IE43700B1 - 9-hydroxydibenzo /b,d/pyrans and intermediates therefor - Google Patents

Abstract

9-Hydroxydibenzob,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

e This invention relates to novel dibenzopyrans and more particularly ) to 1,9-dihydrojcy-hexahydrodibenzopyrans having in the 3-position (1) an aryl oi cycloalkyl group (W) linked to said position by an alkylene group; or (2) a methyl, aryl or cycloalkyl group linked tc said position via (a) 0, S, SO or . SOj groups; or (b) an alkylene group interrupted by an 0, S, SO or SO,, group; IS or (c) an alkylene group attached to said 2-position or to said methyl, aryl or cycloalkyl groups by 0, S, SO or to intermediates therefor and derivatives thereof; and to the use of such dibenzopyrans and derivatives thereof as analgesic, hypotensive, antisecretory and anti-anxiety agents, as immunosuppressants and tranquilizers in mammals, including man.

Despite the current availability of a number of. analgesic agents, the search for new and improved agents continues, thus pointing to the lack of , an agent useful for the control of broad levels of pain and accompanied by- a minimum of side-effects. The most commonly used agent, aspirin, is of no -2practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesic agents such as d-propoxyphene, codeine, and morphine, posses addictive liability.

The need for improved and potent, analgesic agents is, therefore, evident The ar-algesic properties of 9-nor-9g-hydi'oxyhexahydrocannabinol and ρ of other cannabinoid structures, such as δ -tetrahydrocannabinol 8 (Δ -THC) and its primary metabolite, ll-hydroxy-Δ -THC have been reported by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), and d-.Med^ Chem., 17, 475-476 (1974).

U.S. Patents 3,507 and 3,636,058, issued April 21, 1970 and January 18, 1972, respectively, describe various l-hydroxy-3-alkyl-6Haibenzo-2l, U.S. Patent 3,649,850, issued larch 14, 1972, disclose a series of tetrahytir&-6,S,S-ina7fcyMK-dib2.,.:r$.#pyran derivatives having at the 1position ana a.“dia lkyl amin.·;· Ik·? German Specification .-.,401,934, published May 7, 1975, describes l.O-dihydroxy.-hexahydrcdibenzoZbjd/pyrans and certain 1-acyl derivatives thereof having at the S-position an alkyl or alkenyl group, as hypotensive, psychotropic, seflat’v· and analgesic agents. The precursor hexah.ydro-9Hdibenzozbjd/pyran-g-cnes used in their preparation, and which are reported to have the same utility as the corresponding 9-hydroxy compounds, are described In German Specification 2,451,932, published May 7, 1975, German Specification 2,415,697, published October 17, 1974, describes l-hydroxy -6,6,9-trimethy1-hexahydrociibenzo Ζ5,$7 pyran derivatives, and intermediates therefor, having at the 3-position an aralkyl, (substituted aralkyl) or pyridylalkyl group. They are useful as analgesic agents and as milk tranquilizers. - 3 0700 'aJ- ί O.S. 3,856,821, issued December 24, 1974, describes a series of 3& ’ alkoxy substituted dibenzo[b,d]pyrans having antiarthritic, antiinflammatory and central nervous system activity. Λ stereospecific synthesis of (-)trans~6a,7,S,l0a-tetrahydro-35 pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-l-ol, more commonly known as (-)A^-tetrahydrocannabinol, has been reported by Razdaft et al. ,(J_. Am. Chem. Soc. 96, 5860-5, 1974). The process, a one-step synthesis, comprises the reaction of cis/trans-(+)-p-mehtha-2,8-dien-l-ol with olivetol in the presence of 1% boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0° C. The tetrahydro compound thus produced is converted to the corresponding 9-keto hexahydro compound by the procedure of Wildes et al., 3_. Org. Chem., 36, 721-3 (1971). The procedure involves methylation of the 1hydroxy-tetrahydro compound to its methyl ether and thence to the hydrogen chloride adduct by reaction with zinc chloride and HCl at 0° C. in chloro15 form. The adduct is then dehydrohalogeaated by reaction with potassium tricyclopentylcarbinolate to give the corresponding Sa,7,8,9,10,10a-hexahydrO“’ 3-penty 1-6,6-dimethy 1-9-methylene-6H-dibenzo [b, d)pyran-l-ol methyl ether.. Oxidation of the 9-methylene group with potassium permanganate-periodate affords the 9-ketone, Demethylation of the methyl ether with pyridinium chlor|20 ide or other acid reagent affords the alcohol.

Bergel et al., i. Chem. Soc., 286-7 (1943) investigated the replacement of the pentyl group at the 3-position of 7,8,9,10-t&trahydro-3-pentyl6,6,9-trimethyl-6n-diben2o[b,d]pyran-l-ol by alkoxy (butoxy, pentoxy, hexosiy and octoxy) and found that it led to biological inactivity. The hexoxy deri25 vative was reported to exhibit feeble hashish activity at 10 to 20 mg./kg.

The remaining ethers showed no activity in doses up to 20 mg,/kg. 1 Xn a more recent study, Loev et al., J. Med. Chem., Id, 1200-6 (1973) report a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9- 3a - containing compound was 50% less active in central nervous system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as iis compound in which oxygen is replaced by methylene.

There has now beer, round a class of compound effective as analgesic, hypotensive, anti-secretory and anti-anxiety agents and as immunosuppressants ana tranquilizers; namely, l.S-dihydroxydibenzo fh.d/pyrans (formula I) which are non-narcotic and free of addiction liability. Further, valuable inter-issdiates (formulae II and III) for the preparation cf safe compounds and derivatives of said compounds useful as dosage forms (fcraula I, R ,- hydrogen) have also been found.

Tho compounds have the formulae III wherein R is hydrogen or alkanoyl having from one to five carbon atoms; R-] is hydrogen, alkanoyl having from one to five carbon atoms and -CO-(CHgJp-NRg-Rg wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is hydrogen and alkyl having from one to four carbon atoms; R2 and Rg when taken together with the • 5 nitrogen to which they are attached item a 5- or 6+membered heterocyclic ring selected from the group consisting of piperidino, pyrrole, pyrrolidino, morpholino, and N-alkylpiperazino having from one to four carbon atoms in the al'kyl group; each of R^ and Rg is hydrogen, methyl and ethyl; Rq is oxo and alkylenedioxy having from two to four carbon atoms; Z is (a) alkylene having from one to nine carbon atoms; (b) -(a1i;-|)m“X-(a1 k2)n- wherein each of (alk,) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms m (alk-j) plus (alkg) is not greater than 9; each of m and n 1s 0 or 1; X is selected from the group consisting of 0, S, SO and St>2; and H is methyl, pyridyl, piperidyl. wherein wt ; a is sn integer from 1 to 5 and b is 0 or an integer from 1 to 5, with the proviso that the sum of a and b is not greater thaa 5; with the proviso that when W is methyl, Z is -(alk^J^-X-falk2)n-. -rCompounds having the above formulae contain asymmetric centers at the 6a- and/or lOa-positions. There may be additiowl asymmetric centers in the 3-position substituent (-Z-W), the b-position and the 9-position. Diasteriomers with the 9s-configuraticn are generally favored over the 9c-isomers because of greater (quantitatively) biological activity. Similarly, the trans (6a, 10a) diasteriomers sre favored over the cis (6a, 10a) diasteriomers.

