,hydroxyl); ôO41-8061 (b d.D,2-H,pyrldine aromatic)0 dl-5-hyaroxy-2,2-dimethyl-7~(1-methyl-3-phenoxypropyl)-4-chromanone is prepared ~rom 3-(3,5-d~hydroxyphenyl)-1-pheno~ybutane as an oilO
Rf = 007 (silica gel3 18-benzeneOl-ethyl acetate) MS: (molOion) 340 Analysis Calc'd for C21H2404- C, 74009; H~ 7 11 %
FoundO C, 74004, H, 7019 %
dl-2-(3,5-Dihydroxyphenyl)-1-(2-phenylethoxy)propane is converted to dl-2,2-dimethyl-5-hydroxy-7-[1-methyl-2-(2-phenylethoxy)ethyl]~4-chromanone (an oil)0 NMR: ~CDCl 1 21 (d, J=7Hz, methyl), 1048 (s, gem dimeth~l), 2073 (s, C 3 methylene), 2.86 (+, J=7Hz, CH2Ph), 209 (m, methine), 3 50 (d, J~7Hz, -CH2Q-), 3065 (t, J=7Hz, -OCH2-), 6 31 (d, J~lXz, ArH), 6038 ~d, J=lHz, ArH), 7026 ~sg Ph) and 13033 (s, phenol)0 . ~

,: : , :~

z~9 ~XAMP~ 2 dl-5-~ydroxy-3-hydroxym~thylene-292-dimethyl-7-(1-methyl-4-phenylbutyl)-4~chromanone To sodium hydride obtained by wa~hing 50% sodium hydride in mineral oil dispersion (6067 gO) ~ith pentsne is added dropwise, over a 30-minute period, a solution of dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanone (407 gO) and ethyl formate (2301 gO)O The reaction mixture is then cooled to room temperatur& and ether (350 ml.) ~ddedO The resulting mixture is refluxed for 18 hours, cooled to room temperature and acidi~ied with lN
hydrochloric acid. The ether layer is separated a~d the water layer extracted with ether (3 x 100 ml, ), The combined ether extracts are dried over sodium sulf~te and concentrated under vacuum to yield 507 gO o~ dl-5-hydroxy 3-hydroxy-methylene-2,2-dimethyl-7-(1- methyl-4 ~ phenylbutyl)-4~chromanone a8 ~n oil.
NMR: CDCl 1.05-1.8 (M,13,gem dimethyl, a-methyl, ethylene), 2 45 (M,3,benzylic-methylene, methinyl), 602-6.5 (M,2,aromatic), 7~o-7.6 (M,6, aromatic, methinyl ether), 1103, 11~36 (2bdoS~ l,phenolic hydroxyl), 1303, 1305 (2bdoS~ l,hydroxyl)0 IR: (CHC13) C~0 1625 cm 1 In liXe manner, the products o~ Example 1 are ccnverted to:
dl-5-hydroxy-3-hydroxymetl1ylene-2,2-dimethyl-7-(1 methy].-5-phenylpentyl)-4-chromanone:
NMR: ~cDScl 102 (D,3~-methy:',J ~ 7 Cp8), 106 (S,6,gem dimethyl)~
100-2.0 [M,6,~CH2-(CH2)3-CH(CH3)Ar], 203-200 (M,3,benz~1ic-methylene, methi-nyl), 602-6.4 (M,2,aromatic), 7 1-7~4 ~M,6,aromatic, vinylic), 1104 (bdoS~l phenolic hydroxyl);

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5-hydroxy-3_hy~roxy~et~ylene 292~dimethyl-7-(2-~henylethyl)-4-chrom~none (an oil):
IR: (CHC13) C=O 1625 cm ~MR ~CDCl l.S(S,6,gem dimeth~l), 2.85 (S,4,ethylene), 6.2, 603 (d,2,aromatic), 7.0-7.5(M,6,aromatic, methinyl), 11.35 (S,l,hydroxyl-D20 overlay), 13.4~ 13.6 (d,l,hydroxyl-D20 overlay).
MS:(mol.ion) 324 dl-5-hydroxy-3-hydroxymet~lene 2,2-dimethyl-7-(1 - methyl-3-phenyl-propyl)-4-chromanone (an oil):
NMR: ~CDCl 1.15 (d,3,methyl), 1.5 (S,6,gem dimethyl), 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-D20 overlay), 13.3, 13.8 (d,1,hydroxyl-D20 overlay).
MS:(mol.iqn) 352 dl-5-hydroxy-3-hydroxymethylene-2_methyl~7-(l~ methyl-4-phenyl-butyl)-4-chromanone:
TMS
NMR: ~CDCl 1.1 (D,39a-methyl, J = 7 Hz), 1.5 (D,3,2-methyl, J =
7 Hz), 1.3-1.8 (M,4-ethylena), 2 3-2.9 (M,3,benzylic), 4.9 (M,l,methinyl ether, J = 5 ~z), 6.2, 6.3 (2D,2,aromat~c~ J - 1 Xz), 6.9-~.4 (M,6,aromatic, vinylic), 11.2 (bd~S, l,phenolic OH).

~ -33-,: , , :: .:

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dl-5-hy~roxy-2,2-dimethyl-7-(1-methyl-4~phenoxybutyl)-4-chromanone is converted to d,l-5-hydroxy~3-hydroxymethylene-2,2-dimethyl-7-~1-methYl-4-phenoxybutyl)-4 chromanone: Rf = 0 44 [silica gel, 18-benzene:l-ethyl aceta~e]
MS: (mol.ion) 382 dl-5-hydroxy-2,2-dimethyl-7-[1-methyl-4-(4-pyridyl)butyl]-4-chro-manone i9 converted to d,1-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-[1-methyl-4-(4-pyridyl)butylJ-4.-chromanone, a vis~ou~ oil:
R~ = 0.15(silica gel, 1-benzene:1-ethyl acetate) dl-2,2-Dimethyl-5-hydroxy-7-[1-methyl-2-~2-phenylethox~)ethyl]-4-chromanone is con~erted to dl-2,2-dimethyl-3-hydroxymethylene-5-hYdroxy~7-[1-methyl~2-~2-phenylethoxy)ethyl]-4-chromanone (an oil)~
R~ = 0.35 (silica gel, 1:1 pentane:ether).

-3l~-$;2~91 EX~MPLE 3 dl-6a,7-Dihydro-l-hydroxy-6~6-dimethyl-3~ methyl-4-~henylbutyl)-6H-dibenzo-~b 9 d]pyran-9(8H)-one To ~ solution of 5-hydroxy-3-hydroxymethylene-2,2-dimethY1-7-(1-methyl-4-phenylbutyl)-4-chromanone (0,~16 ~0) in methanol (4 ml.) and methyl vin~l ketone (0.037 n~.) is added triethylamlne (0.09 ml.). The reaction is stirred ~or 16 hours at room temperature and ~hen diluted with ether (50 ml.). The resulting ether solution i9 extracted ~ith 10% sodium carbonate solution (4 x 5 ml.), dried over sodium sulfate and conc~ntrated under vacuu~.
to yield 1.09 g. of an oil~ The residue i9 refluxed with ~thanol (7.3 ml,) and 2N potassium hydroxide (7.3 ml.) for 16 hours. ~hereafter, the reaction solution is cooled, acidi~ied with 6N hydrochloric acid and extracted with dlchloromethane (3 x 20 ml.). The organic phase is dried over sodium sul~ate and evaporated to yield 0.99 g. of an oil which cry3tal1i~e3 from ether:
hexane (1:1) to yield 0.49 g. of dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-~l-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-9(8H) one~ m~p. 145-148C.
after crystallization Irom isopropyl etherO
TMS
NMR: ~CDCl 1-2~35 ~M~lo~a~methylene~ ethylene, remaining proton~), 1.55 ~S,6,gem dimethyl), 2.35-3 0 ~M,59~-methylene, ben~ylic-methylene, methinyl), 6.1-6.7 (M,2,aromatic), 7-7,35 (M~5,aromatic), 7.9-ô.2 (bd:.S,l~
olefinic proton), 10.8 (S~l,phenolic OH~
IR: (CHC13) C=O 1600 cm Analysis: Calc'd for C26H3003: C, 79.97; H, 7.14 %
Found: C, 79.91, H, 7.78 %
` MS: (mol.ion) 390 ~ -35-,~ ' :: :

6~

Similarly, dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-~1-methyl-5-phenylpentyl)-6H-dibenso[b,d~pyran-9~8H)-one is prepared from 5-hydroxy-3-hydroxymethylene-292-dimethyl-7-~1-methyl-5-pheny].pentyl)-4-chromanone, m.pO 204208C.

NMR. ~CDCl 1,1, 1.5 ~2S,6,~em dimethyl), 1.0-3,0 ~M,17-~-methyl, ~CH2)3-CH(CH3)-Ar, benzylic, remaining pro~ons], 602, 6.5 (2D,2,aromatic prontons, J = 2 Cp5), 7.0-7~4 (M,5,aromatic), 8 05 (D.l.vinylic, J = 2 cps)~
10.8 (S,l,phenolic hydroxyl).
IR: (KBr) C=0 1613 em Analysis: Calc'd for C27H3203: C, 80-16; H~ 7.97 %
Found: C, 80.00~ H, 8.29 70 dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-~2-phenylethyl)-6X-dibenzo ~b,d~pyran-9(8H)-one is prepared from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-~2 phenylethyl)l~-chromanone, mOp, 233-235C.
NMR: ~ CDCl 1.0-1.4 (M,3,5a-methinyl, 7-methylene), 1.5 (S,6,gem dimethyl), 2035-2.85 (M,2,8-a~methylene), 2.9 (S,4,ethylene), 6.3, 6.55 (2nd, 2,aromatic)9 7,3 (S,5,aromatic), 7.95 (d,1910-ole~lnic proton), 10.5 (S~l, hydroxyl-D20 overlay), MS: (mo]Oion) 348 and dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-3 phenyl-propyl)-6H-diben~o[b,d]pyran-9~8H)-one from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(1-methyl-3-phenylpropyl)-4-chromanone, m,p, 181Co NMR: ~CDCl 1,2, 1.3 (d,2,methyl), 1,55(S,6,gem dimethyl)a 106-301 (M,8,remaining protons)~ 6,3, 6.55 (2d,2,aromatic), 7 2, 7.25 (2S,6, aromatic, hydroxyl-D20 o~erlay, 8,05 (d,l,olefinic proton)0 MS: (mol 5 ion) 376 ,~, ~36-Z~9 dl-6a~-7-dihydro-1-hydroxy-6~-methyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-~(8H)-one is prepared ~rom dl-5-hydroxy-3-hydrox~methyl-ene-2_methyl-7-(1-methyl-4-phenylbu~yl)-4-chromanone; m,pO 195-197C~
NMR: ~ TDSC1 1 . 2 ~D,3,a-methyl, J - 7 Hz), 1 4 (D,3 3 6-methyl, J =
7 Hz), 1.3-l.ô (M,6,7-methylene~ allylic), 308 (M,l,methinyl ether, J vicinal =
11 Hz), 7 0-7.4 (M,5,aromatic), 7.9 (D,l,vinylic, J ~ 1 Hz), 9a6 ~S,l,phe~olic OH)~
IR: (KBr) C = 0 1639 cm Analysis: Calc'd ~or C25H2803: C, 79.75; ~, 7050 %
Found: C, 79.76; H, 80~3 %
U V 2 5 = 226 (~ ~ 14~400), 324 (~ = 26000) m~x MS: ~moI;ion) 376 dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenoxybutyl)-6H-dibenzo[b,d~pyran-9(8H)-one is prepared from the correspondin~ 3-hydroxy methylene derivative; mOpO 165~175Co MS: ~molOion) 406 R~ = 0031 (silica gel, 18-benzene:3-ethyl acetate) Analysis: Calc 26 30 4 Foundo C9 76080; H, 7057 %
dl-6a,7-dihydro-1-hydroxy-6,6-dimethyl-3-[1-methyl-4~~4-pyridyl)-butyl]-6H-dibenzo~b,d~pyran-9(8H)-one i9 prepared ~rom the corre~ponding 3 hydroxymethylene derivative as a glassy solid~
MS: (molOîon) 391 Analysis Calc'd ~or C25H29NO30H20: C, 73032; H9 7062; Ng 3042 %
Fou~d C3 73 22; ~, 7~)l7; N, 3.25 %

. : ,~, , ~ ,, : .
,:

dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-[1-metnyl-2-~2-phenyl-ethoxy)ethyl]-6H-dibenzo-[b,d~pyran-9~8H)-one is prepared from dl-2,2-dimethyl-3-hydroxymethylene-5-hydroxy-7-tl-methyl-2-~2-phenylethoxy)ethyl]-4-chromanone, m.p~ 185-187C.
IR: (CHC13) C = 0 1613 cm NMR: ~CDCl 1015 (s, one methyl of gem dimethyl), 1~20 (d, J~7Hz, methyl), 1.48 (s, one methyl of gem dimethyl), 200-301 tm), 2~85 (t, J=7Hz, CH2Ph), 3.4-3.8 (m, -CH20CH2~), 6035 (bs, ArH), 6063 (bs, Ar~), 7.30 (9, Ph),

8.10 (d, J=2Hz, C-10 H) and 12,3 (s, phenol)0 MS: m/e 406 (~ ), 391~ 376, 363, 315, 302 (100%), 287, 285 and 2720 .
:: :

dl-~a~,7,10,10a~-~etrahydro-1-hydroxy-6,6-dime-thyl-3~ methyl-4-phen~lbutyl)-6H-dibenzo[b~dlpyran 9l8H)-one A solution of dl-6a,7-dihydro-l-hydroxy~696-dimethyl-3~ methyl-4-phenylbutyl)-6H-dibenzotb,d]pyran-9(8~) one (0 976 g.) in tetrahydrofuran (7 ml.) is added to a rapidly stirred solution of lithium (0,1 gO) in liquid ammonia (35 mlO) (distilled through potassium hydroxide pellets)O The reaction is stirred for 15 min~te~ and then ~olid ammonium chlorlde ls added to dischargethe blue colorO The excess ammonia iR allowed to evaporate and the residu~ iB
diluted with water (35 ml.) and acidified with concentrated hydrochloric acidO
The water solution is extracted ~ith dichloromethane (3 x 25 mlO) and the dichloromethane extracts dried o~er ~odium sul~ate and~evaporated to yield o.g8 g. of a mixture of trans- and cis-6a,10a-diastereomers as a crude oil which is purified via column chromatography on silica gel to yield the tran~-diastereomer followed in later fractions by the cis-diastereomer, The following are thus obtained 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, 200-205Co N~R: ~CDCl 1-2 35 (M,119a-methyl, ethylene, remaining protons), 1.55 (S,6,gem dimethyl), 2.35-3 O(M,79a-methylene~, benzylic-m~thyleneg methinyl), 6.2-6.45 (M,2,aromatic), 7-7,35 (M~5,aromatic), 7.8 (bd S,l, hydroxyl-~20 overlay).
IR: (CHC13) C=O 1600 cm and dl-6a~,7,10,10a~-tetrahydro-l-hydroxy-6,6-dimethyl-3-(l-met7nyl-4-phenylbutyl)-6H-dibenzo~b,d]pyran-9(8~)-one as a solid foam, IR: (CHC13~ C-O 1690 cm , OH 3275 cm O
NMR: ~CDCl 0095-2.12 ~M,ll,a-methyl, ethylene, remaining pro~ons)~
1.35, 1.4 (2S9 6,gem dimethyl), 2025-2095 ~M,7,a-methylene3, benzylic-methylene9methinyl), 6.1-6.35 (M,2,aro~atic), 701(bd.S.,l,hydroxyl), 7,25 (,S,5,aromatic)0 Repetition of the above procedure but using the product~ of Example 3 as reactants affords:

, .;.-dl-6a,~7~lo~loacl~-tetrahydro-l~hydroxy-6~6~dimet~yl-3~ 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,~-methyl, ~-CH2-(CH2)3-CH(CH3)-Ar, benzylics, remaining protons], 3 9-4.4 (bd.D,l,a-car-bonyl), 6.2 (M,2,aromatic), 7 0-7 4 (M,5~aromatic), 7.8 (S,l,phenolic hydroxyl)~ IR: (KBr) C~O 1695 cm Analysis: Calc'd for C27H3403: C, 79 76, H, 8.43 %
Found: C, 79.49; H, 8 43 %
and the corresponding ci~diastereomer:
dl-6a~,7,10~10a~-te~rahydro-1-hydroxy-6,6-dimethyl-3-~1-methg1-5-phenylpentyl)-6H-dibenzo~b,d]pyran-9(8H)-one; m p. 91-130~C.
IR: (K3r) C=O 1709 cm MS: (mol.ion) 406.
dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-~2-phenylethyl)-15 6H-dibenzo~b,d]pyran-9(8H)~one, m.p. 206-209C :
IR: (KBr) OX 3260 cm , C=O 1710 cm NMR: ~CDC1 1.05-1~45 (2S,6,gem dimethyl), 2075 (bs,4,et`hylene), 1 1-3.1 ~M,7,remaining proton~), 3 75, 4 0 (2d,1,10a~ proton), 6 2 (d,2,aroma~ic), 7.15 (S,5,aromatic), ô.8 ~S,l,hydroxyl-D20 o~erlay) MS (mol ion) 350.
dl-6a~,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimeth~1-3-(1-methyl-3-phenylpropyl)-6H-dibenzo[b,d]pyran-9(8X)-one, mOp 165C .
IR (K~r) OH 3175 cm 1, C=O 1695 cm 1 and dl-6a~,7,10,10a~tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-meth~rl-3-phenylpropyl)-6H-dibenzo~b,d~pyran-9(8H)-one a~ a solid ~oam:
IR: (CHC13) C=O 1685 cm 1, OH 3250 cm NMR: ~CDCl 1.35, 1 45 (2S,6,gem dimethyl), 2 8 (bd,s,)l,ethylene), 1.75-3.6 (M,8,remaining protons), 6.3 (M,2,aromatic), 7 25 (M,6,aromatic,hydroxyl)0 --1,o--.

dl-6a~7~lo~loa~-tetrahydro-l-hydroxy-6~6-~imeth~rl-3-~l-methyl-4 phenoxybutyl)6H-dibenzo[b,d]pyr~n-9(8H)-oneo M.P. 160C.
MS: (mol~ion) 408 Rf = 0.53 (silica gel, 8-benzene:2-ethyl acetate) NMR: ~CDCl 7 41-6067 (multiplet,6,phenolic OH, C6H5); 6 3 ~S,2, aromatic H2 ~ Hl~); 4.33-1.50 (Ms, 15, remaining methylene and methine proton~);
1.47 (S,3,CH3); 1027 and 1~17 ~D,3,Me), 1012 (S,3,CH3).
Analysis: Calc'd for C26H3204: C, 76 44; ~ 7-89 %
Found: C, 76061; H, 7 90)%
dl-6a~,7,10,10a~-tetrahydro-1-h~droxy-6,6-dimethyl-3-[1-methyl-4-(4-pyridyl)butyl]-6H-dibenzo~b~d~pyran-g(8H)-one:
MoP~ 60-70C
R~ = 0~4 (silica gel, ethyl acetatc) MS: (molOion) 393 NMR: ~CDCl 0,83-l~f3 (M,15,methyl9methylene),:1~73-3 0 (M,8,1_ methine, remaining protons), 3 97-L~,2 (bd D,lgaliphatic), 6 27 ~S,2,aromatic), 7.03, 7.13 (D,2,pyr~dine arom~tic), 7~55 (S,l,hydroxyl), 8,~2 (M,2,pyridine aromatic) dl-6a~,7,10,10aa-tetrahydro-l-hydroxy-6~-methyl-3-(l-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-9(8H)-one, m p~ 163-167C (pre-softening at 140C.~
IR: (KBr) C-O lfOg cm Analysis: Calc'd for C25H3003: C, 79,33; H~ 7 99 %
Fou~d: C, 79 43; ~, 8 03 MS: (mol.ion) 378 --L~

, ' ' : ' ~ . ~ . . ;:, , . .

,. : . .

dl-6a~,7,10,lOa~ tetr~hydro-l-hy~roxy-6a6-dim0thyl-3-~l-me~hyl-2-~2-phenylethoxy)ethyl]~6H-dibenzo[b,d]pyran-9~8~)-one ~a solid gla~s):
~MR: ~TMScl 1013 (s,one methyl of gem dimethyl), 1,24 (d,J-7Hz, methyl), 1050 (s,one methyl of gem dimethyl), 106-302 ~M), 3.2-3.8 (M), 4.05 (M,one proton), 4.30 (M,one proton), 6 33 ~s, ~wo ArH): 7.30 ~s,Ph) and 7.70 (s,phenol).
MS: (mol.ion) 408 (M-) 1001o), 392, 375, 3049 287, 2869 274 and 2730 Rf = 0057 (silica gel, ether) and the corresponding cis-isomer:
dl-6a~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-[1-metn~l-2-(2-phenylethox~)etbyl]-6H-diben~o~b,d]pyran-9(8H)-one, mOp~ 127-130Co:
NMR: ~TDcSl 1020 (d,J=7Hz,methyl), 1.32 and 1.39 (s,gem dimethyl), lc6-3.8 (M)g 6025 (s, two ArH), 7.07 (s, phenol) and 7.28 (s~Ph)o MS: (mol~ion) 408 (M , 100%)9 393~ 391, 325, 316, 304, 287, 2869 274, 273 and 245.
Rf = 0.50 (silica gel, ether)O

,~, ." ~

` -: `
: `' ' . 1~ '' ' i,

9~9 rx~Ml~ 5 dl-6a(~,7,8,9,1.0,10a~-llex.~llydro-1-llydroxy-6,G-(llmcthyl-3-(1-mc~ y].~ 6~ el~zo [l~ ?y~l n-9r~-ol _ , To a solution of dl-6a~,7,10,10a~-tetrahydro-l-llydroxy-6,6-dimethyl-S 3-(l-methy]-/l-pllenyll~utyl)-6H-di~enzo[~,d]pyrall-9(3l~)-one (0.25 g.) in etllanol (200 ml.)s~irred a~ room temperature under nitrogen is added sodiun~ borollydride (0.5 g.). The reaction is stirred ~or 30 minutes and acidified wi~h 6N hy(lro-chloric acid, then diluted ~lth water (50 ml.) and extracted with ether (3 x 50 ml.). The combined ether extracts are dried over sodium sulfate and concentra-ted under vacuum to yield 0.25 g. of a mixture of 9-OH a- and ~-isomers. Column chrom~ography (s Uica gel) yields 0.087 g. of dl-6a~,7,8,9,10,10a~-hexahydro-l-hydroxy-6~6~ imethyl-3-(l-metllyl-4-phenylbutyl)-6ll-dibenzo[b~d]pyran-9 m.p. 156-158 C. after crystaJlization from ether.hexane (1:2).
. MS: (mol.ion) 394 ~nalysis Calc~d for C26l134O3: C, 79.159 ~I, 8 69 %
! ' ' Found: C, 78.94; H, 8.79 %
The follo~ing compounds are prepared by means of ~he àbove procedure from appropriate reactants of Example 4:
d~ 6a~,7,8,9,10,10a~-hexahydro-l~hydroxy-6,6-dill;ethyl-3~ methyl-5--phenylpentyl)-6H-dibenzoEb,d]pyran~9~-ol: `
NMR: ~CDCl 1.0, 1.4 (2S,69gem dimethyl), 1.2 (D,3,~-methy],J=7cps), 0.8-4.0 (M,18,remaining protons), 4.1-4.7 (M,2,phenolic-OH and alcoholic OH), 6,1, 6.2 (2D,aromatic,J=3c~s)7 7.0-7.3 (M,5,aromatic).
Analysis: Calc d for C27H36O3: C, 79.37; I, 8 %
2S Found: C, 79.58; H, 8.92 % ~^~
dl-6a ,7,8,9,10,]0a -hexahydro~l-llydrox~-6,6-dimethyl-3-(2-pllenyl-ethyl)-6H-dibenzo~b~d]pyran-9 -ol; m.p. 213-215 C.:

- .~ 43 -9 ~ t ~ (laL) 0~l 3357 cr. , ~1?~
; l~ N~ CDCl 1.0, 1.35 (25,6,gem dime~hyl)9 2.B5 (S~4,ethylene)~
3.85 (bs,l,hydroxyl-D~O overlay), 3.6 (M,l,lOaa pro~on), 0.8-3.6 (M,8,remain-ing pr~tons), 6.2 (2d, 2,aromatic), 7.2 (S,5,aromacic), 8.75 (S,l,llydroxyl-D20 overlay).
MS: ~mol-ion) 352 d:l-6a~,7,8,9,10,10atx-hexallydrD-l-hydroxy-6,~-dimet:hyl-3-(1- methyl-3 -phenylpropyl)-6H-dibenzo[b,d]pyran-9~-ol, m.p. 171 172~ C.:
N~R ~CDSCl 1.15, 1.25 (d,3,methyl)~ 1.35 (S,6,gem dimethyl), 1.6-1.95 tM,2,methylene), 2.15-2.7 (~1,3,benzylic-methinyl and methylene), 1.0-3 8 (M,lO,remaining protons and hydroxyl), 6.1, 6.25 (2d, 2,aromatic), 7.2 (S,5,aromatic)~
~nalysis: Calc'd for C25~13203: C, 78-91; Il~ 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-diben~o[b,d]pyran 9~-ol~
This product is obtained as 2 mi~ture of the diastereomeric alco-hols. The mixture, a foam, is separated into two component$ by preparative - layer chromatography on silica gel plates using 5~ methanol in chloroform as eluting solvent.
The diastereomeric mixture exhib ts maxima in the infrared region (in chloroform) at 3827 and 3333 cm l (OH).
From 60 mg. of the foam, 10 mg. of component A is isolated; R~ =
0.65. Its NL~ spectrum is provided below.
X~ ~CDCl 7.0-7.5 (M,5,aroMatic), 6.2, 6.3 (2D,2,aromatic), 1.
(D,3,~-methyl, J = 7 H~), 0.8-4.5 (M,22,remaininp protonfi).

, ` .

- ~r4- , il I
;l i g l1 Component B, 42 m~., R~ - 0.75, ls ~in~ rly i~olated. Its N~
i' spectrum is provi~ed bclo~
NMn~ DCl 7-0-7-5 (M,5,aromat:Lc), 6.1~ 6,3 (2D,2,aromatic), 1.2 (D,3,~-methyl, J = 7 I-lz), 0.~-4.$ ~M,22,rema~ning protons)D

~! dl~6a~,7,8,9,10,10a~-hexahydro-1-hydroxy-6,6-dimethy1-3-(1 meth~
4-pheno~ybutyl)-61~-clibenzo[b,d]pyran-9~-ol, m.p. 144-146 C.
" R~ = 0.31 (silica gel~ 9-ether:l-hexane) Analysis: Calc'd for C26113404: C, 76-06; ~1, 8.35 %
Found: C, 75.85; 11, 8.22 %
IO NMR: ~CDCl 6.75 (M,~,phenolic OH -~ C6ilS); 7.95 and 7.80 (BS,2, ~romati.c ~12 + H4); 4.17-1.00 (M,26,non-aromatics including 1.42 [S,Me], 1.28 and 1.17 ~D,Me~, 1.10 [S,C~13~, methylene, methine and hydroxyl).

dl-6a,~7~8~9~lo~loa~-he~ahydro-l-hydro~cy-6~6-dimethyl-3-(l-meth , 4-pheno~butyl)-611-dibenzo[b,d]pyran-9~-ol, an oil.
~f = 0.37 (silica gel, 9-ether:l-hexane) MS:~mol.ion) 41Q

dl-6a~,7,8,9,10,1ûa~-hexahydro-1-hydroxy-6~6-dimethyl-3-[1-metllyl-4-(4 pyridyl)butyl]-6H-dibenzolb,d]pyran-9~-ol:
M.P. 1iO-190 C.
Rf = 0.19 (silica gel, 9-benzene:l-methanol) - NMR: ~cDSl 8.50-8,45 ~D,2,pyridine aromatic); 7.32 (S,l"~;leDolic hydroxyl); 7.12-7.07 (D,2,pyridine aror,latic); G.26 (BS,l,benzene aromatic);
6.10 (BS,lsbenzene aromatic); 4.60-3.30 (~1,3,methine ~ 011 [singlet 3.83]);
2.80-0.80 (~1,26,alkyl, including singlet at 1.44 [Me3, doublet 1.24-1.17 [C~l3~, singlet 1.12 [Cll3~ and remaining methylene and metlline ab~orptions).

.

. . .

il ., 9~$g I dl-6aP~,7,10,:1.0aa-teLrclllydro-l-hydroxy-6,6-dimel:hyl~3-[1-meLhyl-2--(2-phenylethoxy)ethyl~-6Il-dil~enzo~b~d]pylan-9(8ll)-one Ls converted to dl-6-1~,7>8, 9,lO,lOa~-hcxahydro-l-hydroxy-6,6-dlmetllyl-3-11-met:hyl-2-(2-pllenyletlloxy)e~ y].]-6II-cIibenzo~b,d~pyran-9B-ol (a sol`id):
IR: (CHCl3) ûH 3597 and 3333 cm NMR: ~CI)Cl 1.02 (s, one methyl of gem dimethyl), 1.20 (d,J=7Hz,inethyl), 1. 37 (s ~ one met]lyl of gem dimethyl)~ l.6-4.2 (~ 6.l9 (bs, ArH)~ 6-30 (bs A
ArH) and 7.27 (s,Ph).
dl-6a~7,10,lOaB-tetrahydro-l-hydroxy-6,6-dimethyl-3-[l~methyl-2-(2-phenylethoxy~etllyl]-6H-dibenzo[b~d~pyran-9(8H)-one is converted to dl-6aB,7,8, 9,10,10a~-hexahydro-1-hydroxy-6,6-dimethyl-3-11-methy3.-2-(2-phenyle~,hoxy)-ethyl]-6II-diben~oLb,d]pyran-9g-ol, m.p. 90-105 C.
IR: (CHCl3) OH 3534 and 3279 cm NMR: ~CDCl 1.12 (M,three methyls), 1~73 (M), 2.32 (M), 2.82 (t,J=7Hz, 15 C112Ph), 3.0-4.1 (M), 6.13 (d,J=2Hz,ArH), 6.30 (d,J=211z,ArH), 6.90 (bs,phenol) and 7.25 (s,Ph).
MS: (mol.ion) 410 (M ~3 ) and 105.

~6 j Is*~
; ~ .
d~ 5-lly~ .y-2,2-dim~:hy1.-7-(~- llel~tyl~xy)-4-chrom;lnone To a solll~ion of 5$7-dihydroxy-2,2-dimethyl-4-chrom~none (18.5 g., S 87.1 ~) and potassium hydroxid~ (2.44 g.~ 43.5 1~5) in N,N-dime~hylformamide t58 ml.) is added with stirrin~ 2-bromol~ep~ane (15.77 g., 88.0 n~5). The mix-ture is heated for four days at 100 C., cooled to roo~l temperature and then added to a mixture of aqueous sodium hydroxide (110 ml. of lU), water (45 ml.) and chloroform (150 n~.). The mixture is agitated and the chloroform ayer

10 separa~ed. The aqueous layer is extracted with more chloroform (150 ml.).
The comLi~ed chloroform layers are washed with lN sodium hydroxide (2 x 100 n~l.) drièd over sodium sul~fate and concentrated ~o an oil. The unreacted 2-bromolleptane is removed by distillation and the residue pnrified by silica gel chron~atography to give 5.90 g. (22.1%) of the title product as an oil.
NMR (CDC13) ~ - 12.4 (one proton si~glet, hydroxylic), 5.7 and 6.0 (tt~o one proton doublets, J = 3 Hz., aromatic protons), 4.1-4.7 (one proton multiplet, ether mcth~ne), 2.7 (2 proton sin~let, C-3 methylene), C.7-2.0 ~(22 proton multiplet for the remaining protons, gem dimethyl appearing as a singlet at 1.5.).
In like~manner, dl -5-hydroxy-2,2-dimethyl-7-[2-(5-phenyl)pentyl-oxy]-4-chromanone is prepared by substituting 2-broD~o-5-phenylpentane for 2-bromoheptane; m.p. 83-S4 C.
IR (~Br) C = 0 1639 cm N~ C~Cl 1.3 (D,3,~-methyl, J = 7 Hz), 1.3-2.0 (~1;4, ~5 ethylene?, 1.5 (S,6,gem dimethyl), 2.7 (S,2,u-methylene), 2.5-2.9 (M, ~
benzylic methylene), 4.1-4.7 (M,l,methine), 5.9-6.1 (~,2,aromatic), 7.1-7.5 (M~59aro~atic), 12.2 (S,l,phenolic) .
MS. (mol.ion) 354 Analysis: Calc~d for (`2~ll260~ C~ 74-55; ll, 7.39 %
Found: C, 74.68; Il, 7.46 %

', ,: .

~q~z~

dl-5-hydroxy-2,2~dimethyl-7~ methyl 3-phenylpropox~)-4-chrom~none is prepared ~rom 2-bromo-4-phenylbu~Qne as an oil:
NMR: ~cDscl 1 25, 1035 (d,3,methyl), 104 lS,6,gem dimethyl), 106-2.~ ~M,2,methylene), 2.6 (S,2,benzylic met~ylene), 2.85 ~S,2,3 ~-methylene), 4.05-4.7 (M,l,methinyl)g 5.9 (6d,2,aromatic), 7,25 (S,5,aromatic).
dl-5-hydroxy-2,2-dimethyl-7-cyclohexyloxy-4-chromanone i~ prepared ~rom bromocyclohexane:
M P, 72-75C.
IR (KBr) C=O 162cm 1; OH 3390 cm MS: (mol.ion)290 NMR: ~CDCl 1-2.1 (M,lO,C5H10-cyclohe~yl), 1.4 (S,6,gem dimethyl), 2.65 ~S,2,~-methylene), 400-4~45 (M,l,cyclohexyl me~hinyl), 5.85-6005 (M,2, aromatic), 11.9 (s~hvdroxyl~ D20 overlay).