In addition, it should be noted that the above formulae depict the racemic compounds. Tbs racemic modifications can be used as such because they Contain 50?' of the more active enantiomer. The wavy lines are intended to depict the diastereomers at the 9- and the 6a, 10a - positions.

In generas, the optically active enantiomers containing the same absolute configuration at both the 5a- and lOa-positions as the natural r.annabir.ol$ are favored because of greater (quantitatively) biological activity. The utility of the racemic mixtures, the diasteriomsric mixtures as well as cf the pure enantiomers and diasteriomers is determined by the biological evaluations described below.

Although compounds c' formula II are described herein as intermediates for compounds of formula I, many, particularly those wherein the C-9 substituent is oxo '--G), also exhibit analgesic and tranquil iter activity.

The preferred compounds cf formula I are those wherein the CP. group at the C-9 position has the p-configuration. Such compounds are of greater potency and efficacy than are the corresponding «-compounds.

Of special interest are compounds of formula I wherein the several variables have the significance shown below in Table A: ba 4370( TABLE A 0R] OR Z Ji X (3-CH OH alkylene having 1 to 6 carbon atoms ““ phenyl, pyridyl 5 β-OH OH -(alk^-X·^^- 1 1 phenyl, pyridyl g-OH OH -(a1kl)m-x- 1 - phenyl, pyridyl 0 (3-OH oh -X-(alk2)n- - 1 phenyl, pyridyl Particularly favored because of their potency are those compounds of formula I, Table A, wherein Z-IJ, the C-3 substituent, has the values shown in Table B. below: TABLE B: (a) -(CH2)q-C5H5 (b) -CH(CH3)-(CH2)t-C6Hg M <(CH2)q7in-0-f(CH2)t7n.C6H5 (d) -ZCH(CH3)-(CH2)q7m-0-rCH(CH3)-iH2)i7n-.C5H5 (e) -f(GH2)7n)-0-ZlCH2)^n-CH3 (f) -ZeH(CH3)-(CH2)q7R3-0-ZeH(CH3)-(CH2)t7n-CH3 In the above table, eaeh of q and t is an integer from 1 to 4; and each of m and n is 0 or 1; with the proviso that only one of m and n is 0. 437'.>O Additionally, ths intermediates for the above-mentioned compounds of interest (Tables A and 8) and, ir. particular, the 6a,7-dihydro-6H-dibenzo2b,d7pyran-9(8H)-ones and the 6a,7,10, 10a-tetrahydro-6H-dibenzo Zb,d7pyran-9(8H)-ones of formulae II and III are the preferred classes of intermediates by reason of their orc-cursor relationship to the compounds of Tables A and S above.

The compounds of this invention of formula III are readily prepared by ring annelation of the appropriate 5-R^-3-hydroxymethylene2-^^-7-(24i)-4-chromanone with methyl vinyl ketone in the presence of a bases for example, an alkali metal hydroxide or alkoxide or a tertiary organic base -such as triethylamine, to effect a Michael addition, followed by treatment with a base, e.g., an alkali metal hydroxide or alkoxide (sodium or potassi-v» hydroxide, ethoxide or methoxide) to complete aitiol cyclization.

The ί-esulting 5a,7-dihydro-I-R,-·.o-Ra»R--3-{Z-W)-6H-dibenzo/b, The reduction is convenient j -arried out using lithium as the metal.

Sodium or potassium cen tiro be used. The reaction is conducted at a temperature of from aoout -35°C. to -80°C. The Birch reduction is favored because it offers stereoselectivity resulting in formation of the desired trans-ketene of formula II.

Treatment of the compounds of formulae II and III wherein R is oxo with the appropriate alkylene g1ycol having from two to four carbon atoms in the presence of a dehydrating agent juch as p-toluenesulfonic acid, or other acio used in kctalization (oxalic, adipic), affords the corresponding ketals. - 7 «3700 Reduction of the 9-oxo groups of formulae II and III compounds (Ro “ oxo) via metal hydride reduction affords compounds of formula I (R = H). Representative of the metal hydrides useful for such conversion are lithium aluminum hydride, lithium borohydride and sodium borohydride. Sodium borohydride is favored as reducing agent in this step since it not only affords satisfactory yields of desired product, but reacts slowly enough with hydroxylic solvents (methanol, ethanol, water) to permit their use as solvents. A temperature of from about 0° C. to 30° C. is generally used. Lower temperatures, even down to about -70° C., caii be used to increase selectivity of the reduction. Higher temperatures cause reaction of the sodium borohydride with the hydroxylic solvent. If higher temperatures are desired or required for a given reduction, isopropyl alcohol or the dimethyl ether of diethylene glycol are used as solvents.

Agents such as lithium borohydride or lithium aluminum hydride require anhydrous conditions and non-hydrosylie solvents (1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether af diethylene glyeol).

The isomeric 9a- and 9d-hydro:ty compounds are produced in this step. The above-described reaction sequence is sumparized below. ch3coch=ch2 Rase HaBH^ II (+ cis Isomer) - a V' The required 5~R,-S-hydroxyinethylene-S-R^iC-/^(Z-Wj-H-chronianoneE (IV) are prepared from 3,5-dihydroxybenzoic acid by the following abbreviated sequence: CO-Y.

Oci OY, S_-: Y,0 JPaj , r d'' Γ·ν* C-Z'-tf VIII ' ?.,a,c«cK-co!)ij ; o ! BF,· (C, .· - :j £.

VIX F (Β, X HCOOC.H. 'z-w Mall The starting aatari&l, 3,5-dihydroxybenaoic aoid (V) is converted 5 to a compound cf iormula (VI) wherein Y9 represents an alkoxy group, desirably methoxy or ethoxy for ease of preparation, or an amino group; and Y^ is a hydroxy protecting group, by methods described in the literature. - 9 4 3 70( When Z is alkylene, 7^ is desirably alkyl having from one to four carbon atoms or benzyl. Tha function of group Y^ is to protect the hydroxy groups during subsequent reactions. Ittis its ability to perform a specific function; i.e., protection of the hydroxy groups, rather than its structure which is important. The selection and identification of appropriate protecting groups can easily and readily be made by one skilled in the art. The suitability and effectiveness of a group as a hydroxy protecting group are determined by employing such a group in the above-illustrated reaction sequenc It should, therefore, be a group which is easily removed to permit restoration of the hydroxy groups. Methyl is favored as a protecting alkyl group since it is easily removed by treatment with pyridine hydrochloride. The benzyl group, if used as a protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

Wiien Z is -(alk^-K-Calk/L·-,fe preferably benzyl or a substituted ben15 - zyl group since it can subsequently ba removed without detriment to the Z group.

The diprotected benzoic acid derivative (VI) is then converted to a compound of formula VIII by known technology. In one procedure VI is hydrolyzed to the corresponding acid (7, e Oh)» or lithium salt, and reacted with the appropriate alkyl lithium to produce an alkyl disubstituted phenyl ketone (Y^ = alkyl). When methyl lithium is used, the resulting acetophenone derivative is treated with a Grignard Reagent (W-Z’-MgBr). The intermediate adduct is hydrolyzed to the corresponding alcohol which is then hydrogenolyzed to replace the hydroxy group with hydrogen. This procedure is especially useful for those compounds wherein Z is alkylene, The ether groups are deblocked by suitable means: treatment with pyridine hydrochloride (7^ ° methyl) or catalytic hydrogenolysis (7^ *= benzyl), - 10 4 3 7 0 0 or by treatment with an acid such as trifluoroacetic acid, hydrochloric, hydrobromic or sulfuric acids, or pyridine hydrochloride. Acid debenzylation is, of course, used when the group -2-H contains sulfur.

A further method for converting compounds of formula VI to those of 5 formula Till comprises reaction of a ketone of formula VI (Y^ “ alkyl) with the appropriate triphenyl phosphonium bromide derivative [(C^H^),Γ'-Ζ-WjBr ln the presence of a base (e.g., sodium hydride). The reaction proceeds via an alkene which is subsequently catalytically hydrogenated to the corresponding alkane (Z-’J) and deblocked to the dihydroxy compound (VIII). Of course, when -Ϊ- is (alk^)ffl-X-(alkj|) and Y^ ia benzyl, the catalytic hydrogenation also results in cleavage of the benzyl ethers.

Alternatively, conversion of structure ΥΪ compounds to those of structure VII2 can be achieved by ti.a sequence - VII -> VIII. In thia sequence, the diprotected beissteaid.·: 'VI, Y^ =· HH^) is converted to the ketone (VII, » 1 less, 'ins CH.. group) iy reaction with the appropriate Grignard reagent (BrMg-2’-'·/ fo)loved by reaction with methyl- or ethyl-magnesium halida to form the ccr«‘vac Ling carbinol· tahydration of the carbinol, e.g. with p-toluanesulfoaia acid, affords the corresponding alkene which is then catalytically hydrogenated (Fd/C) to the alkane (VIII). The ether groups are deblocked 'converted to hydroxy) as described above.

The conversion of VIII co the 4-c-hromanone (IX) is achieved by the reaction of 7111 with crotonic acid or an acid of the formula R^Rg-C=CH~COOH in the presence of boron trifluoridi acherate at froa about 20° to about 125°C) In addition to structure IX products, a second product, isomeric to IX (72S hvdroxy-2,2-R,R.-5-Z-V-4-chromanone), is also produced. • -4 J Tiie 4-chroaanones of formula IX are then converted to hydroxymethylene derivatives of formula IV by reaction with ethyl formate and sodium hydride. - 11 43790 Compounds of formula VIII wherein -Z-W is -alkylene-17 or -(alk^)X’-(alk-) -17 wherein (alk,), (alk.), W and n are as defined above and X' is ί n Li or S, are obtained by the following sequence! OY CY, I * Cil CH.,-OTs z R1 .cu, Oil I R' 2-CUgBr W-X’H V ^CSH5^ 3P OY, OY, H CH2-X’-W 'CU <· © R1 Br- acid !r'-c-(cu2)v-w V <*3700 The first step in the above sequence (the Wittig reaction) provides opportunity, by choice of appropriate reactants, to produce compounds having straight or branched alkylene groups. In the given illustration, the value of k' as methyl or ethyl permits formation of a compound having alkyl substi5 tut ion on the carbon atom (a) adjacent to the phenyl group. Substitution of a m,:thyl or ethyl group at other sites, e.g., the 2-carbon Mioa of the alkylene group, is achieved by choice of the appropriate carboalkoxv alkylidene triphenylphosphorane, e.g., (P.’)-COOl JL. The unsaturated ester | thus produced is reduced tc the corresponding saturated alcohol by reaction 10 with lithium aluminum hydride, generally in the presence of a small amount of aluminum chloride. Alternatively, when is other than benzyl (e.g. methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium-carbon, followed by treatment of the saturated ester thus produced with lithium aluminum hydride. Conversion of the alcohol to the corresponding tosylate or mesylate followed by alkylation of the tosylate or mesylate with an alkali metal salt of che appropriate HX’-(aIk,,)~'>i reactant, and finally removal of the protecting groups (γρ affords the desired resorcinol. When X1 is sulfur, the protecting group is methyl. Λ variat < ).-. of the above sequence comprises bromination of the alcohol rather than converting It to a tosylate or mesylate. Phosphorous tribromide, is a convenient brominating agent. The brome derivative Is Chen reacted with the appropriate l!X'-(alk,)-W in the presence of a suitable base (Williamson reaction).

The bromo compounds also serve as valuable intermediates for in25 creasing the chain length of the alkylene moiety In the above sequence to give compounds wherein ί is -alkylene-W. The process comprises treating the bromo derivative with triphenyl phosphine to produce the corresponding triphenylphosphoniun bromide, heaction of the triphenylphosphonium bromide with the Ή I I appropriate aldehyde or ketone in- the presence of a base such as sodium hydride or n-butyl lithium affords an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

In this variation, the value of the protecting group (Y^) selected depends upon the particular sequence followed, When the Vertical sequence on ths right is used, benzyl is the preferred protecting group by reason of the catalytic hydrogenation step, Methyl is the preferred protecting group whan the left vertical sequence Is followed, since it is conveniently removed by treatment with acid as described herein. - 13a ,37 J Ο Compounds o£ formula 11 wherein -Z-W is -(alkj)rr-X-(alk,) -W and X is -SO- ur -Sf^- are °htained by oxidation of corresponding compounds in which X is -S-. Hydrogen peroxide is a convenient agent for oxidation of the thio ethers to sulfoxides. Oxidation of the thio ethers to corresponding sulfones is conveniently accoraplished by means of a peracid such ao perbenzoie, perphthalic or n-chloroperbenzoie acid. This latter peracid is especially useful since the by-product m-chlorobenzoic acid is easily removed.