~40-, ~

:
, , 26i~ 1

11 ~
~IFXt~MPI~ 7 I -dl-5-1~ydrox~-3-lIydroxymethy]~ne-2,~-Dim~tl~yl-7-(2-IIeptyloxy)-,/ '~ 4-('llro~ none _ ¦

To the sodium llydridc obtained by washing 9.23 g. (192 J~M) o~ 50~ !
sodilml hydride in mineral oil dispersioll with pentane is added drop~Jise, over ` a 30 minute period, a solution of dl -5-hydroxy-2,2-dimethyl-7-(~- heptyloxy)- ' 4-chromanone ~5.90 g., 19.2 m~l) and ethyl ~ormate (34,9-ml., 432 mM). ~iter the addition is complete, ether (475 ~l.) is added and the resulting mix~ure~
~ refluxed. After 18 hour~, the reaction mixture is co~led to room temperature and acidified with lN hydr~chloric acid. The organic lay~r lS sep~rated and the aqueous laye~ is further extracted with ether (3 x 125 ml.). The combined ;;
etl~er extracts are dried over sodium sulfate and concentrated under vacuum to yield 6~41 g. (~100%~ of dl-s-hydrox~r-3-hydroxymethylene-2~2-dimethyl-7 ~2- heptyloxy)-4-chromanone as an oil~ .
NMR ~TCDcl3 13.4 (or.e broad singlet pro~on, hydroxylic), 11.8 ~one proton singlet, phenolic hydroxylic), 7.4 (one broad proton singlet, vinyl), 6.1, 6.0 (2 one proton doublets, J = 3Hz, 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 Examp].e 6 are converted to:
dl-5-hydroxy-3-methylene-2~2-dimethyl-7-[2~cS-phenyl)pentyloxy]-4-chromanone, an oil.
NMR: ~CDCl 1.3 (D,3,~-methyl, J = 7 Hz), 1.3-2.0 (~I,4, ethylene), 1.4 (5,6,gem dimethyl), 2.3 2.8 (hdO,T,2-benzylic methylene), 4.1-4.7 (M,l,methine), 5.8-6.0 (M,2,aromatic), 7.0-7.4 (M,6,aromatic a~d vinylic)9 10.0 (S,l,phenolic), 13.3 (bd,S,l,hydroxylic);

, ~ 49 -. . I
~ ~ .

:- ~ . I
' I ' dl-5-llydroxy~ hydroxymçt:~y.Lene-~, 2-di~ne~hy].~7- [ 2~ pil~:llyi j -~ j buty.~oxy~-4-chromanone, an oil; -!, M-5~hydroxy~3-hydroxymethylene-2,~-~llmethyl-7-cyclohexyloxy-4-', cl~ron anone;
5 . IR (~Br) C=0 1620`cm ; 0ll 3420 cm li MS: (mol.ion) 318 N~ CDCl 1.1-2.3 (M,lO,C5lll0-cyclohexyl), 1.55 (S,~,~em dimethyl), 4.1-4.5 (M,l-cyclohexyl-methinyl), 5.9-6,1 (M,2,aromatic)1 7.1~7.5(d,1,lDeth-~ inyl), 11.6 tS,l,hydroxyl, D20 overlay).

dl -5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-~1-methyl-3-phenoxypropyl)-4-chromanone, an oil (from reactant of Example 1):
Rf 2 0.42 (silica gel, 18-benæene:l-ethyl acetate) ` MS: ~mol.ion) 360 .

: , ' ' , . ' ' ' ' ' ;
. ' ` ` ,,, ~ ~ ~ 50 ~
, '.

,~1 . ', '.
I' ` !

.

i!

X~ML'I.E 8 :¦ dl-6a,7-Dilly~lro-~ ydroxy-6,6-Dimetllyl-~-(2-llcpl:yloxy)- t 6!l-DLi~enzo-irl~dJ~yran-~(o1l)-One _ To a solu~ion of d:i -5-hydroxy-3-hydroxymcthyleile-2,2-dlmetllyl-7-; (2 -hept:yloxy)-4-chromanone (5.17 g~, 15.ll mM) and methylviny] ketone (2.27 . . . ~ti~l., 27.9 n~) in methanol (23 ml.) is added ~rietl~ylamine (0.54 ml.). ~`he reaction is stir~ed for 16 hours at room temperat~lre and then dlluted with ether (250 ml.). The resulting ether solution is extracted with 10% sodium carbonate (6 x 30 ~1.), dried over sodiu~ su]fate, and concen~rated under vacuum to yield 6.11 g. of an oil. The residue is refluxed with ethanol (45 ml.) and 2N potassium hydroxide (45 ml.) for 16 hours. Thereafter, the reac tion solueion is cooled, acidified witll 6N hydrocllloric acid and extraci:ed witll dichlorome~llane (3 x 100 ml.). The organic phase is dried over sodi~lm sulfate and evaporated to yield 6.3 g. of a dark solid. The solid is tri-turated in hot ether to yleld 1.00 g. of the title compound~ m.p. 185~-189 C.;
1.26 g. of further material is obtained via silica gel chromatography of ~he mother liquor. The total yleld is 42.3%.
NMR (CDC13) ~ - 11.2 (one broad proton singlet, phenolic OH), 7.9 (one broad proton singlet, vinyl), 6.2, 5.9 (two one pro~on doublets, J ~ 3Hz, aromatic protons)9 4.6-4.0 (one proton multiplet, metlline ether), 3.0-0.6 (25 proton multiplet, remaining protons).
IR (KBr) C = 0 1600 cm 1, Analysis: Calc'd for C22H3004: C, 73.71; Il, 8.44 %
Found: C, 73.41; H, 8.37 %
W ~ CH3CH2H = 342 m~ - 2i,800).
The ~ollowing compounds are similarly prepared ~rom appropriate reactants o~ Example 7:

:
.' ' . I

. ..
, ' ~.
.

~LlDCa~2~9 dl-6a,7-dihydro-1-hydro~-6~6-dimethyl-3-~1-methyl-4-phenylbutoxy)-6H-dibenzo[b,d]pyran-9(8H)-one; mOp~ 140-168C;
CDC13 1.3 (D,2,~-methyl, J = 7 Hz), 101-203 (M,15,remainlng protons), 2.3-3.0 (bd,T,2,benzylic-methylene), 401-4,7 (M,l,methine), 5.95 (D, l,arom~tic,J = 2 Hz), 6.3 (D,l,aromatic, J = 2 Hz), 7.2-704 (M,5,aromatic), 8,0 (D,l,vinylic, J = 2 Hz)o IR: (KBr) C = 0 1563 cm Analysis: CQlc'd ~or C26H3004: c~ 76~82; X~ 7-44 %
Found: C, 76074; H, 7048 %
MS:(mol.ion) 406 dl - 6a,7-dihydro 1-hydroxy-6,6-dimethyl-3-~1-methyl-3-phenylbutoxy)-6H-dibenzo~b,d]pyran-9(8H)~one;
M,P 163C.
NMR: ~cMcl 102, 1.3 ~d,3,me~hyl), 1045 (S,6,gem dimethyl, 1.65-202 (M~2~methylene)~ 2~3-2.95 ~M,4,methylene,benzylic methylene), 4.1-4.6 ~M,l, methinyl), 509, 6.15 (2d~2,aromatic), 7.15 (S,6,aromatic, hydroxyl-D20 o~er-lay), 7.95 (6S~l,olefinic proton), MS: (mol.ion) 392 dl ~ 6~,7-dihydro-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6~-diben~o-~b,d~pyran-9(8H)-one;
M.P, 259-254C.
IR (XBr) C=O 1590 cm 1; OH 3390 cm NMR: ~DMSO 1~05-3.0 (M,15,C5~ O-cyclohexyl, 6a-methlnyl, 7-methylene, 8-~-methylene), 1.45 ~S,6,gem dimethyl), 4.0-4.4 ~M,l,methinyl), 5.8-6.1 (2d,2,aromatic), 7.1-7425 (d,l,olefinic proton), 703 (S,l,hydroxyl-D20 overlay).

i, ~

dl-6a,7-dihydro-1 hydroxy-6~6-dimethyl-3~ me~hyl-3-phonoxypr 6H-dibenzo[b9d]pyran-9(8H)-one, a light yellow solid:
M.P. 203-206C.
MS: (~Qol.ion) 392 Analysis: Calc'd ~or C25H2gO4: C, 76.50~ X~ 7-19 %
Found: C, 76.33; H, 7.12 %

~`-- 7 ! ~ ~

.' ' .: ', ~

'I - . I I
2$~9 I
! EXAMPL~ g , dl-6a~,7,10,10au-Tetrahydro~l-llydroxy~6,6-Dimethyl-3-- : _ (2-lleptyloxy)-61!~]jibenzo~b,~]pyran~9(~11)-One _ ,~
A solution of dl-6a~,7-dihydro-l-hydroxy-6,6-dimethyl-3-(2- heptyl-oxy)-6H-dibenzo[b,d]pyran-9(8H)-one (1~2 g., 3.3 mM) in tetrahydrofuran (9 ml.) is added dropwise to a rapidly stirred solution of lithium (25 mg.) in liquld ammonia (45 ml.) at -78 C. During the addition an additional 75 mg. of lithium is added to insure the blue color. After an additional 15 minutes of stirring solid a~monium chloride i9 added to discharge the blue color. The excess ammonia is allowed ~o evaporate and the residue was diluted with water (45 ml.) and acidifiea with 10% hydrochloric acid. The aqueous solution is extracted with dichloromethane (3 x 50 ml.) and the dichloromethane ex~rac~s dried over sodium sulfate and evaporated to yield 1.30 g. of a crude semi-solid which is purified via silica gel column chromatography to yield 0.614 g. (50.9%)of product, m~p. 155-158 C. after recrystallization from chloroform/hexane.
NMR (CDC13) ~ - 8.2 (one proton singlet, phenolic OH), 5.8-6.3 (2 proto`n multipl`e~, a~omatic~, 3.9-4.6 (2 proton multiplet, methine ether and C-10 equatorial), 0.3-3.2 (26 proton multiple~, remaining protons).
IR (KBr) C - O 1737 cm ~S (mle~ 360 (M~), 261 (M-99).
Analysis: Calc'd for C22H3204: C, 73.30; H, 8-95 %
Found: C, 73.05; H, 8.82 %
.
and the corresponding cis-isomer:
dl-6à~,7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(Z-heptyloxy)~
6H-dibenzo[b,d]pyran-9(8H)-one~ m.p 141-146 C. (from ether/hexane).
IR: (~r) C=O 1718 cm tmle) 360 t~l ), 261 ~I-99) - Similarly, the followi~lg compounds are prepared from products of Example 8: -., .1 ~

,, -~

i dl-6a~,7,10,10~-tetrahydr~-1-hydroxy-6,6~dimethyl-3~(1 metlly]-4-~phellylL~utoxy~-61l-dibcnY.o[b,d]pyran-9(8ll)-one; m.p. 122-125 C.
`' NMR: ~CDCl 1.3 (D,3,a-methyl,J-7}1z), 1.1-3,0 (~,16,remaining pro~ons), 2.3-3,0 tbd.T,2,benzylic methylenej, 4.1 (bd.D,l,C-10 equatorial,J=14}1z), 4.1-4.7 (~I,l,methine), 5,95 (D,l,aromatic,J=2Hz), 6.1 (D,l,aromatic,J~211z), 7.2-7.4 (~S,5,aromatic)~ 7.9 (S,l,phenolic).
IR: (KBr) C=0 1709 cm Analysis: Calc'd for C26H3204: C, 76.44; H, 7.90 %
Found: C, 76~22; H, 7.79 and the corresponding cis-isomer:
dl-6a~B,7,10,10a,3-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-metllyl-4-phenylbutoxy)-6U-dibenzo[b,d]pyran-9(8H)-one, m.p. 141-142 C.
IR: (KBr) C=0 1707 cm MS: (~ol.ion) 408 Analysis: Calc'd for C26H3204: C, 76.44; ~, 7.90 %
Found: C, 76.58; P., 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. 160 C.
NMR: ~TcMcl 1.2, 1.3 (d,2, -methyl)~ 1.4 (S,6,gem dimethyl), 1.65-2.9 QM,ll,remaining protons), 3.9-4.5 (M,2,10aa-proton,methinyl), S.9-6.1 (2d,29 ~aromatic)9 7.2 (S,5,aromatic), 7.9 (S,l,hydroxyl-D20 overlay) MS: tmol.ion) 394 dl-6a~7,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo[b,d]pyran-9(8H)-one, m.p. 215-218 C.
IR (RBr? C=0 1695 cm ; 0~l 3225 cm ~IS: (mol.ion) 344 NMR: ~CDCl 1.0-3.2 (M,18,C5H10-cyclohexyl, 6a~,7,8,10,10a~-pro~ons)9 1.5 (S,6,gem dimethyl), 3.9-4.3 (M,l,cyclohexyl-methinyl), 5.9, fi.05 (2d,29 aromatic), 8.9 (bs,l,hydroxyl-D20 overlay).

_ ., . I

dl-6a~,7,10,10a~-tetrahydro-l~hydroxy-6,6-dimethyl-3-~1-m~thyl-3-phenoxypropyl)-6H-diben~o[b,dJpyrQn-9(8H)-one.
M.P. 167 170C.
MS: (mol.ion) 394 Analysis: Calc'd for C25H3004: Cs 76-11; ~, 7-66 %
Found: C, 75,93; H, 7.63 %
NM~ ~ 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-aromatic~--including triplet centered at 3.90 for -CH2-0-, singlet at 1.48 for CH3, doublet centered at 1.27 for CH3, singlet ~t 1.13 for CH3 and 11 other methylene, methine protons).

~ -56-. .

dl-6a~,7,8,9,lO,lOa~-Hexahydro-l-Hydroxy-6 9 6-Dimethyl-3~
~2-Heptylo ~ -6H-Dibenzo[b~ ~ yran-9 ~
To a solution o~ dl-6a~,l,10,10a~-tetrahydro~l~hydroxy-6,6-dimethyl-3-(2-hept~loxy) 6-H-dibenzo~b,d]pyran-9(8H)-one (Oo60 gO, 1 66 mM) in ethanol (18 ml.), stirred at room temperature under nitroge~ i5 ~dded ~odium boro-hydride (275 mg ) The reaction i~ stirred for 30 minute~ and poured onto Q
mixture of ice (35 ml ) 10% hydrochloric acid (35 ml,) and ether ~200 ml.)O
The ether layer is separated and the agueous layer extractcd with additional ether (2 x 100 ml~). The co~bined e~her extracts are dried over ~odium 9ul-fate and evaporated to an oil, Cry~tallization ~rom hexane yielded 305 mgO
~50.3%) of product, m.pO 102-104C
NMR ~CDCl - 709-6.7 (one broad proton singlet, hydroxylic), 601-508 (two broad proton singlet, aromatic), 405-0.5 (31 proton multiplet, remaining protons).
IR (XBr) OH 3390 cm 1 Analysis: Calcld for C22H3404: C, 72089; H, 9045 %
Found: C, 72052; H, 9018 ~
Similarlyg the following are prep~red ~rom appropri~te tetrahydro ~ompounds:
dl-6a~,7,8,9,10,lOa~-hexahydro-l-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenylbutox~)-6H-dibenzo[b,d]pyran-9~-ol, an amorphous ~olid~
IR: (KBr) OH 3390 cm MS: (mol.ion) 410 NMR: 3CDC1 1.3 ~P,3,~-methyl)3 100-4 5 (M,24,remaining protons), 5.8-6.o (M,2,aromatic), 6,8-7.3 (M,5,aromatic)0 .
: . ' ' '~ ' ' .

dl-6a~,7,8,9,10910a~-hexahydro-l-hydroxy-6,6-dimethyl-3-(l-methyl-3-phenylpropDxy)-6H-dibenzo~b,d~pyran-9~-ol, an amorphoua 301i d.
MS: (molOion) 396 dl-6a~,7,8~9,10,10a~-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo[b,d~pyran-9~-ol:
M~Po 214-216Co IR (KBr) OH 3365 cm 19 3125 c~ 1 MS: (molOion) 346 ~MR: o 1.0-3.0 (M,23,C5Hlo cyclohexyl,gem dimeth~l, 7,8,9~,10 prontons), 3.5-4.15 (M~216a,~,10a~ protons), 4.35-4.7 ~M,l,cyclohexyl methinyl), 4.85-5.05 (bd,l,hydroxyl-D20 overlay), 601-6045 ~M,2,aromatic), 9.7 ~S,1, hydroxyl-D20 overlay).
dl-6a~,7,8,9,10,10a~-hexahydro-1-hyd~oxy-6,6-dimethyl-3-(1-methyl-3-phenoxypropyl)-6H-dibenzo[b,d]pyran-9~-ol.
MoPo 151-152~C.
Rf - 0.25 (silica gel9 9 ether l-hexane) MS: (mol.ion) 396 Analysis: Calc'd for C25H3204: C, 75072; H, 8014 %
Found: C, 75,79; H, 8039 %
dl-6a~,7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-d1methyl-3-(l-methyl-3-phenoxypropyl)-6H-dibenzo[b,d]pyran-9~-ol; an oil.
Rf = 0.35 (9ilica gel, 9 ether:l~hexane) MS: (molOion) 396 ~lO~9Z69 1 1~
i:.~l'llJJ,~', L~
.i ¦ . The ft~llowln~ compouncH3 are prepa~cd accor(ll-l~ to the l~roce~lures oL j l~xamples 1-5 from apl)ropriate (3~5-dihydro7cy)pllenyl coMpounds of the for~ula j ¦ 3,5-(H0)2C6113-Z-Il antl ~he appropriate acid o~ f~rmula R4R5C=CII-C0011.