Alternatively, the compounds of this invention can be prepared according Co the procedure described by Fahrenhcltz, et al., J. Am. Chem. goc. 89, 5934-5941 (1967). This process comprises Ven I’eehraann condensation of the appropriate -Z-’.’ substituted 3,5-dihydroxyhenzene with diethyl-a-aeetoglutarate in the presence of phosphorous oxychloride. The ethyl-5-hydroxy-4Bethyl“7-(Z-l.')-couttarin-3-propionete thus produced is chen cyciised to 7,10diliydro-l-hydroxy-5-(3“W)-6ii-di’e;i;rc-fh,.j]pyran-6,9(6!!}-di.one by reaction with sodium hydride in dimethylsulfoxide. The dibenzo[b,d}pyran thus produced is converted to the corresponding 9-ketal derivative hy reaction with ethylene glycol and p-tol.ienesu3 foni, acid. Treatment of the ketal with the appropriate alkyl magrssitai iodide followed by aeid hydrolysis affords dl-6a,7-dihydrc 2--hydroxy-6,6-d ialkyl-3- (Z-Wl-SH-diber.zoEbjdlpyran-S (8H)-one. Birch reduction of the thus-prud .cad dihydro compound provides the corresponding tetrahydro compound, which is converted to the 1,9-dihydroxy compound having formula I by reduction with sodium borohydride as described above. -14 A further method for making compounds of formula VIII wherein Z-W is (alk^)-X-(alk2)-U comprises reaction of the appropriate 3,5-(di~protected : hydroxy)styrene oxide with an alcohol or thio alcohol (HX-(alk2>-W) as its alkali metal (preferably sodium or potassium) salt. Methyl is a favored S protecting group for the 3,5-dihydroxy styrene oxides because of its ease of , removal. The resulting 3,5-(di-protected hydroxy)phenyl hydroxyalkyl ether ' compound (formula VIII-A) is converted to the corresponding alkyl ether (formula VIII-B) by treatment with phosphorous oxychloride followed by dehalo-i genation of the thus produced chloro derivative by means of hydrogen over , palladium. Removal of the protecting groups as described above affords I the desired compound. The reaction sequence is presented below (Y^ = benzyl, alkyl having one to four carbon atoms; X! Is 0, S; R’ = H, CH^, and may be alike or different).

Yl° OY, Yl° Cll-CH-X'-(alk2)-W L' R' vui-n 4H on HO vCH-Cil-X'-(alk2)-U R' R' Vllt - 15 ¢3700 Λ further mcthud fur making iCMiytiuiitL· uf i.urmula Viii wherein Z—Vi is (alk2)-X-(a.lk2)-W comprises reaction of the appropriate 3,5-(di«protected hydroxy)etyrene oxide with an alcohol or thio alcohol (UX-falk^)-··') as its alkali metal (preferably sodium or potassium) salt. Methyl is a favored J protecting group for the 3,5-dihydrcxy styrene oxides because of its ease of , removal. Tiie resulting 3,5-(di-protected hydroxy)phenyl hydroxyaikyl ether compound (formula VIII-A) is converted to the corresponding alkyl ether (formula VIII-B) by treatment with phosphorous oxychloride followed by dehalo genation of the thus produced chloro derivative by means of hydrogen over palladium. Removal of the protecting groups es described above affords the desired compound. The reaction sequence is presented below (Y^ = benzyl, alkyl having one to four carbon atoms: X’ is 0, Sj P? = ii, CH^, C^Hj and may be alike or different). io ι YjO ^ 'C-CH pj r:! .Λ*·*· * ' fell ., g''' '•C— CH»X'-(alk,)-W i I VIII-A P0C1 +h2/m-c '‘C’l-Ch-X'-Calk,,)-» i ί Z R' R* VIII-B ii+ -15 0. ‘13 7 0 0 The analgesic properties of the compounds of this invention are determined by tests using nociceptive stimuli.

Tests Using Thermal Nociceptive Stimuli a) Mouse Hot Plate Analgesic Testing The method used is modified after Woolfe and MacDonald, J. Pharmacol. Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied to the feet of mice on a 1/8 thick aluminum plate. A 250 watt reflector infrared heat lamp is placed under the bottom of the aluminum plate. A thermal regulator, connected to thermistors on the plate surface, programs the heat lamp to maintain a constant temperature of 57° C. 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 observed at 0.5 and 2 hours after treatment with the test compound for the first flicking movements! of one or both hind feet, or until 10 seconds elapse without such movements. Morphine has an ΜΡΕ^θ= 4-5.3 mg./kg. (s.c,). b) Mouse Tall Flick Analgesic Testing Tail flick testing in mice is modified after D'Amour and Smith, J, Pharmacol. Exp. Ther., 72, 74-79 (1941), using controlled high intensity heat applied to the tail. Each mouse is placed in a snug-fitting metal cylinder, with the tail protruding through one end. This cylinder is arranged so that the tall lies flat Over a concealed heat lamp. At the onset of testing, an aluminum flag over the lamp is drawn hack, allowing tho light beam to pass through the s!it and focus onto the end of the tail. A timer is simultaneously/ activated. The latency of a sudden flick of the tail is ascertained. Untreated mice usually react within 3-4 seconds after exposure to the lamp. The end point for protection is 10 seconds. Each mouse is tested at 0.5 and 2 hours after treatment with morphine and the test compound. Morphine has an ΜΡΕ,-θ of 3.2-5.6 mg./kg. (s.c.). -1643700 c) Tail Immersion Procedure The method is a modification of the receptacle procedure developed by Benbasset, et al., Arch, int. Pharmaeodyn., 122, 434 (1959). Male albino mice (19-21 g.) of the Charles River CD-I strain are weighed and marked for identification. Five animals are normally used in each drug treatment group with each animal serving as its owr, control. For general screening purposes, new test agents are first administered at a dose of 56 mg,/kg. intraperitoneally or subcutaneously, delivered in a volume of 10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post drug, each animal is placed in the cylinder. Each cylinder is provided with holes to allow for adequate ventilation and is closed by a round nylon plug through which the animal’s tail protrudes. The cylinder is held ir, an upright pas J tion and the tail is completely lmerssd in tha constant taraerature waterbath (56s C.). The endpoint for each trial is an energetic jerk or twitch of the tail coupled with a motor' response. Ir. some cases, tha endpoint may be less vigorous post drug. To prevent undue tissue damage, the trial is terminated and the tail removed from the waterbath within 10 seconds. The response latency is recorded in seconds to the nearest 0.5 second. A vehicle control and a standard cf known potency are tested concurrently with screening candidates. If the activity of a teat agent has not returned to baseline value3 at Che 2-houi testing point, response latencies are determined at 4 and 6 hours. A final measurement is made at 24 hours if activity is still observed at the end of the test day. - 16a »370 V Teat Using Chemical Nociceptive Stimuli Suppression of Phenylbenzoquinone Irritant-Induced Writhing Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. Twenty minutes (if treated subcutaneously) or fifty minutes (if treated orally) later, each group is treated with intraperitoneal injection of phenylbenzoquinone, an irri cant known to produce abdominal contractions. The mice are observed for 5 minutes for the presence or absence of writhing starting 5 minutes after the injection of the irritant, MPEG's of the drug pretreatments in blocicing ' writhing are ascertained.

Tests Using Pressure Nociceptive Stimuli Effect on.the Haffner Tail Pinch Procedure A modification of the procedure of Haffner, Esiperlmentelle Prufung Schaergstillender. Mittal Deutch Med. Wschr., 55» 731-732 (1929) is used to 15 ascertain the effects of the test compound on aggressive attacking responses elicited by a stimulus pinching the tall. Male albino rats (50-60 b.) of the Charles River (Sprague-Dawley) CD strain are used. Prior to drug treatment, and again at 0.5, 1, 2 and 3 hours after treatment, a Johns Hopkins 2.5-inch bulldog clamp is clamped onto fhe root of fhe rat's tall. The endpoint at each trial is clear attacking and biting behavior directed foward the offending stimulus, with the latency for attack recorded in seconds. The clamp is I removed in 30 seconds if attacking has not yet occurred» and the latency of response is recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.), Tests Using Electrical Hociceptivs Stimuli 25 The Flinch-Jump Test A modification of the flinch-jump procedure of Tenen, Paychopharmacologia, 12, 278-285 (1968) is used for determining pain thresholds. Male albino rats (175-200 g.) of the Charles River (Sprague-Dawley) CD strain are used. Prior to receiving the drug, the feet of each rat are dipped into a - 17 .-,3700 20X glycerol/saline solution. The animals are then placed in a chamber end presented with a series of 1-second shocks to the feet which are delivered in increasing intensity at 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.73, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal’s behavior Is rated for the presence of (a) flinch, (b) squeak and (c) jump or rapid forward movement at shock onset. Single upward series of Shock intensities are presented to each rat just prior to, and at 0.5, 2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possible 10 effect (S MPE). 'ins 7s Ml’E of each group io statistically compared to the '1 MPE of the standard and the predrug control values. Tiie % MPE is calculated as follows; <·.· iron _ test time - control, tine , ' cut-?f rias ,. control time x The compounds of the present invention 2re active angesics via oral 15 and parenteral administration an! are conveniently administered in composition form. Such compositions include a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they nay be administered in the fora of tablets, pills, powders or granules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered in capsules, in admixtures with the same or equivalent excipients. They nay also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs which may contain flavoring and coloring agents, for oral administration of the therapeutic agents of this invention, tablets or capsules containing from about 0.01 to about 100 mg. are suitable for most applications.

The physician will determine the dosage which will be most suitable for an individual patient and it will vary with the age, weight and response ~ 43T00 S' of the particular patient and the route of administration. Generally, however, the initial analgesic dosage in adults may range from 0.01 to 500 mg. per day in single or divided doses. In many instances, it is not necessary to exceed 100 mg. daily. The favored oral dosage range is from about 0,01 to about 300 mg./day; the preferred range is from about 0.10 to about 50 mg./day. The , favored parenteral dose is from about 0.01 to about 100 mg./day; the preferred! range from about 0,01 to about 20 mg./day. , By means of the above procedures, the analgesic activity of several compounds of this invention and of certain prior art compounds are determined.

The data are reported in terms of maximum possible effect.

The following abbreviations are used in tabless PBQ = phenylbenzoquinone-induced writhing; TF = tail flick; HP => hotj plate; RTC ° rat tail clamp; PJ α flinch jump; and TI « tail immersion assays. - 19 ί·· © · <3 · & H -a H r** H co « · · · * to » O 53 O >i -) o rtf • -i CM H rH H i (M .· r* 30 » &» . co » ;?· ,-j y * · Ζ» ffi CM Cr- ''w • r-i CM G f'·' O' rH · · /. © CO lA C Λ tt , Ί · * f 5 ri CM (O CO -Μ Ο P·» ffi • s—! » ffi Λ Λ I r-i CO MJ *.- C> CM <· C c>l « · s · .—i · κ ,-i © a L ’* P) ,»J Ο O i vT’ © ffi © © y.·» l ni m3 © I rl cd ffi ffi v_z ' ZZ3 ui n tn ’‘ffi ~ κ © vO ffi ffi 1 J CJ © CM -j i’\ :'i Cu S'e ffi Cm cm V ι ι cn #-* α 3J ίθ © CO co -- © © © iii( rn cn H r-j ffi G£ \Z> ffi xi it» ffi I ffi r- ffi <0 • nJ G © o O a a © © © ffi c S 3 o O cu ffi K o o c a ffi <·* ffi 0?‘ u w •rs in »n in m r-i m 'M re* r-i >i * '“ffir\o CG m m © © ( ”In © 1 c CJ I cn o } c 1 co rM H ZN J ffi ! Ci. &· CM co •Μ λ (3 β .A ffi zn CM C3 $ © h-Z CM 3J © ς? -»Z . f! G £ Λ ffi J © l Jl- © MS Ut ZN <> © J tn I m I 1 ZN 0 O •rt zn ffi r-f z^» cn ffi © cn ύ CO co ffi < w 33 v ffi u UJ D ffi ’“hb ffi © © U 4J 'm-’ u © ffi XwZ CM β a V o © l o 1 a m a © © * 3 1 Φ 0 c o C3 fi o 1 1 1 11 * a ffi 3* ffi H 6 ffi c o & © © co a* cn 31 m cn cn CO z> ZN ffi ffi « o 0 ffi s 5 □ rj o is © © £i NZ - 20 437 &-* H 5-f fo fo fo Η Η Η Η fo fo Ά fo fo CM cn © ιΛ α ω fo 23 Η fo Η Ή fo fo ΚΗΗΚΗεαΚΗ fofofofofofofofo O H • I H » · fo Η fo CM cn e*3 cn . I o rrt 5Π J J ° Η Η © CM << H ° iA © ιη ΙΛ ΙΑ ο κ 22 fo in m in u·) © © © £< 22 S3 22 O CJ U © © © © I 1 I υ ο υ o cm m ό l J I | .·*» /-\ T rl cm cn *? cn cm cm cn ri /> z-s s·* 2J 52 fo ΓΜ CM CM CM CJ CJ CM m in 22 5i 22 s ό «-* ft a fo ο ο cj CJ I I □ | © V»’ •a·' O' /“% Z\ rtZ />. υ ί ι ι ι _?n cn i cn | z. r» <-« S ϊ pm cn cn cn cn cj cj ·>. fo fo 22 S *-* *-.* CM 0 CJ U U cn ι * rtO * o I CM „ cj cj ss fo fo fo ι o CJ CJ O CJ o I ( I i 1 I rtrt u 52 ι b o 1 I CM U vrt I -» cn fo fo H © G H t? rtrt o ό b tP ( I I Λ Ή fes V ψ cn cn cn cn u o G G fo cn cn cn fA srt 52 fo — 1 cj cj o £5 «η cn cn Oi 52 54 CJ CJ CJ - 21 i3700 Their antihypertensive utility is determined by their ability to' lower the blood pressure of conscious hypertensive rats and dogs a statistically significant degree when administered orally to said hosts at the abovementioned dosages.