~5 ~ Z W ~ j Rl R5 Z ~ W

! CH3 C113-(CH2)6 C6H5 . H H~CH2)7 ~ CH3 CH3(C~12)8 C H
,` CH3 H -CH(CH3)(C~12)5~ C H
C2}15 C2H5 -CH(CH3)~C112)6 6H5 CH3 CH3 -CH(CH3)(CH2)7- C6H5 }I H ( 3)( 2)3 4-Fci6H4 ~ ` .
CH C2H5 -C(CH3)2(CH2)3 C6H5 i, CH3 CH3 -(CH2)3~c~(cH3)- . 6 Sl .
CH3 H -CH(CH3)(CH2)2CH(C~3)- C6H5, d 2 5 -CH(CH3)(CH2)3- 6 4 C2~15 C2H5 -CH(cH3)( 2)4 4-ClC6H4 ~, CU3 CH3 -CH(C~13)(CH2)2 4-ClC6H4 , H -CH(CH3)(CH2~- 4-ClC6~4 ¦
20 ;I CH3 CH3 -CH(C~13)(CH2)- 6 4 '~ CH3 CH3 -Cl!(C~13)(CH2)2 4-pyridyl H H -(CH2)3 2-pyridyl 1 i i~ C2H5 H -(CU2)3 3-pyridyl `I CU3 CH3 -(CH2)3 4-pyridyl H C2115 -(CH2)3 . 2-piperidyl `,; H H -(C~12)3 4-piperidyl C}13 H~. (CH2)4 2-pyridyl C2U5 H ( 2)4 4-pyridyl C2H5 C2~s -(CH2)4 3-piperidyl C113 CH3 ~CU2)4 4-piperidyl ~¦ H H -(C112)2 . 6 5 ~ 11 11 ~CII(Cll3)(cll2)2 4-FC6114 .¦ ~3 -Cli(C113)(C112)2 4-clc6~1~, .
. I C2115 C2115 -Cll(C113)~C112)2 C6115 35 ~ 11 11 -al(C113~(C1~2)3- 6 5 I

I' i, 1> 1~
'I '`4~ æ _ ~ w !' C113 CH3 -C1~2CII (C113)C}32 2~pyridyl H H -CH2CII(CIl3)C112- 4-pip~ridyl ~1 (C113) Cll (C113 1 CE12- 3-pyridyl 2 5 C21~5 -CH(CH3)CII(CH3)CH2- 4-py~ldyl U El -CH(CH3)CEI(CH3)CE12- 3-piperidyl CE13 C2115 -C~l (CH3) ( CE12 ) 2 2-pyridyl '; CU3. C21l5 -CEI(CH3) (Cl 2)2 3-pyrldyl : Cll CE13 -CH(CH3) (CE12)2 4-piperidyl H H -Cll(CH3)(CH2)3- 3-pyridyl C1~3 C~3 -CH(~l3) (C 2)3 4-piperidyl CH3 CH3 -CH(CH3)CH(C2H5)CH2- 4-pyridyl C2~5 CH3 -CH(C2Hj)(CIl2)2 4-pyridyl C2H5 H CH(C2H5)(C~2)2- 2-piperidyl H H -CEI (C2E15) (CE12) 2 4-plperidyl CE-13 H -CH2CH (C2E15) C~12- 3-pyridyl CH3 CH3 -CH(C2H5~(CE12) 3 . 3-pyridyl C~3 CH~ -CH(C2E15)(CH2)3- 4-pylridyl 1~
2H5 C2H5 CH(C2H5)CH(CH3)CH2- 2-pyridyl It H H -Cll(C2H5)CH(c2Es)cH2 4-pyridyl - H H -CEI (C2H5) C~l (C2H5) CE12 2-piperidyl CH3 CH (CH ); Cll(CEI ) C6H5 CE13 C~3 ~ (CH2) 3CEI ( CH3) - 6 4 1 CH3 3 ( 2) 3 ( 3) 4-pyridyl H H (CH2) 3CH (CE13~- 6 11 .
CEl3 3 ( 2) 3 ( 3) 6 11 C113 CH3 -CH (C113) (CH2) 2c~ (cE~3) - C6H5 C~13 H -CE(CH3) (CH2)2CH(C~13)- 6 11 2E15 C2H5 -CH(cEl3~ (C~12)2CIl(CH3)- 4-piperidyl CU3 CH3 -CH(CH3)(CH2)3- C61l El H -CH (CEl3) (CH2) 2CH (C113)- C6Hll C2H5 C2H5 (CE 2) 3 6 11 CH3 }I 1 ~CH2) 4 C6Hll j CH3 C2E15 (CH2) 8 C6 11 !

, _ 60 - ' !~ , ... ' ,~ I

1~ 269 Ij R~ R5 Z ~7 !l , .
1 C113 CH3 (2) 2 C4H7 , C113 C113 2 ( 3) 2 5 9 ~. H C~13 -C112CII (C113) Cil2- C51{9 S C~13 C}13 -Cil(C113) (C112)2- C7~ll3 H H -ClltC113)CII(C113~CH2- 6 11 C113 CH3 -Cll(C~3) (Cl12)3- CSI~9 C~13 CH3 - (CH2 ) ~- C6H5 C1~3 CU3 - (C112) 2CII (C2115) C6H5 C~13 C~13 -C (Cll ) - C6H5 H CH3 -CH(CH3)C112C~I(C2H5) 6 5 H CH3 -CH (CH3) CE12- C5Hg H CH3 -CH (CH3) CH2- C3H5 C2H5 H - CH (C113) CH (CH3) - C6H
CH3 CH3 -Cll(C,H3) (C~12)4- C5H9 CH3 C113 -CN~C2115)(c1l2)2 C6U5 ';
, ` ` . ~.

61 -- - .

., , ~1 1 1, l~q~YZ69 ~ I ~
I ~XA~.~LE 12 ~1 ..
~! Compounds oE the ~ollowin~ formula are obtained from approl~riate reactants of l~reparations K and Y and ~ppropriate acids of Lormula R4R5C=CH-COOll by the procedures o~ Examples 1~4 (R4 and R5 = H, CH3 or C2115):

. O .

(alkl ) -X- ( alk2) n-~l , Reduction of the keto compounds with sodium borohydride according to tl~ procedure of Example 5 affords the corresponding 9-hydroxy compounds (both isomers formed; the ~-form predominates). The sulfoxide and sulfon~.
compounds of Examples 15 and 16 are reduced in like manner to the corresponding 9-hydroxy co~unds.

.

, " ~ 62 - , ' ''' ' ~ I

~ XAMP~3 13 dl~ ydroxy-2,2-dimeth~1-7~ m~thyl-4-phen~butox ~ 4-ohromanone A mixture o~ 5-phenyl~2-pentanol (16,4 g " 100 mM)~ trlethylamine (28 mlO, 200 mM) and ~ry tetrahydrofuran ~80 ml.) under a nitroge~ a~mosphere is cooled in an ice/water bathO Methanesulfonyl chloride ~8 5 mlO, 110 mM) in dry tetrahydrofuran (20 mlO ) i9 added dropwise at such a rate that the tempera-ture holds essentially constantO The mixture is allowed to warm to room tem-perature and is then filtered to remove triethylamine hydrochlorideO The filter cake is washed with dry tetrahydrofuran and the combined wash and fil-trate evaporated under reduced pressure to give the product as an oilO Theoil is dissolved in chloroform (100 ml,) and the solution washed with water (2 x 100 ml.) and then with saturated brine (1 x 20 mlO)0 Evaporation of the solvent affords 2107 gO (89.7%) 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-chromanone (2 08 g" 10 mM), potassium carbonate (2076 gO~ 20mM)g ~-dimethylformamide (10 mlO) and 5-phenyl-2-pentanol mesylate (20 6IL gO~ 11 mM)~ under a nitrogen atmosphere, is heated to 80-82Co in an oil bath for 1075 hoursO The mixture ~9 cooled to room temperature and then poured into ice/water (100 mlO)o The aqueou~
solution is extracted wlth ethyl acetate (2 x 25 mlO) and the combined ex-tracts washed successively with water (3 x 25 mlO) and saturated brine (1 x 25 ml.). The extract iB then dried (MgS04), decolorized with charcoal and evaporated to give the product as an oil which crystallizes upon seeding with pure product; mOpO 83-84Co Yield = quantitativeO
In like manner, the following compounds are prepared from ~ppropriate 2,2-R4R5-5,7-dihydroxy-4-chromanone~ and appropriate alkanolsO The necessary alkanol reactants not previously described in the literature are prepared ~~rom appropriate aldehydes or ketones via the Witting reaction of Preparation Go 2~
~H

R4~ J ~
O- ( Qlk2 )-W

V ~ C) V
~;
~-i r~ ~ ~ rl r~ r~ r~ ~
~ ~ ~ h h ~t P~ h ~ '~ h ~t r~ r~ ~r~
h h h P~ P~ ~D c> ~) h h h p~ S~ h P~ ~ v .r ri V ~ h p~ p~ ~ V

N ~1 NC~J N ~ N
~C~i ~ N N ~~:CN ~N ~

~ ~ P ~ ~ tC v v~ P r r ~P ~

~h ~h rchi h ~ h h V V C~ V V V V V V V V V V C~l N N N

V ~
P: V N
:r~ V r v ^ v r _ ~-- ~ ~ V
N ~i ~N ~J ~ N ~
r~~C i ~`~ ~N V N ~ t~l N ~C i ~C~I CU
~ r v ~: ~ c~i r e~ -- v ~
r v ~ VN ~r~ V N _ 1 Vi ~- ~) CJ~ Cr~ ) t~ N C~l V V C~ N V V V N CU CU V CU N V V CU C\i CU
N N ~ r -- N N r x ~ --~ r tc: -- N P~
P~ v P~ ~ ~ v v v r v v x r v v v V V ~ _ V V V _ _, V _ _ V V

I ~ ~ r'^ rU' ~ ~ ~ ~ rU' u~ ~ C~l CU ~ ~: ~ r cu r ~
K V V P~ r v c> v ~ v ~ ~ ~ v ~ v v v r j r v ~ cu ~ v P~ ~ P VN v ~ r :~ cu ~ 64--.
:

o o c\l ,~
~1 ~ ~ U ~) ~ ~ x ~ x ~D

C\l C~

~u ~ ~ ~ _ ~ ~ ~ ~d ^
I ' ' ' m ~ c, ~ m ~:

U~
~-~; v v p~ ~ ~ ~ v~ ~ ~:

x ~ v V V ~ ~ ~ x~
v c~ v v ~ v ~ ~ v~ ~ ~ ~D xL^ ~ pL^ ~~
3: ~It~ Lr~ V 11~ ~1 ~1~ ~Lt~ ~1~ ~ ~ ~0~ ~0~ ~1 prl ~ V V C) V V

I v ~ v v V p:: V ~:c V 1:1 V td v v ~ I v v v tq v c~

~1 ~ ~ VW P ~d C I WN t~r ~r1 W~ W fr~ C~ V V V V V V V

.

-` ,.

.. .. . .
- .
.
.

EXAMP~E ll~
The products o~ Examples 13 are converted to compounds having the formula below b~ the procedures of Examples 1-5.
OH

9~\' R4 ~ ¦ O ¦
~ ~ ~ -~lk2)-W

:. ,;

~ $Z6~
EXhMPLE 15 dl-6a~,7,10,10aa-Tetrah~dro-l-hydroxy-6,6-dimethyl-3~
meth~l-3~phenylsulfinylprop~1)-6H-di~ .o~b,d]p~ 9(8H)-one Equimolar amcunts o~ m~chloroperbenZoiC acid and dl~6a~,7,10,10a~-tetrahydro-l-hydroxy-6~6-dimethyl-3-~l-methyl-3-phenslthiopropyi)6H-dibenzo-[b,d]pyran-~8H)-one are reacted together in a mixture of chloroform and ace-tic acid (2-1) at room temperature for one hour. The organic phase is washed with water, dried ~MgS04) and evaporated to drynes~ to give the productO
In like manner the thio ethers of Example 12 are oxidiæed to the corresponding sulfoxide~ of formula f~ O~I

L ~ ~al~l)-S-~al~2)-W

' :~

~%~
:ISXAMP~E 16 dl-6a~,7,10~10aa-Tetrahyaro-l~hydroxy-6~6-dimethyl-3-(1-methyl-3-phen~lsul~onylpropyl)-6H-di n~ ,d3p~ran-9~-one The procedure o~ Example 15 is repeated bUt u6ing t~o equivalents S o~ m-chloroperbenzoic acid as oxidi~ing agent per mole of thio ether reactantO
Similarly, the thio ethers of Example 12 ~rc con~erted to their cor-respondine sulfonyl derivatives to give compounds o~ the ~ormula:

~
¦~ OH

~alkl )- 1_ ~alk2 )-W

. , .

$~

Trans 3-~l~methyl-4-phenylbutyl~-6Q,7,8,10Q-tetrahydro-6,6,9-trimeth~l - H-d;be~o~d~pyra~ 3l To a stirred solution Of (~) p-metha~e-2,8-dien-1-ol ~4.9 gO~ 0 0032 mole) and 5-(1-methy1-4-phenylbutyl)-resorcinol ~8.2 g., 00032 mole) in dry methylene chloride (200 ml.) is added anhydroua magne~ium sulfate ~4 gO~
0.332 mole)O The mixture is stirred under a nitrogen atmosphere and cooled to 0C. Freshly distilled boron trifluoride etherate ~2 mlO, 0.016 mole) i9 then added dropwise over a 5 minute periodD ~he reaction mixture is stirred for 1.5 hours at 0CO and anhydrous sodium bicarbonate (10 g., 0.1119 mole) i8 added. Stirring is continued until the dark color f~de~O ~he reaction mlxture is filtered and evaporated to give 1107 g, ~9306~) of a resinous prod-uct. The product is purified via column chromatogra~hy on an activated mag-neaium silicate, available from M C & B ManufQcturing Chemists, 2909 Highland AYenue, Cincinnati, Ohio, under the~trademark "Flarisii", to ~i~e 3.4 gO
(27~) of the desired product as a mixture of optically active diasteriomersO*
~MR ~ CDCl lOl~S,3,Cl-methyl3, 103, 1045 ~2S,6,gem dimethyls), 1.75 ¢S,3,Cg-methyl), 007-300 ~M,12,remaining protons), 300-306 (M,l,Clo -proton), 5005 (S,l,hydroxyl,D20 overlay, 601 (S,l,C4-proton, aromatic)a 604 ~M,2~C2-pro-ton,aromatic~C10-proton), 701-705 ~M,5,aromatlc protons)O
MS: ~molOion) 390 It is converted to the optically acti~e 6a~,7,10,10a~-tetrahydro-1-hydroxy-3-~ methyl-4-phenylbutyl)-6,6-dimethyl-6H-dibenZo[b,d]pyran-9(8E)-one diasteriomer5 according to the procedure of Wildes et al., JO ~. ChemO, 36, 721-3 ~1971) -*~]2d5 ~C = 1.0, C~C13) = 100~8o ~XAMP~ 18 dl-6aB,7,10,10aa-tetrahyaro~ 4 morpholi~obu~yryloxy)-6~6-dimethyl-3-~1-methyl-4-phe~y1bl~yl~-6H-diben~o~b,d~ pyran-~8H)-one h~dro~o~lde -To a stirred solution of dl-6a~,7,10,10a~-tetr~hydro-1-hydroxy-6,6-dimethyl-3-~1-methyl-l~-phenylbutyl)-6H-dibenzo[b,d~pyran-9(8H)-one (Oo52 e, 1028 mM) in dry methylene chloride ~25 ml,) is added 4-morphoIinobutyric acid hydrochloride ~00268 g., 1028 mM)0 ~he mixture îs stirred at room temperature under a nitrogen atmosphereO A 0.1 M solution of dicyclohexylcarbodiimide in methylene-chlori~e~ 2~8~ 9 l~28 mM) is added d~opwise and the:mixture stirred for 24 hours. It is filtered and evaporated to give the title product, which is purified by column chromatography on silica gel.

,, . :

EX~MPLE 19 The procedure of Ega~ple 18 is repeated but U~ing the appropriate dl-6a3,7,10,10ac~-tetrahydro-6,6-RIlR5-3-~Z-W)-6X-dibenzotb,d]pyran-9~8H)-ones of Ex~mples 4, 9 and those produced as penulti~ate products in the procedures of Examples 11, 12 and 14; and the appropriate alkanolc acid or acid of ~ormula HOOC-~CH2)p-NR2R3.HCl to produce estera of the ~ormula ~1 ~Z-W

wherein R4; R5, Z and ~ are as defined in Ex~mple~ 4, 9, 11, 12 and 14 and R
is R *

: COCH3 -CO(CH2)3NHC4Hg -COCH2CH3 -CO(CH2)2N~C4H9)2 -CO(CH2)3CH3 -COCH2-piperidino -COCH2NH2 -COCH2-pyrrolo ( H2)2 2 -COCH2-~N-methyl)piperidino -CO(CH2)4NX2 -CO~CH2)2-rnorpholi~O
-COCH2N(CH3)2 -CO~CH2)2-~-butyl)piperidino -CO~CH2)2N(C2H5)2 -CO(CH2)3-pyrroliaino CO(CH2)4NHC~13 -CO(C2H~ N-ethyl)piperidino -CONH2 -CO-piperidino -CON(CH3)2 -CO-(N-methyl)p~peridino -CON(C4Hg)2 -CO-morpholino -CON(C2H5) -CO-pyrrolo *Basic esters are obtained as their hydro~hlorlde salt~.
Careful neutrali~ation with sodi~m hydroxide afford~
the free ester.

. .

~AM
dl-6a,B,7~8~g,10,10au-Hexahydro~ 4~mc>rpholinobu~yrylo~
6~6-dimethyl-3-(l-methyl-4-phenyl~ut~ 6H-dibenzo~b~d]p~Jran ol hydro~n~
~he title product o~ E~ample 5 i~ e~terified according to the proce-dure o~ Example 18 to produce th~ abo~e-n~med e~tQr s~lt.
In like manner, the remaining products of ExQmple 5 ~nd those of E~mples 10-12 and 14 are converted to. esters having the formul~ shown belo~
therein R4~ R5, Z and W are as de~i.ned in said Example3 and Rl ha9 the v~lues given below:
O ~.

~Z-W
R~

-COCX3 -COC~2~pyrro1o CO ( CH2 ) 2 H3 -COC112-pyrroli dino C0 (CE2 ) 3C~I3 -COCH2-morpholino -COCH2NH2 -COCH2-(N-methyl)pipera&ino -COCH2N(CH3)2 -COCH2-~N~butyl)piperazino -CO(CX2)2NHCH3 -CO¢CH2)2-piparidino -C0 (CH2 ) 2N( i~C3H7 ) 2 -C0 ( CH2 ) 2 ~N-i ~opropyl)piper~ino 20 . -COCH2~(C4X9)2 -C0(C}~2)3-pYrro1idin -CO(CH2)4~(C2X5)2 -co~cH2)4-~N-ethyl)piperazino -CONH2 -CO piperidino -CON(CH3)2 -C0-(~-methyl)piper~zino -CONIIC2H5 -C0-morpholino C N( 4 9 )2 -C0-pyrrolo ~ . .... .
~,. 72-,.~

1~a9;~
EXAMP~E 21 dl-6a,7-Dihydro-l-h~droxy-6,6-dim~thyl-3-(1-methyl-4-hen~lbutyl)-~H-di~en~b~b~d~ra~-~(8H)-one A) dl-Ethyl 5-Hydrox~-4-~thyl-7-(1-methyl-4-phenylbutyl)coumarin-3-ro ionate -P P _ . . _, _. . . ~
A mixture o~ 2-~3,5-dihydro~yphenyl)-5-phenylpentane (33 g., 0.13 M), (Preparation C) diethyl ~-acetoglutarate (32.2 g., 0.14 M) and pho3phorous oxychloride C20.g., 0.13 M), protected from atmospheric moisture9 is stirred at room temperature. A~ter 1~ days~ the mixture i8 di~solv~d in chloroform, washed three ti~es with ~ater, dried ~a2S04)9 and evapor~ted. The residue is subJected to silica gel chromatography ~eluent~ - 9 bQn~ene:l ether) to yield 22 g. of the desired ester, m~p. 58-70C. from hexane. Further recrystalli-zation from ethyl acetate/hexane affords an analytic~1 sample: m.p. 78-85Co Analysis: Calc'd for C26H3005: C, 73.91; H, 7.16 %
Found: C, 730 82; H, 7~13 %
MS: (mol,ion) 422 B) dl-7 ,10-Dihydro-l-hydroxy-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b~d]-~ran-6 9(8E)-dione -To the sodium hydride powder obtained by wa~hing 10~0 g. (0.21 mole) of 50~ sodium hydride in mineral oil dispersion with dry hexane is added 20.6 g. (0.049 mole) of the ester of part A o~ thia ex~mple and the two powders are mixed thoroughly. The reaction flask is cooled to 1517C. 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 refreigerator. 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 a~ needed to keep the mixture cold. The slurry thu~ produced i8 stirred for an additional hour t Zf~9 and is then decanted. ~he residual gum i~ heated on the steam bath with excess concentrated sodium bicarbonate ~olution and, while still warm, the resultant solid is filteredO The ~ilter cake is waRhed with bicarbon~te solution and water and recrystallized from ethyl acetate/hexane to give 4.5 g. of cyclized product, m,p, 163-164Co Further purification i5 achieved by recrystalliza-tion from methanol, m.pO 166-167Co Anal~sis CR1c'd for C24~244 C~ 76 57; ~ 6 43 %
Found: C, 7~.5~; H, 6,56 MS: ~mol.ion) 376 C) dl-7,8,9,10-Tetrahydro-l-hydroxy-3-~1-methyl-4-phenylbutyl)~piro-~6H-dibenzo~b d]~Yran-9 2'- El ~ 3 ~ ] dioXoIan}-6-one A solution o~ 0.031 mole of the cycli~ed product of part B of this ex~mple in ben~ene (500 mlO) containing ethylene elycol ~10 ml.) and p-toluene-sulfoni. acid ~10 mgO) is he~ted overnight under reflux ~Dean-Stark trap)0 The solution is cooled, poured into water containing exces~ sodium bicarbonate and the organic phase separated, dried (Na2S04) and evaporated to yleld the desired ketalO
D) dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-~1-methyl-4-phenylbutyl)-6H-dibenzo~b,d~yran-g~8H)-o~è _ _ _ _ _ A slurry of Oolf5 mole of the above produced ket~l in ether ~105 liters) is added over 90 minute~ to the Grignard reagent prepared from magnesi~
um ~44,6 g., 1.84 e-atoms) and methyl iodidQ ~110 mlO, 251 g., 1077 moles) in ether (108 liters~, After re~luxing for 2 days the reaction i~ treated care-fully with 1~ hydrochloric acid ~200 ml ), and then with 6N hydrochloric acid (74 mlO). The mixture i9 stirred vi~orously for 1 hour and then the ether layer washed once with water and once with 5% sodium bicarbonQ~eO The ether layer i.6 dried (Na2S04) and concentrated to yield the desired unsaturated ketone. If desired, it is puri.fied by crystalli~ation snd/or column chroma tography (see Examples 3 and ô)O

~ -7~-. ~ . ~, 31i~ 72~
In llke manner, the remaining 1-~2-W-substituted)-3,3-dinYdroxy-benæenes o~ Preparation C ~nd thos~ OI Prepar~tion3 D, E, K, M9 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 E~MP~E 22 dl-6a~,7,10,lOa~-Tetrah~flro-1-hydroxy-6,6-dimethYl-~
methyl-4-phenlbutylo~]~6H-dlben~o~b,d]pyran-9~8~)-one, E~ Ké~al A solution o~ dl-6a~,f,10,10a~-tetrahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbutyloxy)-6H-dibenzo~b,d~pyran-9~8H)-one ~60 mg., O.145 mM), ethylene glycol (0.5 ml. )9 benzene ~10 ml.) and ~ cry3tal of p-toluenesulfonic acid is heated at re~lux ~or three hours. Th~ reaction mixtUre is then cooled and concentrated. The concentrate i~ ~haken u~ in chloroform and the chloro-form phase washed first Nith sodium bicarbonate and then with w~ter. It is then dried (MgS04) and concentrated to gave the ketal as a light ~rown oil ~63 me-)-Repetition of this procedure but using propylene glycol~ trimethyl-ene glycol and tetramethylene glycol, in plaoe of ethylene glycol, sfforda the corresponding ketals.
2~ ~y means of this procedure the ketone product~ of Examples 3, 4, 8, 9, 11, 12, 14-16, 18, 19 and 21 ~re converted to the correspon~ing ethylene, trimethylene and tet~ramethylene ketal~.

-75~

'' , X.~ 23 i d~ 2,2-dim~,tll l t2-hepty]mercap~o)~ hromanonc To a s~lution of 5-hydroxy-7-mercapto-2,2~dimQthyl-4-chromanone ~ (19.7 ~., 87.1 n~) and potassium hydroxide (2.44 g., 43,5 ~) in N,N-dimethyl-5 ,' formamide (58 ml.) is added with stirring 2-Dromoheptane (15,77 g., 88,0 mM).
e mixture is heated for fQur days at 100 C., cooled`to room temperature and then added to a maxture of aqueous sodium hydr~xide (110 ml. oE lN), water (45 ml.) and chloroform (150 ml.). The mixture is agitat~d, the phases ,~ separated and the aqueous layer extracted with more cllloroform (150 ml~).
The combined chl'orof~rm layers are washed with lN sodium hydroxide (2 x 100 ml.) dried over sodium sulfate and c~ncentrated to an oil. The unreacted 2-bromoheptane is removed by distillation and the residue purified by silica gel chromztography to ~ive the title product. I
The following rompounds are similarly prepa~ed from appropriate 'lS reactants of the formula Br-(alk2)n-W from the appropriate 5-hydro~-7-mer-capto-2,2-R4R5-substitu~ed-~t-chromallone: , , , O OH

R5 ~ ~ ~ 5-(alk2) -a `, 4 5 n (alk2) W

" ~ CH 1 -C~(CH3)(C~I2)4 C~3 , C215 ~C2H5 1 -Cll(CH3)(CH2)4- ~CH3 20 ~ CH3 ,CH3 1 -CH(CU3)(CH2)3- C~HS
Il 'CH3 1 -C}l(CH3)(CH2)3- C6U5 ; , CH3 , CH3 - 1 -CH(CH3)(CH2)2- C6H5 CH ~H3 1 -C~C~13)(C~I2)3 4 pyridyl , . H H 1 -C~ 3~(c}~2)3- 4-pyridyl .

, .

" 1~ 1 .

~ 4 r~S n (~k2) W
I ~ , _. ,~
Ii Cll3 CH3 1 C112 C6H5 i CH3 C~13 1 (CH2)4 C6 5 " CH3 C21~5 1. (C1~2)7 C~H5 ~ 3 CH3 1 -C~C~3)2(C112)5 CH3 ' 3 ( 3~2( 2)5 3 ~, CH CH3 1 Cll(C113)CII(C113)(CH2)4 C~13 H CH3 1 -CH(CH3)CII(CIi3)(CH2)4- CH3 C}13 ~3 1 -(CH2?3- 3-pyridyl C~13 ll 1 -(CH2)3- 4-pyridyl H CH3 1 -CH(CH3)C112- 2-pyridyl H H 1 ( 2)2 4-pyridyl C2H5 C~3 ( 3)(2)2 4-piperidyl ,CH3 CH3 0 -- C6H5 H ~ O --- 4--FC6H4 2 5 4-ClC6114 C2H5 C2H5 0 -- C~H5 ~ CH3 - CH3 o -- .C3Hs 20 . H H 0 -- C3H5 CH3 H 0 ~_ C4H~
C~13 CH3 0 -- C5H~
C~3 H 0 _- 7 13 CH3 ~13 ~ O - 2-(C6H5)C3H4 CH3 3 2-~C6H5)C5H8 j, CH3 3 4~(C6Hs)C6H10 CH3 CH3 0 -- ( 6 5~ 7 12 H H 0 -- . 4 (C6~l5)c6HlO
CH3 CH3 0 -- 4-pyridyl 30 ~ CH3 C~13 0 ~ piperidyl ~ ~ .
.
-~

~, ~ 77 - I

, .

.
Il .

~z~

dl-6a~7 310, lOaa-Tetrahy~ro-l~acetoxy-6,6-dimethyl-3~ ethyl-o~ ~ ra~-9~8~
Pyridine (15 ml.), acetic anhydride (15 ml. ~ and dl-6a~,7,10,10aa-tetrahydro-1-hydro~y~6,6-dimethyl-3-~1-methyl-4-phenylbutoxy)-6H-dibenzo[b,d]-pyran-9(8H)-one (4.o6 g.) are combined at 0C and the mixture stirred for a half-hour at 0C. The reaction mi~ture is poured onto ice/water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate ~2 x 100 ml.), the extracts com~ined and washed with brine. The extract is then dried ~MgS04) and evaporated to give a colorleæ~ oil which i9 crystal-lized from ether-pentane. Yield = 1.69 g.; m.p. 95-96C.
Ana~ysis Calc'd for C28~345 C~ 74-64; ~ 61 %
Found C, 74,55; H, 7.59 %
Evaporation of the mother liquor gives a second cryætalline fraction which is digested in hexane. Yield ~ 1.74 g.; m.p~ 94-96C.
By means of this procedure but using the appropriate alka~oic acid anhydride and the appropriate dl-6a~,7,10,10a~-tetr~h~dro-6,6-R4,R5-3-~Z-W)-6H-dibenzo[b,d~pyran-9(8H)-ones of Ex~mples 4, 9, 11, 12 and 14 aæ reactants, a~ords the propionyloxy, butyryloxy and valeryloxy esters thereof.
Reduction of the 9-keto group of the thus-produced mono esters accord-ing to the procedure of Example 5 afford~ the corre0ponding 9~hydroxy der;va-tives. A mixture o~ the 9~- and 9~ omers is produced.

... ,.,. . ::: ,........... : .

ta$~

Mp7.r.,~r~
., dl-6a~,7,8,9,10,10a(~.-llexahydro-1,9-diacetoxy-6,6-dimetllyl-., 3~ metllyl ~ lenyll~u~yl)-GIl-dibe ~ llpyran A solution of di-6a~,7,o,9,10,10a~-hexahydro-1-hydroxy-6,6-dimethyl-3-(1-methyl-4-phenylbl~tyl)-6}1-diben~o~b,d]pyran-9~-ol ~2.0 g.) in pyridine ~20 ml.) is treated at 10 C. with acetic anhydrice (20 ml.) and the mixture stirred for 18 hours under nitrogen. The reaction mixture ls worked up according to the procedure of Example 24.
In li~e manner, the l,9-dillydroxy compsunds of Examples 5, 10-12, 14 and 15 are converted to their diacetoxy, dipropionyloxy, dibutyryloxy and divaleryloxy esters.

, .j ~

. . ~

~9~

~XAMP~E 26 dl-6a~7~lo~loa~-Tetrahydro~ 4-N-piperidyl-butyroxy)-6~6-dimethyl-3-~2-(5-ph~nyl)pentyloxy~-6H-dibenzo~b,d]pyran-9~8H)-o~ie hydro~o~ide _ _ S A mixture o~ dl-6a3,7~10,10a~-tetYahydro-l-hydroxY-6,6-dimethyl-3-~2- ~5-phenyl)pentylo~ 6H-dlbenzo~,d]p~ran-9(8H)-one ~1.26 g., 3.08 mmoles), 4-N-piperidyl butyric acid hydrochloride ~00639 g., 3.08 ~noles) and dicyclo-hexylcarbodiimide (o.690 g., 3.39 mmoles) in dry dichloromsthane ~3.5 ml.) is stirred at 20C. ~or 18 hours. ~he reaction i8 cooled to 0C., ~tirred for a half-hour and ~iltered. The filtrate is evaporated to an oil which is washed with ether (3 :~) and evaporated to yield 1.78 g. ~97%) of dl-6aB,7,10, lOao~-tetrahydro-l-~-N-piperidyl-butyroxy)-6,6-dimethyl-3-12-~5-phQnyl)pentyl-oxy~-6H-dibenzo[b,d]pyran-9~8H)-one hydrochloride as a solid, white ~oram.
IR~ Br) NH 3 2667~ 2564, C ~ 0 1779 and 1730 cm MS ~mol.ion): ~M ~-HCl), 407, 262, 247, 154, 98 and 91o :~ . -80-. : , . : , : ~., . ;, , ;:: : ' ; ~iCl~jAltJ~'l`lON A
~,-'' '' . _ I
2.-Eror~p!lenylpent~ne To phosphorous pentabromide, prepared by addition of bromine (9.0 g.) in methylene ch]oride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0 C., is added 5-phenyl-2-pentanol (8.2 g.) ; in methylene chloride at 0 C. The mixture is stirred for 2.5 hours at 0 C.
and is then allowed to warn~ to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chlori~e layer separated.
The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
NMR: ~CDCl 1.6 (D, 3, methyl, J = 7Hz),l~1.6-200 (M, 4, ethylene)~
2.3-3.0 (bd, T, 2, benzylic-methylene), 3.7-4.2 1, methine), 6.9-7.4 (~I, 5, aromatic).