Their tranquilizer activity is demonstrated by oral administration to' r:sts at doses of from about 0,01. to 50 mg./kg. with subsequent decreases in spontaneous motor activity. The daily dosage range in mammals is from about 0.01 to about 100 mg.

, In addition to their analgesic, hypotensive and tranquilizer activities, compounds of formula I are also useful as immunosuppressants and antisecretory agents.

Their gastric antisecretory effect in pouch dogs (Heidenhain) is determined by the following procedure.

Gastric antisecretory activity is studied ia overnight fasted, conscious Heidenhain pouch dogn pentagastrin, histamine or food to stimulate' acid output, hentagastrin or histamine is administered as a continuous infusion into a superficial leg vein at doses earlier detersiined to stimulate near maximal acid output from the gastric pouch. Food stimulus consists of onehalf can of Ken-t,-Ration (approx. 220 g.) per dog; dogs weighing 9-12.5 kg. are; used. Gastric juice is collected at 30 minute intervals following the start of a histamine or pentagastrin infusion or the ingestion of a standard food meal. A total of ten collections are made for esc.· dog during an experiment. Drug Is administered orally at levels of from 0.01 to 50 eg./kg. after the third gastric juice collection. All sample volumes are recorded and acid con- „ centration is determined by titrating sample aliquots (1.0 ml.) to pH 7.4 with 0.1N haOH using a pH meter (Radiometer) and auteburette. The drug is given orally after placing it in gelatin capsules. ^3700 Immunosuppressant activity is evaluated by means of a mixed lymphocyte culture assay procedure. This assay measures the effects of the test compounds on antigen-stimulated lymphocyte proliferation. Spleen lymphoid cells from BALS/C and C57BL/6 mice, 8 x 10 calls from each strain, are sus5 pended in 2.0 ml. of a serum-free medium containing the test compound and incubated at 37° C. in a 102 carbon dioxide atmosphere. The culture conditions !i and technique are described by R. W. Dutton in 2· Exp. Med., 122, 759 (1965) and the cellular medium is described by V. T. Weber in J.. Retie. Soc., _8, 37 (1970). Half of the medium, 1 ml., is replaced with fresh medium every 24 3 hours. K-TdR incorporation (24 hour pulse) into desoxyribonucleic acid is then determined by trichloroacetic acid precipitation of desoxyribonucleic acid and assessment of radioactivity in a liquid scintillation counter. The percent inhibition is determined by comparing each test compound-treated mixed culture with the control mixed culture. Ή' EXAMPLE 1 dl-5-Hydroxy-2,2-dimethy1-7-(1- methyl-4 - phenylbutyl)______ 4-chrpmanone______ A mixture of 2-(3,5-dihydroxyphenyl)-5~phenylpentane (9.6 g.) and 3-methylcrotonic acid (4.5 g.) is heated to 125° C. under nitrogen, and boron trifluoride etherate (S.7 al.) is added. After refluxing for one hour, the reaction is cooled ar.d water (10 ml.) is added followed by 6;I sodium hydroxide (40 mi.)- The reaction mixture is heated for j minutes on a steam bath, cooled and acidified with 6H hydrochloric acid. The aqueous layer is extrac-. ted with ether (3 χ 100 al.) and the combined ether extracts washed with 10S sodium bicarbonate (’ x 25 ml.) and water (1 x 25 ml.). The organic phase is dried over sodium sulfate and concentrated under vacuum to afford 12.7 g. of a crude oil which Is purified by silica gel chromatography to yield 5.0 g. of dl-5-hydroxy-2>2-diBefhyl“?-Cl-sif-thyi-4-phcnylbt!tyl;-4-chromanone as a colory leas oil.

IS: (CtiClj) IMS f; 2635 cm .

H.'ffi: l-i.? (K,7,α-methyl, ethylene), 1.5 (S,6»gem dimethyl). 2.3-2.9 (M. j,benzyl,ic-mcritylene, methinyl), 2.55 (S,2,ci-methylene), 6.1-6.35 (M,2,aromatic), 6.9-7.4 (M,5,aromatic), 11.53, 11.63 (d,l, hydroxyl).

Similarly, 2-(3,5-dihydroxyphenyl)-5-phenylhaxane is converted to dl~5~hydroxy-2,2-dimethyl-7-(l*-methyi-5-pbenylpentyl)-4-chronanQne (an oil); JiMRi ^cDcl 1,:έ (<1>-»e“meei,y3, 1 7 cps), 1.4 (8,6,gem dimethyl), 1.0-1.9 iM,6,0-CH,j»(eiL)j-CCIHjJ-Ar], 2.3-2.8 (M,3,benzylic-iiiethylene, r,ethinyl) s 2.7 (5,2,a-methylsne), 6,2-6.4 (M,2,aromatic), 7.1-7.3 (M,5,aromatic), 11.6 (S,1,hydroxyl); _24 1- (3,5-Dihydroxyphenyl)-2-phenylethane is converted to 5-hydroxy2.2- dimethyl-7-(2 -phenylethyl)-4-chromanone (an oil): IR: (CHC13) C=0 1645 cm-1 TMS NMR: 1.45 (S, 6,gem dimethyl), 2.65 (S,2,a-methylene), 2.35 · (S,4,ethylene), 6.25, 6.3 (2d,2,aromatic), 7.2 (S,5,aromatic), 11.6 (S,l, Lydroxyl-DjO overlay).

MS: (mol·ion) 296 . 2-(3,5-Dihydroxyphenyl)-4-phenylbutane is converted, to dl-5-hydroxy 2.2- dimethyl-7-(l -methyl-3 -phenylpropyl)-4-chromanone (an oil): TMS NMR: 1.3 (d,3,methyl), 1.45 (S,6,gem dimethyl), 1.55-2.1 (M,2,methylene), 2.25-2.75 (M, 3,benzylic-methylene, mathinyl), 6.15 (d,2, aromatic), 7.1 (S,5,aromatic), 11.6 (Sjljhydroxyl-D^O overlay).