_ 81 - :

. ~ , ! i I

PREPAP~IOE B
~=
A solution of l-bromopropylbenzene (5107 gO) in ether (23~1 ml~) is added dropwise over a 2-hour period to a refluxing mixtUre of magnesium (7032 g.) in ether (78 mlO). The reaction mixture iB re~luxed ~or 30 minutes long-er and then a solution o~ 3,5-dimethoxy-acetophenone (50 g.) in ether (78 mlO) i8 added drop~ise and heated to reflux ~or 105 hours. Ihe reaction is quenched by addition o~ saturated ammoni~m chloride (234 mlO), the ether layer is separated and the aqueous phase extracted with ether (3 x 200 ml~)O
The combined ether extracts are dried over magneaium sul~ate and concentrated under vacuum to yield ôl g. o~ an oilO Forty grams of the oil is hydrogenated in a mixture containing ethanol ~300 mlO), concentrated hydrochloric acid (2 ~.) and 5% palladium-on-carbon (5 g~)O The catalyst is filtered off and the e~hanol removed-~nder ~acu~O me resi`due is di~t~iled'un~r'''vac`ùum yielding 28 g. o~ 2-(3,5-dimethoxyphenyl)-5-phenylpentane (b.po 0.125 mm.
154-159C.).
~ MR: ~CDCl 1.25 (d,3~a-CH3), 103-201 (M,4,ethylene)9 202-209 (Mg 3,benzylic-methylene, methinyl), 3045 (S,6,methoxyl), 602-607 (M,3,aromatic)g 702 (S,5,aromatic).

-;j -82-2~

IO~ C

2-(3,5 Di~dr~yJL_~y~ y~ e A mixture of 2-~3,5-~imethoxyphenyl)-5-pllenylpen~ane (22 ~.) and pyridine hydrochloride (9bl g.) under nitrogen is heated ~o ]90 C. for 2 hours with vigorous stirring. lhe reaction mixture is cooled, dissolved in 6ll hydrochloric acid (200 ml.) and dilu~ed wlth water to 600 ml. The aqueous solution is extrac~ed with ethyl acetate (4 x 100 ml.), the ethyl ace~ate extracts dried over sodium sulfate and concen~rated und~r vacuum to y:ield 24 ~. of crude product. The product is purified by silica gel chrornatography to yield 19.2 g. of 2-(3,5-dihyd~oxyphenyl)-5-phenylpentane as an oil.
NMR: ~CDCl 1.1 (d,3,~-methyl), 1.35-1.65 (M"4,ethylene), 2.2-2.8 (M,3,be~zylic-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 Preparations B andC, the compounds ~sted below are prepared by substituting the appropriate l-bromoalkylbenzene for l-bromopropylbenzene:
2-(3,5-(dihydroxyphenyl)-6-phenylhexane--NM~: &CDCl 1.1 (D,3,~-methyl, J-7 cps), 1.0-1.9 [M,6,~CH2(CP2)3-CH(CH3)-Ar], 2.2-2.8 (M,3,benzylic methylene, methinyl), 6.0 tbd.S.,2,phenolic OH), 6.2-6.4(M,3,aromatic), 7.1-7.4(M,5,aromatic).
1-(3,5-dihydroxyphenyl)-2-pheny~ethane--m p.: 76-77 C. ~ .
2-~3,5-dihydroxyphenyl-4-phenylbutane (an oil)--NMR: ~TMCl 1.1, 1.25 (d,2,methyl), 1.45-2.0 (M,2,methylene), 2,15-2.7 (M,3,l~enzylic-methylene, methinyl), 6.3 (S,3,aromatic), 6.85 (S,2, hydroxyl-D20 overlay), 7.l (S,5, aromatic).

. ~

.

2~

The ~ollowing compounds are prepared in like manner ~rom the appropriate alcohol and 3,5-dimethoxy~nzaldehyde or 3,5-dimethoxyaceto-phenone by the methods o~ Preparations A, B and C:
OH

HO ~ z_~
Z W
_ ~ 3) 2 C5Hg CH(CH3)(CH2)2 C5Hg CH(CH3)CH2 C3H5 CH(CH3)CH(CX3) C6H
CHccH3)(cH2)3 C6H
CXCCE3)(CH2)4 C5Hg CHccH3)(cH2)5 C6 ~ 1 CHCc2H5)(cH2)2 C6~ 1 ( 2)3 ~5Hg CH(C2H5)(CH2)3 C6H5 C(CH3)2 ~6H5 (CH2)4 C6H5 (CH2 )2CH( C2H5 ) C6H5 CH~CH3) ~2 ( 2 5) C6H5 `~

32~!g PREPARA~ION D_ l-t3~5-Dih~d~o~ n~j-2-methyl-4-phenylbutQne A solution o~ n-butyl lithi~m ~29 mlO of 2.2M) is ~dded dropwi~e to 3,5-dimethoxybenzyl triphenylphosphonium bromide ~31,5 g.) in tetrahydrofuran (200 ml.) with stirring and the re~ulting deep r~d ~olution i6 ~tirred for one-hal~ hour. Benzyl acetone ~9.4 g.) is added dropwi3e ~nd the reaction mixture stirred ~or 12 hours. It i9 then adJusted to pH 7 by ~ddition of acetic acid and concentrated under reduced pre3sure. The residue is extracted with methylene chloride and the extract evaporated to ~iv~ crude 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene aa an oil. It i~ purified by chromatography on silica gel ~400 g.) a~d ~lution with benzene. Yield: 10 g.
an oil.
NMR: ~CDCl 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-me~hyl-4-phenyl-1-butene ~9.4 g.) thus prepared is dissolved in ethanol ~250 ml ) and cat~lyticQlly hydro~enated at 45 p.3.i, in the pre~ence of p~lladtum-on-charcoal (1 g, of 10%) and ~on-centrated hydrochloric acid ~1 ml.). Yield: 9.4 g. o~ 1-(3,5-dimethoxyphenyl)-2-methyl~4-phenylbutane as an oil.
NMR: ~CDCl -9 (d,3), 1.35-1.95 ~M,3)9 2.2-2,9 ~M,~), 3.75 (S,6~, 6.35 (S~3), 7.25 ~ (S,5).
It i5 demethyla~ed aocording to the procedure o~ Preparation C to ~i~e 1-~3,5-dihydro~yphenyl)~2-~othyl-4-phenYlbUtane.
Ihe 3,5-dimethoxyben~yl triphenylphosphonium bromide is prepared by re~luxing a mixture o~ 3,5-dimethox~ben~yl bromide ~12 ~.) and triphenyl-phosphine ~14.2 g.) in acetonitrile (200 ml,) ~or one hour. The reaction mixture i8 then cooled and the crystalline produot rscovered by ~iltration, ~ashed with ether and dried ~20 g.); m.p 269~27~C.

~ ; -85-.. ; ' :- : . .. . ..

.
. ~ I

z~

PRE~ARATION E

To a solution o~ the Grlgnard reagent prepared ~rom 2-phenylbromo-ethane (5.5 g.), magnesium ~o.8 g. ) and dry ether (60 ml.) is added a solution of 2-methyl-2-(3,5-dimethoxyphenyl)propionitrile ~2 75 gO) in dry ether (20 mlO)O
The ether is distilled of~ and replaced by dry ~enzene ~50 mlO) and the mix-ture re~luxed ~`or 48 hours. It i5 then decompoaed by care~ul treatment with dilute sul~uric acid and heated on a steam bath ~or one hourO The mixture is then extracted ~itb ether, the e~tract dried ~MgS04) and concentrated to an oil. Distillation of the oil in ~acuo Hffords 2-methyl-2-¢3,5 dimethoxyphen-yl3-5-phenyl-3-pentanone; bop~ 168 C~/0~2 mm. (Yield: 2.32 g., 60%) The thus-produced pentanone ~58 ~.) i3 dissolved in ethHnol (400 ml.) and treated with sodium borohydride ~10. g.) at room temperature. The reaction mixture is stirred ~or 12 hours and i~ then cooled ~nd neutralized with 6N hydrochloric acid. The ethanol is r~moved under reduced pressure and the residue extracted with etherO ~he axtract i~ drlsd (M~S04) and con-centrated to give 2-methyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentanol a~ an oil t52 g., 88% yield).
The pentanol (16 g.) is t~ken u~ in e~her (100 ml.)~and reacted with po~dered potassium (2.5 g.) ln ath~r ~200 ml.). Carbon disul~lde (equimolar to the potassi~m) is added Hnd the mlxture ~tirred for a half hour. Methyl iodide (9.0 æ. ~ iB then added and the reaction mixture stirred ~or 6 hours. Tb~ resulting suspension i~ ~iltered and the filtrate concen-trated under reduced pressure. ~he residue i~ takQn up in ethanol (150 mlO), Raney nic~el added (25 g.) and the mixture re~luxed for 18 h~x~. Evaporation of the alcohol and distillatio~ of the rssldu~ gi~e~ 2 methyl-2-(3,5-dimethoxyphenyl)-5~phenyl-3-pentene.

-~ .

: ~ .

Z~7~

The pentene derivative is catalytically hydrogenated accordin~ to -the procedure of Preparation D and the resultin~ 2-methyl-2-~3~5-dimethoxY-phenyl)-5-phenyl-3-penta~e demethylated via the pro~edure of Preparation C to give the product, :^, `7~ -- 8 7--'.

: ~ r PREPARATION F
3, 5-Dibenzylo~;yacetophenone Over a period of loS hours, methyl lithium (531 ml~ of a 2 molar solution, 1006 M) i~ added under ~ nitrogen a~mosphere to a rapidly stirring solution Or 3,5-dibenzyloxybenzoic acid (175 gO~ 0.532 M) in ether (250 ml,) -tetrahydrofuran (1400 mlO) maintained at 15-20C. After stirring an addi-tional 0,~5 hour at 10-15C " water ~600 ml~) is slowly ~dded keeping the reactio~ temperat~re below 20C, The aqueou~ layer i9 separated and extrac-ted with ether (3 x 250 ml.), The org~nic ph~ses ~re com~ined, wa~hed with saturated sodium chloride solution (4 x 300 mlO), dried ovcr sodium sulf~teg and concentrated under vacuum to give an oil which slowly crystallized from isopropyl ether, The crude~roduct i3 recry~tallized from ether-hexane to yield 104.7 ~, (59%) of product; m.p~ 59-61C, _88-,~`` ' .

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~Q~ g PREPARATIOII G
Ethyl 3-(3,5-Dibenzyloxyphenyl)Cro~oslate (Wittin~ Reaction) A mixture of 3,5~dibenzyloxyacetophenone (43.2 g., 0013 mole) and carbethoxyrnethylenetriphenylpho~phorane (90.5 g., 0.26 mole) i9 heated under 5 a nitrogen atmosphere at 170C. ~or 4 hours. The clear melt i~ cooled to room temperature, triturated wit.h ether and 1;he precipitate o:~ triphenyl phosphine oxide removed by filtration. The filtrate i9 concentrated under vacuum to an oil residue which is chromatographed over silica ~el (1500 g.) and eluted with benzene:hexane solutions of increasing benzene concentration beginNing with 10 40:60 and ending with 100% benzene~ Concentration of appropriate fractions give an oily residue which is crystallized from hexane. Yield: 4002 g.
(77%); m.p. 73-75C.
Analysis: Calc'd ~or C26H26O4: C, 77058; H~ 6.51 %
Found: Cl 77~72; ~1$ 6.60 %
In like manner, ethyl 3-(3,5-dimethoxyphenyl)crotonate is prepared from 3,5-dimethoxyacetophenone (51.7 g.) and carbetho~ymethylene triphenyl-phosphorane ~200 g.). Yield = 61.8 gO~ 86%, bop~ 146-162Co at 003 mmO

32~
PE~EPARATION H
___ _ ~ tanol A solution o~ ethyl 3-(3,5-d~be~zyloxyphenyl)crotonQte (2401 g~
60 mM) in ether (250 ml.) is added to a mixture o~ lithium aluminum hydride (3~42 g., 90 mM) and ether (250 mlO)~ Aluminum chloride ~0018 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooledO Water (304 ml.), sodium hydroxide (3,4 ml, o~ 6N) a~d water (10 ml,) ~re then added suc-cessively to the reaction mixt~e. ~he inorganic salts which precipitate are ~iltered o~f and the filtr~te is then concentr~ted in VQCUO to give the desired alcohol as an oil - 2.4 g, (98%), R~ = 0,25 [silica gel: benzene(l8?:ethyl acetate~l), MS: (mol.ion) 362, Analysis: Calc~d for C24H2603: C, 79.53; H, 7.23 %
Found: C, 79.37j H7 7 oll %
In like manner9 ethyl 3 ~3,5-dimethoxyphenyl)crotonate (60.4 e.) i9 reduced to 3-(3,5-dimethoxyphenyl)butanol (48.o g., 90%)O
PREPARATION I

Tosyl chloride ~11.1 g~, 58.1 mM) i~ ~dded to a solution of 3-(395-dibenzylox~phenyl)-l-butanol (2007 g., 57 mM) in pyridine (90 mlO) at -45Co The reaction mixture 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 mlO)0 ~he combined extracts are washed with saturated sodium ~hloride ~olution (4 x 250 ml,) and then dried (Na2S04), Concentra~ion of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexaneO
Yield: 24.63 g. (84%).
Analysi9: Calc'd ~or C31H3205S: C, 72006; H, 6,24%
Found: C, 72,05; ~, 6.29%

~i ~90~

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~'A~ ol~l J
3 9 S - Dibe~yl~ L~

, A solution of pllenol (4.5~ g., 48.6 m~I) in dimethylformamide (40 ml.) ; is added under a nitrogen atmosphere to a su~pension of ~odium hydride (2.32 S ' g. 9 48.6 mM o 50% previously washed with pentane) in di~ethylformamide (70; ml.) a~ 60 C. The reaction mi~ture is stirred for one hour at 60-70 C., after which a solution of 3-(3 ,5 -dibenzyloY~ypl1enyl)butyl tosylate (23.93 g.,46.3 mM) in din~ethylformamide (80 ml.) is ~dded. ~le reactlon mixture is stirred at 80 C. for a ~1alf hour and is then cooled to room temperature, di luted with cold w,ater (2500 ml.) and extracted with ether (b~ x 400 ml.). The com~ined extracts are washed successively with cold 2N hydrochlorlc acid (2 x 300 ml.) and saturated sodium chloride solution (3 x 300 ml.) and then dried (Na2S0~). Removal of the solvent u~der reduced pressure affords the product as an oil. The oily residue is dissolved in benzene and filtered `~
lS through silica gel (lO0 g.). Concentration of the filtrate under reduced pressure gives the product as an oil. Yield: 14.86 g. (7370).
Rf = 0.7 (silica ge~, benzene).
MS: (mol.ion) 438 Analysis: Calcld for C3~113003: C, 82,16; El, 6.89 %
Found: C, 82.07; ~, 6.84 % ;
Repetition of Procedures G through J, but using the 3,5 dibenzyloxy derivatives of benzaldehyde~ acetophenone or propiophenone, the appropriate ~ i;r carbethoxy (or carbometho~y) al1~ylidene triphenyl phosphorane; and the appropriate alcoi-ol, phenol, thiophenol, hydroxypyridine or hydroxypiperidine ss reactants affords the following compounds:

i' '.

~I5 6 H2 talk )-X (alk2) -W

For convenience, the vario~s values o~ W for given v~lues of -talki~-X~~alk2~n- are coll~ctively tabulated~

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,~ 3- (3, 5 ~ Dil-ly~y,~ne A solution o~ 3 (3, 5 ~dibenzyloxy~llenyl)-l-phenoxybutane (14.7 ~., , 133.5 mlt) in ~ mlxture of ethyl aceta~e (110 ml.), ethallol (110 ml.) an~ con-5 " centrated hydrochloric acid (0.7 m~.) is hydrogenated for 2 hours under 60 p.s.i. hydro~en in the presence of 10% pailadium-on-carbon (1.5 g.). P~emoval o the c~talyst by filt:ration and concentration of the filtrate gives an oil~
The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-et'nyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined an~ concentrated to give the title product: 7.8 g. (80%), as an o~l.
Rf = 0.25 [silica gel, benzene(4), methanol (lj].
MS: (mol.ion) 258 Analysis: Calc'd for C16H1803: C, 74.39; H, 7.02 %
Found: C, 74.13; H, 7.00 %
In like manner, the remaining ethers (X = 0) 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 com~rises stirring a solution of the dibenzyl et're-(X = S) in trifluoroacetic acid at room temperature for two hours. Ihe reac-tion mixture 16 evaporated to drynes~ and t}ie residue taken up in ether.
The ether solutlon is washed with l~ater, dried (MgS04) and evapora~ed to give the debenzyl~ted compound.

;, ` ' `, I

..

2~S~

PREP~RATION L
l-Bromo-3-(3,5-Dimethoxy~henyl~butane A solution of phosphorous tribromide (5.7 mlO, o.o6 mole) in ether (30 ml.) is added to a solution of 3-(3,5-dlmethoxyphenyl)-1-butanol (30~0 g~, 0~143 mole) in ether (20 mlO) at -5C. to -10C. and the reaction mixture stirred at -5C. to -10C. ~or 205 hoursO It i9 then warmed to room tempera-ture ~nd stirred for an additional 30 minutesO The mi~ture i9 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 solu~ion (3 x 50 mlO )3 saturated sodium chloride solution (1 x 50 ml~) and dried (~a2S04) Removal of the ether and vacuum distillation o~ the residue af~ords the title product, 25 g. (55% yield), b,p. 125-132C. at 0.4 mm.
The ~ollowing compounds are prepared from 3,5-dimethoxybenzaldehyde, 3~5-dimethoxyacetophenone ~nd 3,5-dimethoxypropioph~none and the appropriate carbethoxyalkylidene triphenylphosphorane by the procedures o~ Preparations G, H and L.