MS: (mol· ion) 324 2- (3j5-dihydroxyphenyl)-5-phenylpantane (5.27 g.) is converted by reaction with boron trifluoride etherate (4.81 ml.) and crotonic acid (2.08 g, of freshly distilled) In place oi 3-methylcrotonic acid to dl-5-hydroxy-2methyl-7-(l -methyl-4 -phenylbutyl)-4-chromanone: TMS NMR: 1.1 (D,3,α-methyl, J = 7 Hz), 1.4 (D,3,2-methyl, J » Hz), 1.3-1.8 (M,4-ethylene), 2,2-2.9 (M,S,a-methylene, bensylie-methylene, ) methinyi), 4.5 (M,l,methinyi ether), 6.1, 6.2 (2D,2,aromatic, J = 1 Hz), 6.9-7.4 (M,5,aromatic), 11.7 (S,l,phenolic OH). _ 2543704' 4-(3,5-dihydroxyphenyl)-l-phenoxypentane is converged to di-5hydroxy-2,2-dimethyl-7-(1-methy1-4-phenoxybutyI)-4-chromanone, a 1ighfc yellow oil: MS: (mol.ion) 354 Rr = 0.61 (silica gel, 18-benzene:-ethyl acetate) Analysis: Calc'd for C22H26°4: 7Λ·55; Η» U™ Found: C, 74.56; H, 7.362 4-(3,5-dihydroxyphenyl)-1-(4-pyridyl)pentane is converted to di-5-hydroxy-2,2-di methyl-7-/1-methyl-4-(4-pyri dyl)butyl? -4-chromanone, lo an oil: Rf =0.39 (silica gel, l-bensene:l-ethyl acetate) NMR: 1-1.90 (M.13-H,methylene, methyl doublet at 1.20,3 = 7 H , and gem dimethyl singlet at 1.5); 2,43-2.86 (Κ,δ-Η, methylene, methinyl, including singlet (two C-3 H's at 2.71); 6.26 (b.d.S,l-H, aromatic); 6.33 (b.d.S,i-H, arasatic); 7.00-7.20 (b.d.D, 2-H,pyridine aiomatic); 7.25 (b.d.S, i-Hshya?rty:); 8.41-8.61 (b.d.f,1,2-H,pyridine aromatic). d 1 -5-hydi'oxy-, 2-dimethyl -7-(1 -methyl -3-phenoxyprapyl) -420 chrcmanone is prepared fret; 3-(3,5-dihydroxyphenyl)-l-phenoxybutane as ar. oil.

Rf = 0.7 (silica gal, 18-benzene:1-ethyl acetate) MS: (mol,ion) 340 Analysis: Calc'd for C21H2404: C, 74.09: H, 7.11% Found C, 74.04; H, 7.19« dl-2-(3,5-01hydroxyphenyl)-l-(2-phenylethoxy) propane is converted to dl-2,2-dimethyl-5-hydroxy*7-/i-methyl-2-(2-pheny1ethoxy) ethyl/-4-chromsnone (an oil).

NMR: 1-21 (d> J=7Hz> methyl), 1.48 (s, gem dimethyl), 2.73 (s, C-3 methylene), 2.5£ (+, J=7Hz, CH2Ph), 2.9 (m, methine), 3.50 (d, J=7Hz,-CH20-), 3.65 (t, J=7Hz, -OCHg-), 6.31 (d, J=7Hz, -CHgO-), 3.65 (t, J=7Hz, -OCHg-), 6.31 (d, J=lHz, ArH), 6,38 (d, J=lHz, ArH), 7.26 (s. Ph) and 13.33 (s, phenol).

EXAMPLE 2 dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethy1-7-(1 methyl-4 - phenylbutyl)-4-chromanone To sodium hydride obtained by washing 50?! sodium hydride in mineral oil dispersion (6,57 g.) with pentane is added dropwise, over a 30-minute period, a solution of dl-5-hydroxy-2,2-dimethy1-7-(1-methyl~4-phenylbutyl)-4chromanone (4.7 g.) and ethyl formate (23,1 g.). The reaction mixture is then cooled to room temperature and ether (350 ml.) added. The resulting mixture Is refluxed for 18 hours, cooled to room temperature and acidified with. IS hydrochloric acid. The ether layer is separated and the water layer extracted with ether (3 x 100 ml.). The combined ether extracts are dried over sodium sulfate and concentrated under vacuum to yield 5.7 g. of dl-5-hydroxy3-hydroxymethylene-2,2-dimethy1-7-(1 - methyl-4 -pheny lbutyl)-4-chromanone as an oil.

TMS KMR: Oqjjci 1.05-1.8 (M,13,gem dimethyl, α-methyl, ethylene), 2.45 (M,3,benzylic-methylane, methinyl), 6.2-6,5 (M,2,aromatie), 7.0-7.6 (M,6, aromatic, methinyl ether), 11.3, 11.36 (2bd.S, 1,phenolic hydroxyl), 13.3, 13.5 (2bd.S, 1,hydroxyl).

. IR: (CHC13) C=0 1625 cm1 In like manner, the products of Example 1 are converted to: dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(l -methyl-5phenylpantyl)-4-chronanone: hid: 5^“^ 1.2 (D,3,a-methyl,J » 7 cps), 1.6 (S,6,gem dimethyl), 1.0-2.0 [M,6,!5CH2-(CH2>3-CH(CR3)Ar), 2.3-2.8 (M,3,benzylic-methylene, methinyl)6.2-6.4 (>i,2,aromatic), 7.1-7,4 (M,6,aromatic, vinylic), 11,4 (bd.S,l phenolic hydroxyl); -27 α3700 -nydroxy-3~hydroxymethylene-2,2-dimethy1-7-(2 - phenylethy1)-4chromanone (an oil) .· IR: (CiiClj) C-0 1625 cn1 XMR: 6?® 1.5(£,6,gam dimethyl), 2.85 (S,4,ethylene), 6.2, 6.3 tjL'”i3 (d,2,aromatic), 7.0-7.5(M,6,aromatic, methinyl), 11.35 (S,l,hydroxyl-i),0 overlay), 13,4, 13.6 (d,l,hydroxyl-DjO overlay).