H3CO ~ Z-Br (c~2)3 (CH2)4 C ( C2H5 )CH2 PREPARA'rION M
4_ ( 3 ~ 5-D~1 ) _~ 4 -p~ri dyl )R~
A mixture of 3-(3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to ~-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran ~40 ml.).
~he 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 atmophere at 0-5C. Following completion o~ addition, the mixture is stirred for one hour at 0-5~ and then concentrated under reduced pressure. The concentrate 0 i9 dill_ted with water (200 ml.) and then acidified with 6N HCl. The aqueous acid solution is extracted with benæene (4 x 50 ml.)0 It is then made basic and extracted with ethyl acetate (3 x 50 ml.). Evaporation OI the combined extracts after drying (MgS04) affords 4-(3~5-dimethoxyphenyl)-1-(4-pyridyl)-l-pentene (7.1 g., 70%) as an oilO
~atalytic hydrogenation of the thu~-produced pentene derivative according to the procedure given in Preparation D give 4-(3,5-dimethoxy-phen~rl)-1-(4-pyridyl)pentane in quantitative yield; mOp, 131~-133Co The pentane derivative thus obtained is demethylated by heating a mixture of the compound (7015 g.g 25 mmoleG) and pyridine hydrochloride (35 20 g.) under a nibrogen atmosphere at 210C, for 8 hours. The hot maxture is poured into water (40 ml.) and the resulting ~olution made basic with 6N
sodium hydroxide. Water ~d pyridine are removed by di3tillation an ~acuo.
Ethanol (50 ml.) is added to the residue and the inorganic salts which pre-cipitate are filtered off. The filtrat;e is concentrated in vacuo and the 25 residue chromatographed on silica gel (150 g.) using a8 eluting agents 5%
ethanol/ben~ene (4 liters), 10% ethanol/benzene (1 liter), 13% ethanol/benz,ene r -.
.

- , (1 liter) and 16% ethanol/benzene ~5 liters). The produ~t i3 isolated as a glassy solid by concentration of appropriate fractions of the el~ate. Yield =
5.0 g. (78%). .
~he 3-(3~5-dimethoxyphenyl)butyltriphenylphosphonium bromide is prepared by refluxing a mixture of 1-bromo-3-(3,5-dimethoxyphenyl)but~ne (21.5 g., 78.5 mmoles) and triph~nyl pho~phine (20.5 g., 78.5 mmoles) in xylene (60 ~1.) for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The ~ilter cake i~ wa~hed 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 afford3 the following ~ompounds.
OH
~0~

Z
(C~2)3 2-pyridyl (CH2)3 3-pyridyl (C~2)3 4-pyridyl (CH2)3 2-piperidyl (CH2)3 4~piperidyl (CH2)4 2-pyridyl (CH2)4 4-pyridyl (CH2)4 3-piperidyl ( H2)4 4-piperidyl ÇH2cH(cH3)cH2 2-pyridyl CH2CH(CH3)CH2 4-piperidyl CH(cH3)cH(cH3)cH? 3-pyridyl CH(CH3)CH(CH3)CH2 4-pyridyl CH(CH3)CH(CH3)CH2 3-piperidyl _99_ '; ' ' .

~!92Ç~

W
CH(CH3)(C~I2)2 2-pyridyl CH(CX3)(CH2)2 3-pyridyl CH(CH3)(CH2)2 4-piperidyl H( H3)( 2)3 3-pyridyl CH(CH3)(CH2)3 4-piperidyl CH ( CH3 ) C~l ( C2H5 ) CH2 4-pyridyl CH(C2~5)(CX2)2 4-pyridyl CH ( C2H5 ) ( CH2 ) 2 2-piperidyl CH ( C2H5 ) ( CH2 ) 2 4-piperi dyl CH2CH ( C2Hs ) CH2 3~pyr~ dyl CK(C2H5)(CH2)3 3-pyridyl CH(C2H5)(CH2)3 4-piperidyl CH(C2H5)CH(CH3)CH2 2-pyridyl CH(C2H5)CH(c2H5) 2 4-pyridyl CH(C2H5)CH(c2Hs)cH2 2-piperidyl (CH2)3 C6H
CH(CH3)(CH2)3 C6H
( CH2 ) 4 C 3H5 ~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 C6~5 CH(CH3)(CH2)7 C6H5 CH ~ CH3 ) ( CH2 ) 3 4 FC6H4 C(CH3)2(CH2)3 C6H5 CH ( CH3 ) ( CH2 ) 3 4 -Cl C6H4 CH(CX3)(CH2)4 4-ClC6H4 3 2 4-ClC6H4 ( 3)( 2 4-FC6H4 ( 3 2 2 4-FC6H4 CH( CH3 )(CH2)2 4-ClC6H4 ~ .

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` i~ i (C1~2) 3CII (C113) C
C~l(cll3) (Cll2)2cll(cll3) C
C~tC~13) (C1l2)2c~ ll3) ` C611:1.1 CH (Cll3) (C112) 2CII (C113) 4-piperidyl CH(C}{3) (C112)3 6 11 CH(C1~3) (C~12)2C~l(cl~3) C6 (CE12) 3 C6H
,~ (CH2)4 C6 (CH2) 8 C6 ' .
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, , PREPl~RATJON N

3.5-Oimethoxy--methylstyrene Oxide -To a solution of dimethylsulfoxonium methylide (69.4 m~l) in dimethyl sulfoxide (65 ml.) at room temperature is added solid 3,5-dimethoxyaceto-5 phenone (10 g.~ 55.5 mM). The reaction mixture is stir~ed for one hour at25 C., for one-half hour at 50 C. and is then cooled. The mixture is diluted wi~h water (50 ml.) and added to a mixture of ice water (200 rnl.)--ether ~250 ml.)--lo~ boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgS04) and evaporated to an oil.
10Fractional distillation of the oil yields 8.0 g. (75~) of 3,5~dimethoxy-~
methylstyrene oxide, b.p. 93-97 C., 0.2 ~m.
IR (CCL4): 2780, 1595, 1196, 1151, 1058 cm UV (95% ethanol): ~ = 279 nm (E = 206S) max MS (mol.ion): 194 15 PMR (CDCl~) (60 Mllz): ~ (1 70 ~S, CH3-), 2.76 (d, J = 6 Hz~-- ~H~9 2.95 (d, J = 6 H~,~H), 3.81 (S, C1130-), 6.41 ~t, J = 2 Hz, ArH) and 6.5S
(d~ J = 2.Mz~ ArH).
Analysis: Calc~d for CllUlb,03 C, 68.C2; Il, 7-27 %
Found: C, 67.96; }1, 7.28 %

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Il . I
~, 2-(3,~ e ~ ~ lro~yproyyl--2-~ enyletllyl Ether A mlxLure of dry 2-ph~llyle~llanol (30 ~1., 251 ~) al~d sodium lll~tal (690 m~,., 30 l~) ls heated at 110~ C. for 30 minutes. ~le re~qll~in~ l~lsoluti~ o~
sodium 2-phenyl~thoY.ide is cooled to 60 C., 3,5-dimethoxy~ tllylstyren~
oxide (2 g., 10.3 ~) add~d and the reactlon heated 15 hours at 60 C. The reaction mixture is cooled and added to a mi~ture of ether and ~ater. lhe ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenyl-ethanoi is ~emoved by vacuum distillation (b~po -65 C~ 0~1 mm.) leaving a 3.5 g. residue. . ~ne residue is purified via column chromatography on ~erck sili~a gcl 60 (300 g.) and eluted in 15 ml. fractions with 60% ether-pentare.
Fractlons 52~88 yielded 2.9 g. (89%) of 2-(3,5~dimetho~yphenyl)-2-hydroxy-propyl 2-phenylethyl ether.
IR ~CC14): 3534s 1595, 1202, 1153 cm UV (95% ethanol): AmaX = 278 (E = 1830), 273 (E = 1860).
MS: (~ol.ion) 316 PMR (CDCl3, 60 ~I~ 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 Hz9 -CH2O), 3.80 (S, OCH3), 6.38 (t, J = 2 Hz, ArH), 6.61 (d, J = 2 Hz, ArH) and 7.23 (S, PhH).
Analysis: Calc~d for ClgH24O4- C, 72.12; H9 7-~5 %
Found: C, 71.92; H, 7.63 %

" ~ 10~-.'" ' ` ' ~

9Z6g !' I
PRI~ l~TI~N P

, 2-(3 5-Dimethoxy~ yl)pro~yl 2-Pllenylethyl Ether To a 0 C. solution of 2-(3,5-dimethoxypllenyl)-2-hydro~ypropyl 2-phellyletllyl et.her (550 mp~., 1.74 n~l) in pyridine (2 ml.) ls added drop~Jisephosphorolls o~ychloride (477 ml., 5.22 m~l). The reaction ls allowed to warm to 20 C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20 C.
and'then added to e~ther (150 ml.) and 15% sodium carbonate (100 ml.). The or~anic phase is sep'arated and washed with 15% sodium carbonate ~3 x 50 I~,), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved il~ absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. I~en hydrogen ~lptake ceases (26.5 ml., 20 min.), the reaction is filtered through diatomaceous earth and the filtrate evaporated,to an oil. The oii is purified via prepara-tive layer chromatography on silica gel plates, eluted twice with 6:1 pentane:
ether to yield 211 mg. (40%) of 2-(3,5-dime~hoxyphenyl)propyl 2-phenylethyl e~her.
I~ (CC14): 1600, 1205, 1155, llO9 c~ 1, ~ ~
MS: (mol.ion) 300 P~ (CDC13, 60 MHz) ~ 1.22 (d, J = 7 Hz, CH3-), 2.82 (t, J = 7 Hz~
C112Ph), ~2~8 (H-C-Me), ~3.6 (-C1l2-0 CH2-), 3.75 (S, OCM3), 6.35 (m, ArH) and 7.18 (S, PhH).

. !

-- ]O-- --;. I

ff ~ f k~ J'l~k/i'i 2 - ~ ~ 5~ ~r~yl~h c ~ n~y l c tl~ h ~ r .~
- A mtxtur~ of 2-(3~5-di~ethoxyphenyl)prcpyl 2-phenyl~hyl ether (~5 m~. ~ o~65 ~ pyrid:Lne (0.4 ml.~ 96 l~) and dry pyrid-lne hydrochloride (4 g., 34~6 n~l) is hea~ed at 190~ C. ~or 6 hour~. The reac~ion mix~ure is cooled .~ .
and added to a mi~ture of water (100 ml.) and e~her (150 ml.). lhe ether e~tract is ~ashed onee wi~h watcr (50 ml.) and, aloDg with a second ether ex~lact (50 ml.) of tile aqueous ph~se, is dried over magnesiutn s~llfa~e and evapora~ed to an oil. The oil i5 purified via preparfl~ive layer chromatography on s:ilica gel p~ates, eluted si~ times with 30% ether~pentane ~o yieid 65.8 ms. (37%) of 2-(3~5-dihydroxyphenyl)propyl 2-phenyletllyl ether.
IR (CUC13)~ 3559, 3279, 1605, 1147, 1105 cm l, MS: tmol.ion) 272 P~n~ (CDC13, 60 l~z) ~ 1.18 ~d, J = 7 H7, CH3-), 2.80 ~t, J = 7 Hz, -CH2Ph), 2.80 (H-C-Me), 3.4-3.8 (~CH20Cla2-), 6.08 (t, J = 2 llz, ArH), 6.21 ~d? J =`2 Hz, ArH) and 7.16 ~S, PhH).
The ~ollo~ing compounds are prepared ~rom approprlate ai~anols by ~he methods of Procedures 0 and P.

110 J~C~ z~O/( .` : . ' ~' ` . I

f ,1 . I
.

z~

( ~lk2 ) W
~ ( CH2 )6- CH3 - ( CH2 ) 6 C6H5 - ( CH2 )l~ CH3 -CH ( CH3 ) CH2 CH3 -CH( CH3 ) ( CH2 )4 ~H3 - ( CH2 )- 4 -FC6H4 ~ ( CH2 ) 2- 4-pyridyl ~ ( CH2 ) 2- 2-pi~eri d~rl -CHtCH3)C~I2- 4-piperid;yl _(CH2)2CH(cH3)(cH2)2 CH3 -CH( CH3 )- c~3 -C ( CH3 ) 2- CH3 ~;1 -106 : ' " : :

2~g PREPAR~TICN R
.
4-(3,5-Dihydroxyphenyl)-l phenoxypentane Under ~ nitrogen ~tmosRhere ~ mixture of 315-dibenzyloxyacetophenone (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phenoxypropyl~riphenyl-phosphonium bromide (7.18 g., 0.15 M) in dimethyl3ulio~ide (450 ml.) is added dropwise over 1.75 hours to a suspension of 50% sodium hydride (7.89 g., 0c165 M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0-5C. After stirriug for 4 hour~ at 0-5C. the reaction i9 allowed to warm to room temperature and i5 then caref~lly stirred into ice water (2000 mlD), acidified with concentrated hydrochloric acid~ and extracted with ethyl acetate (5 x 400 ml.). The combined organic phases are washed with saturated sodium chloride solution (3 x 300 ml.), dried over ~odium sulfate and concen-trated under vacuum to yield an oil which is tritur~ted with et,her to pre-cipitate triphenylphosphine oxide. Filtration, followed by concentration of the filtrate, ~ives an oily residue which i~ chromatographed over silica gel (1300 gO) eluting with benzene-hexane consisting of 30% to 100% benzeneO
From the midale fractions 51 gO (75%) of 4-(3,5-dibenzyloxyphenyl)~l pheno~y-pent-3-ene i9 isolated as an oilj R~ = 0,ô (sllica gel, 2-benzene:l-hexane);
MS (mol.ion): 450.
Analysis: Calc'd for C31X3003: C, 82 D 63~ ~, 6.71 %
Found: C, 82D90; H, 6.69 %
A solution of 4-(3~5-diben~yloxyphenyl)-1-phenoxypent-3-ene (51 g~
0.113 M) in a ~ixture of absolu-te ethanol (160 ml~), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the cataly~t ky filtr~tion Qnd conce~tration of the filtr~te under vacuum yield 30.ô g.
(100%) of product as a vi9cous oil.
Analy~iB: Calc'd for C17H2003: C, 74~97; H, 7~40 %
Found: C, 74~54; H, 7D45 %

~ -107-' . ' " " `
' g269 PREPARATIO~ S
_ 3~5-Dimethoxy-~-meth~styre~e oxide To a -78Co solution of diphenylsulfonium ethylid~ (1.0 mole) in tetrahydrofuran (one liter) i~ slowly added 395-dimethoxybenzaldehyde (1.0 mole). The reaction mixture i9 stirred at -78Co for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether pha~e separated. The ether phase is washed with water, dried (MgS04) and evaporated. Fractional distillation of the residue gives the title product.
PREPARA~'ION T
__ 3-(3,5-Dihydrox~phenyl) p/cj~Lb~'. t~e_ To a solution of sodium butoxide in butanol (0,5 liters of lM) is added 3,5-dimethoxy-~-methylstyrene oxide (6.33 M). ~he mixture is heated for lô hours at 70C. and is then cooled and added to a mixture of ether-water. The ether solution is separated~ dried (MgS04) and e~aporated to give 3-(3,5-dimethoxyphenyl)-3-hydroxy-2~propylbutyl ~ther. It is purified by column chromatographY on silica gel with ether-pentane elution.
By means of the procedure of Preparation P the title product is produced.
Similarly3 t~e following are prepared from appropriate alcohols:
OH
~ C1~3 HO ~ CH2~ `0-(alk)2-W
(alk2) W (alk2) W
CH2 CH3 ( 3 2 CH3 (CH2)6 CH3 CH(C2H5) (CH2~2 CH3 (CH2)3 C6E~5 CH(C~H3)CH2 C6~5 (CH2)2 4-FC6H4 (CH2)2 4-pyridyl :: , ': ~
- . : :
.

~q~Z~9 PREPARATIO~ U
2-R4R5-5~f-Dihydroxy-4-chromanone~
The procedure of British Patent 1,077~066 i9 employed to produce the compounds tabulated belowO It compri~es reacting the appro~riate R4R5C=CH-COOH with an excess (50%) of` 193,5-trihydroxYbenzene and of polyphos-phoric acid (10 to 20 grams per ~ra~s of trihydroxyben~ene) on a steam bath for three hours. The mixture i8 then cooled and poured into ~ater, The pre-cipitate is extracted with ether, ~he ethereal extract wQ~hed with sodium hydroxide sol~tion, dried and evaporated to afford the product. Purif'ication is accompli~hed by distillation of the residue. The following are thus prepared:
O OH

H H

PREPARATIO~ V
__.__ (4-Halophenyl Ao 3- and 4-(4-Fluorophenyl)cyclohexanols A benzene solution containing equimolar amounts o~ 4-fluorostyrene and 2-methoxybutadiene and hydroguinone ~1% by weight based on diene) is heated in a sealed tube at 150Co for 10 hours; The reaction vessel is cooled, the contents removed and conc~ntrated to ~ive l-methoxy-4~and 5)-4-(fluorophenyl)cycloheptene which are separated by distillation in vacuo, Hydrolysis of the ether with 3% hydrochloric acid affords 3- and 4-t4-fluorophenyl~cyclohexanones.
Sodium borohydride reduction of the ketones according to the pro-cedure of Example 5 affords the keto compounds.
In like manner, the corresponding 3- and 4-(4-chlorophenyl)cyclo-hexanols are prepared from 4-chloro3tyrene~
B. 2-(4-FluQro~henyl)cyclohexanol Thi~ compound is prepared from cyclohexane oxide and p-fluorophenyl lithium according to the procedure of Huitri~ et alO, JO ~, Chem,, 27, 715-g (1962), for preparing 2-(4-chlorophe~yl)cyclohexanol, ~i --110--. :
' .

2~

PREPARA~ION W
~n.~ o~lkanols .__ The procedure o~ Huitrlc et alO, JO ~ O ChemO, 27, 715 9 (1962) is emplo~ed but using the appropriate cycloalkylene oxide and p-halo (Cl or F) phenyl lithium reactants to produce the following compounds:

OH
( CH _ ~ ~ X

a X a X
2 Cl 2 F
3 Cl 3 F
Cl S F

-1].1-, . .

~9~32~9 PREPARATIOE X
5~Hydroxy-7-mercap~ 2-dimethyl-4-chromanone A mixture of 3,5-dihydroxyphenyl methyl sulfide (5.85 gO) and 3-methylcrotonic acid (405 gO) i9 heated to 125C~ under nitrogen and boron tri~luoride etherate (8,7 mli) addedc The mixture is refluxed for ~ne hour and is then cooled. Water (10 mlO) is add~d, followed by 6N sodium hydroxide (40 ml~)O The mixture is heated on a steam bath for five minutes, then cooled and acidified with 6N hydrochloric acidO It is ex'racted with ether (3 x 100 ml.) and the combined extracts washed with 10% sodium bicarbonate (1 x 25 mlO) 10 and water (1 x 25 ml.) and then dried (Na2504)~ Concentration o~ the extract under vacuum affords dl-5-hydroxy~2,2-dimethyl-7-methylmercapto-4-chromanoneO
It is purified by silica gel chromatography~
~ he methyl mercapto compound thus produced is hydrolyzed by refluxing overnight with excess 48~ hydrobromic acid, Concentration of the reaction mixture affords the title compoundO It is puri~ied by 3ilica gel chromato-graphyO
me following compounds are similarly prepared but replacing 3-methylcrotonic acid with the appropriate acid o~ the formulQ R4RsC=CH-COOHo O OH

R5 ~ SH

H H

~ -112-,, '; , , PREPARA~ION Y
Alkyla~ion of 315~D ~ rcaptQn A ~olution of 3,5-dihydro~yphenylmercapt~n (3.5 gO~ O.Ol mole) in absolute ethanol (50 ml.) is m~de Just alk~line with sodium ethoxideO The appropriate bromide of formula Br (~lk2) -W (0.01 mole) i.s added and the mix-ture refluxed for 3 hoursO It is then concentrated under reduce~ pressure and the residue extracted with etherO Ev~poration of the ether afford~ the product.
Ihe following compounds are thu~ prepared:
OH

~lo~S-(~lk2) -W
(alk2) W
n __ - _ _ 1 -CH(CH3)(CH2)5- CH3 1 -CH(CH3)CH(CH3)(CH2)4- CH3 1 C(CH3)2( 2)5 CH3 1 -(CH2)8- CH3 1 -(CH2)4- CH3 - ( CH2 ) - C 6H5 1 ( 3 2 3 C6H5 1 -CH2- C5Hg 1 -(CH2)2- C5Hg 1 -(CH2)3- C5Hg 1 -(CH2)5- C6H

1 -~CH2)4- C5H9 -(cH2)3cH(c2H5)- C6H

-(CH2)7- 113- C5H9 : ..
.:: : .
, : . ,. : ., - ~ , : '-: , : ..

~ 2 n ~ k2) W
l -(CH2)4- C7Hl3 -(CH2)2- C7H13 l -(CH2)5- C4H7 l -(CH2)5- C3H5 l -(CH2)- 2-piperidyl l -(CH2)3- 4-piperidyl l -(CH2)- 2-pyridyl 1 -(CH2)3- 3-pyridyl l -(CH2)l~- 2-pyridyl ( 3)( 2 2 2-p~ridyl 1 -CH(CH3)(CH2)3- 4-pyridyl 2 5 2 2 4-pip~ridyl ( CH2 )4- 4-FC6H4 l ( 3)( 2)2 4-ClC6H4 l ( 3)( 2)3 4-FC6H4 o __ C6H5 O __ 4-FC6H4 o 4-ClC6H4 0 -- c3~5 o -- C5Hg 6 ll 0 -~ - 7 13 0 __ 4-pyridyl o -- 2-piperidyl 0 - 2-pyridyl o - 2-(C6H5)C3H4 ~ ( 6 ~) 6 10 0 -- 3 ( 6 5) 7 12 -114~

:, , . .

2~

PREPARATION Z
dl-2-(3,5-Dibenzyloxphenyl)-2-hJdroxy-1-(2-phenylethoxy)-_ pro~ane To a 20C. solution of dimethylsulfoxonium methylide (0.184 mole) in dimethylsulfoxide (185 ml.) i3 added 3,5-dibenzyloxyacetophenone (51.0 gO) 0.153 mole) After stirring 1.5 hours ~t 20C., the reaction i8 diluted with 200 ml. of ice water and added to 500 ml. ether and 200 ml. ice water~ The organic phase is washed with cold water (2 x 200 ml.), dried over magnesium sul~ate and evaporated to an oil. A solution of the thus produced crude 1-(3,5-dibenzyloxyphenyl)-1-me~hylQxtrane~0.153 mol~)- in ~ t~-y~ul~ox~ide (100 ml.) is rapidly added to a 20C. solution of sodium ~heneth~xide (0.306 mole) in dimethylsulfoxide (150 ml., made by the slow addit~on o~ 36.5 ml, ~0.306 mole~ of phenethanol to a slurry o~ 7.34 g. [0.306 mole~ sodium hydride in 150 ml. dimethylsulfoxide). The reaction i8 slowly heated over a half-hour period to 70C., stirr~d 30 minUtes and cooled to 20C. The reac-tion is diluted with 200 ml. ice water and added to ether (2 1~) and ice water (1 liter). ~he organic phase is washed with cold water (2 x 1 1.), dried over magnesium sulfate and ev~porated to an oil. This crude oil is puri~ied vi~
column chromatography on 1.5 kg. o~ silic~ gel, and eluted with 60% ether-pen-tane to yield 30.0 g. (42%) of dl-2-(3,5=dibenzyloxyphenyl)-2-hydroxy-1-(2-p4enylethoxy)propane, as an oilO
IR: (CHC13) OH 3534 cm NMR: ~CDCl 1.46 (s, methyl, 2.85 (t, Jz7Hz, -CH2Ph), 2.81 (s, hydroxyl), 3.55 (s, -CX20-), 3.68 (~, J=7Hæ, -OCH2-), 5.06 ~s, PhCH20-), 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 46~ ( ~ , 453, 377 ~nd 335 (100%).

~ -115 . .
. ' - , 1` '~ ' ~:' PRE~ARATION AA
______ -2-(3~5-Dihy ~
To a 0C. solution of dl-2-(3,5-dibenzyloxyphenyl)-2~hydroxy-1-(2-phenylethoxy)propane (29.0 g., 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 20Co and is stirred ~t 20~Co for 20 hour O The reaction is added to a 0C. solution o~ 3.3N NaOH (3~0 mlO) ~nd ~h~ resultant mixture ex-tracted with ether (3 x 500 ml.). Each extract is washed ~ith saturated po-tassium carbonate (l x 500 ml.) and water (3 x 500 ml.). The combined~ organic extract is dried over magnesium sul~ate, silica gel and then decolorized (car-bon) and evaporated to an oil. ~his oil i9 purified ~ia column chromatography on silica gel (200 g~) eluted with 60% ether pentane to yield 17 g. (61%) o~
an oil (mixture of ole~in~). To a solution of this mixture of olefins (3.62 g.) in ethanol (lO ml.) and ethyl acetate (lO mlO) is added solid sodium bicarbonatelS (300 mg.) and 10% Pd/C (1.2 gq) ~his mixtUre i~ stirred 6 ~our~ under one at~osphere o~ hydrogen. ~he reaction i8 diluted with ethyl ~cetate and fil-tered through diatomaceous earth. The evaporated filtrate is purified Vla column chromatography on ~ilia gel (200 gO) eluted with 80% ether-pentane to yield 2~0 g (92%) of dl-2-(3,5-dihydroxyphenyl)~l (2-phenylethoxy~propa~e as an oil.
IR: (CHC13) OX 3571, 3279 cm O
NMR: ~CDCl l~lO (d, J~7Hz, methyl), 2.80 (t, J~7~z, -CH2Ph), 2;90`(M~ methine), 3.5 (m,--CH20-CH2-), 6.10 (t, J=2Hz, C-4 Ar~), 6.20 (d, J=
2H3, C-2,6 ArH), 6.5 (broad m, hydroxyl) and 7.19 (~, ArH)O
MS: m/e 272 (M~ , 1817 168, 151~ 138, 137, 123 105 (100%) and 91.

~ .

Claims (30)

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

1. A process for the production of a dibenzo[b,d]-pyran of the Formula A:

Formula A

wherein Q is or and wherein R is hydrogen or alkanoyl having from one to five carbon atoms;
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 substitu-ent is phenyl, p-chlorophenyl or p-fluorophenyl;
with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-;
which comprises reducing a compound of Formula B or Formula C:

Formula B Formula C
and if Q is to be wherein R is an alkanoyl group, reacting a compound of Formula A wherein Q is wherein X is hydrogen with an appropriate acid, acid chloride or acid anhydride.

2. A process according to claim 1, characterized in that said reduction of a Formula C compound is effected by use of a metal hydride to produce a compound of Formula A wherein Q is .

3. A process according to claim 2, characterized in that said metal hydride is sodium borohydride.

4. A process according to either of claims 2 and 3, wherein said compound of Formula C is itself prepared by reduction of a compound of Formula B.

5. A process according to claim 1, characterized in that the reduction of the compound of Formula B is effected by means of a Birch reduction to produce a compound of Formula A wherein Q is .

6. A process according to claim 5, characterized in that lithium is employed as the reductant metal in the Birch reduction.

7. A process according to claim 1, characterized in that the compound of Formula B is prepared by the reaction of a compound of the formula:

wherein R1, R4, R5, Z and W have the same meaning as in claim 1, with methyl vinyl ketone.

8. A process according to claim 7, characterized in that said compound of the formula:

wherein R1 is hydrogen, is prepared by the reaction of a compound of the formula:

with ethyl formate in the presence of sodium hydride.

9. A process according to claim 1, wherein there is employed as starting material a compound of Formula C, characterized in that said compound is prepared by acid hydrolysis of a ketone of the formula:

wherein v is 2, 3 or 4 and R1, R4, R5, Z and W have the same meanings as in claim 1.

10. A process according to claim 9, characterized in that said ketal is prepared by reaction of a compound of the formula:

with an appropriate alkyl magnesium iodide.

11. A process according to claim 10, characterized in that said compound of the formula:

is prepared by the reaction of a compound of the formula:

with a glycol of 2 to 4 carbon atoms in the presence of a dehydrating agent.

12. A process according to any of claims 1, 2 and 5, wherein the Z-W group is (alk1)m-X-(alk2)n-W wherein alk1, alk2, W, m and n have the same value as in claim 1, and X is -SO- or -SO2-, characterized in that as a further step of the process a compound wherein X is -S- is oxidized by means of a per-acid.

13. A process according to claim 1, for the pro-duction of a compound of Formula A as defined in claim 1, wherein R is hydrogen so that OR is .beta.-hydroxy;
R1 is hydrogen; R4 and R5 are both methyl; Z is CH-(CH3)-(CH2)3 and W is phenyl; which comprises reducing a compound of Formula B or C as defined in claim 1.

14. A process according to claim 1, for the pro-duction of a compound of Formula A as defined in claim 1, wherein R is hydrogen so that OR is .beta.-hydroxy; R1 is hydrogen; R4 is hydrogen; R5 is .beta.-methyl; Z is CH-(CH3)-(CH2)3- and W is phenyl; which comprises reducing a compound of Formula B or C as defined in claim 1.

15. A process according to claim 1 for the product-ion of a compound of Formula A as defined in claim 1, wherein R is hydrogen so that OR is .beta.-hydroxy; R1 is hydrogen; R4 and R5 are each methyl; Z is -OCH-(CH3)-(CH2)3-and W is phenyl ; which comprises reducing a compound of Formula B or C as defined in claim 1.

16. A process according to claim 1 for the pro-duction of a compound of Formula A as defined in claim 1, wherein R is hydrogen so that OR is .beta.-hydroxy; R1 is hydrogen; R4 and R5 are each methyl; Z is -CH-(CH3)-(CH2)3-and W is 4-pyridyl; which comprises reducing a compound of Formula B or C as defined in claim 1.

17. A process according to claim 1 for the pro-duction of a compound of Formula A as defined in claim 1, wherein Q is and wherein R1, R4 and R5 are each hydrogen and Z is ; wherein q is 3 or 4 and W is 4-pyridyl or wherein W1 is hydrogen, chloro or fluoro which comprises reducing by means of a metal hydride a compound of Formula C
as defined in claim 1.

18. A process according to claim 1 for the pro-duction of a compound of Formula A as defined in claim 1 wherein Q is and wherein R1 is hydrogen;
R4 and R5 are each methyl; Z is (alk1)m-O-(alk2)n wherein alk1 is CH-(CH3)-(CH2)2 or CH-(CH3)-(CH2)3;
alk2 is CH-(CH3)-(CH2)2 or CH-(CH3)-(CH2)3 and each of m and n is 0 or 1; W is methyl or , wherein W1 is hydrogen, chloro or fluoro which comprises reducing by means of a metal hydride a compound of Formula C.

19. A process according to claim 1 for the product-ion of a compound of Formula A wherein Q is and wherein R1 is hydrogen; R4 is methyl; R5 is hydrogen or methyl; Z is CH-(CH3)-(CH2)3 or CH-(CH3)-CH2)4 and W is phenyl or 4-pyridyl, which comprises reducing by means of a Birch reduction a compound of Formula B as defined in claim 1.

20. A process according to claim 1 for the product-ion of a compound of Formula A wherein Q is and wherein R1 is hydrogen, each of R4 and R5 is methyl; Z is -(alk1)m-O-(alk2)n, wherein alk1 is as defined in claim 1 and alk2 is -(CH-(CH3)-(CH2)3 or CH-(CH3)-(CH2)2;
each of m and n is 0 or 1 and W is methyl, phenyl or 4-pyridyl which comprises reducing by means of a Birch reduction a compound of Formula B as defined in claim 1.

21. A compound of the formula:

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

22. A compound of the formula:

whenever obtained by the process of either of claims 2 and 3.

23. A compound of the formula:

wherein R5' is hydrogen or methyl and W is 4-pyridyl or ; wherein W1 is as defined in claim 1 and q is 3 or 4 whenever obtained by the process of claim 17 or an obvious equivalent thereof.

24. A compound of the formula.

wherein alk1 is -CH(CH3)-(CH2)2 or -CH(CH3)-(CH2)3- , alk2 is -CH(CH3)-(CH2)2- or -CH(CH3)-(CH2)3-; each of m and n is 0 or 1 and W is methyl or ;

wherein W1 is as defined in claim 1 whenever obtained by the process of claim 18 or an obvious equivalent thereof.

25. A compound of the formula:

wherein R5' is hydrogen or methyl; Z is alkylene of the formula -CH(CH3)-(CH2)3- or CH(CH3)-(CH2)4- and W is phenyl or 4-pyridyl whenever obtained by the process of claim 19 or an obvious equivalent thereof.

26. A compound of the formula:
wherein Z is - (alk1)m-O-(alk2)n- wherein alk1 is as defined in claim 1, alk2 is -CH(CH3)-(CH2) - or -CH(CH3)-(CH2)2; each of m and n is 0 or 1 and W is methyl, phenyl or 4-pyridyl whenever obtained by the process of claim 20 or an obvious equivalent thereof.

27. A compound of the formula:
whenever obtained by the process of claim 13 or an obvious equivalent thereof.

28. A compound of the formula:

whenever obtained by the process of claim 14 or an obvious equivalent thereof.

29. A compound of the formula:

whenever obtained by the process of claim 15 or an obvious equivalent thereof.

30. A compound of the formula:

whenever obtained by the process of claim 16 or an obvious equivalent thereof.