MS:(mol·ion) 324 dl-5-hydro:iy~3-hydroxys!ethyl«;ne-2,2-diEethyi-7-(l - methyl-3 - phenyl propyl)-4-chroaanone (an oil): ’ll·®: (d,3,methyl), 1.5 (S,6,gem dimethyl), 1.65-2,1 (M,2,methylene), 2.25-2.75 (M.S.benzylic-metiiylaae, methinyl), 6.15, 6.3 (2d, 2,aromatic), 7,1 (M,6,aromatic, olefinic protan), 11.3 (Sjl.hydroxyl-O^O overU-j, 13.2, 13.β (d,l,hydrpjtyi-D-& overlay), MS:(moi’ion) 352 dl-5-hydroxy-o-iivi. o:c/asthylsne-2-s:et;iyi-7“(l - methyl-4- phenylbutyl)~4-chr3twrons: Xl®: 6^1, 1.1 (3,3,0-+-6 thyl, 4*7 Hz), 1.5 (D,3,2-methyl, 4 ·> CuCa. .j Hz), 1.3-1.8 (>l,4-ethyiene), 2.3-2.9 (M,3,&easyllc). 4.5 (K,l,methinyl ether. J * 5 ΐ!ζ), 6.2, 6,3 (2D,2,aromatic, J « 1. Uz), 0,9-7.4 (M,6,aromatic, vinylic), 11.2 ibd.S, 1,phenolic OH). - 28 43700 dl-5-hydroxy-2,2-dimethyl-7-(l-methyl-4-phenoxybutyl)-4- chromanone is converted to d,l-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7(l-methyl-4-phenoxybutyl)-4-chromanone: Rf = 0,44 /silica gel, 18-benzene:1-ethyl acetate7 MS: (mol,ion) 382 dl-5-hydroxy-2,2-di methyl-7-/1 -methyl-4-(4-pyri dy1)buty \] -4chromanone.is converted to d„l-5-hydroxy-3-hydroxymethylene-2,2-dimethyl7-/Ί-methy1-4=(4-pyridyl)butyiy-4-chromanone, a viscous oil: = 0.I5(silica gel, 1-benzene:I-ethyl acetate) dl-2,2-Dimethyl-5-hydroxy-7-/l-mathyl-2-(2-phenylethoxy) ethylj -4-chromanone is converted to dl-2,2-dimethyl-3-hydroxymethylene-5hydroxy-7-/‘l-msthyl-2-(2-phenylethoxy)ethyl/-4-chro[nanone (an oil) Rf = 0.35 (silica gel, 1:1 pentane:ether). - 29 EXAMPLE 3 dl-6a,7-Oilsydro-l-hydroxy-0,6-dimethyl-3-(l - ms thy 1-4phenylbutyl)-6H-dibenso-[b d]pyran-9(8H)-oae To a solution of 5-hydrcxy-3-hydroxymethylene“2,2-dimethyl-7-(l5 methyl-4 - phenylbutyi)-4-chrcmanone (0,916 g.) in methanol (4 ml.) and methyl vinyl ketone (O.C37 ml.) is added triathylamine (0.09 mi.). The reaction is .stirred for 16 hours at room temperature and then diluted with ether (50 ml.). The resulting ether solution is extracted with 107) sodium carbonate solution (4x5 ml,), dried over sodium sulfate and concentrated under vacuum to yield 1.09 g. of an oil. The residue is refluxed with ethanol (7.3 ml.) and 2N potassium hydroxide (7.3 ml.) for 16 hours. Thereafter, the reaction solution is cooled, acidified with (il hydrochloric acid and extracted with dichloromethane (3 :t 20 ml.). The organic phase is dried over sodium sulfate and evaporated to yie|d 1-.95 g. of en oil which crystallizes from ether: hexane (1:1) tc yield 0.49 g, D ci-6a,7-dihydrc-l~bydroxy-6»6-dimethyl-3(l-aethyl-4 -phenyIbuty!--'.;'-dibenco(b,dlpyran-C(8H)-one, m.p. 145e-148' C. after crystallization from isopropyl ether.

X;.R: 5?,!’,., 1-2,35 (X, 10, α-me thylene, ethylene, remaining protons), 1.55 (3,6,gam dimethyl), 2,35-3.0 (M,5,a-methylene, benzylic-methyleae, msthinyl), 6.1-6.7 (M,2,aromatic), 7-7.35 (M,5,aromatic), 7.9-8.2 (bd.8,1, olaf’nis proton), 19.8 (S,i,phenolic OH). ir: (α;α3) oo ieoo cm-1 Analysis: Calc'd far C26H,003: C. 79.97; H, 7.74 X Found: C, 79.91; 11, 7.78 X IS: (mcl-icn) 390 Similarly, dl-Sa,’7-dihydro-l-hydroxy-6,6-dimethyl-3-(1- methyl-5 phenylpentyl)-6H-dibenzo[b,d]pyran-9(8H)-one is prepared from 5-hydroxy-3hydroxymechylene-2,2-dimethyl-7-(l - methyl-5 -phenylpentyl)-4-chcomanone, n.p. 204°-208° C.

TMS SHR: 4COC1 1.1, 1·5 (2S,6,gem dimethyl), 1.0-3.0 [II, 17,a-methyl,' 0CH, (CH2),-CH(CI!.p-Ar, benzylie, remaining protons], 6.2, 6.3 (2D,2,nrrimatie protons, J = 2 cps), 7.0-7,4 (M,5,aromatic), 8.05 (D.l.vinylic, J = 2 cps), .8 (S,l,phenolic hydroxyl).

IR: (KBr) OO 1613 cm1 Analysis: Calc'd for d271132O3! C, 80.16; II, 7.97 % Found: C, 80.00; H, 8.29 % dl-6a,7-Dihydro-l-hydroxy-6,6-dimethyl-3-(2 - phenylethyl)-6Hdibenzo[b,d)pyran-9(8H)-one is prepared from 5-hydroxy-3-hydroxymethylene2,2-dimethyl7-(2-phenylethyl)-4-chroaanone, m.p. 233°-235° C.

SMR: 1.0-1.4 (M,3,6a-nst'ninyl, 7-metbylena), 1.5 (S,6,geta dimethyl), 2.35-2.85 (M,2,8-a-methyleae), 2.9 (S,4,ethylene), 6.3, 6.55 (2d,' 2,aromatic), 7.3 (S,5,aromatic), 7.95 (d,l,10-olefinic proton), 10.5 (S,l, hydroxyl-B^O overlay).

MS: (mol.ion) 348 and dl-6a,7-dihydro-l-hydroxy-6,6-dimethy1-3-(1- methyl-3·- phenylpropyl) -6H-dibenzo [b , d) pyran-9 (SH) -one from 5-hydroxy-3~hydrozrymethylene-l, 2dimethyl-7-(l - methyl-3-phenylpropyl)-4-chromanone, m.p. 181“ C.

KMR: 1.2, 1.3 (d,2,methyl), 1.55(S,6,gem dimethyl), 1.6-3.1 (Ms8,remaining protons), 6.3, 6.55 (2d,2,aromatic), 7.2, 7.25 (2S,6, aromatic/ hydroxyl-D^O overlay, S.05 (d„l,olefinic proton).

MS: (mol*ion) 376 31dl-6aa-7-dihydro-l-hydrossj-6a-oethy 1-3-(1 - methyl-4 - phenylbutyl)6H-dibenzo[b,d)pyrsn-9(8H)-one is prepared fre.?. cl-5-h7droxy-3-hydroxymetUylene-2-methyl-7-(l - methyl-4 - pheny3butyl)-4-cbrotiai!one; κ.ρ. 19S4-197° C. —\ις MMR: 1.2 (D,3,a-!!mthyl, J - 7 Hz), 1.4 (I),3,t-siethyl, J = 7 Hz), 1.3-1.8 (ii,6s7-Eethylene, allylic), 3.-3 (M,l,methinyi ether, 'jyidna'1 Hz), 7.0-7.4 5,aromatic), 7.S (D,l,vinylic, J - 1 Hz), 9.6 (H, 1,phenolic«:).

IA: (Kiri C ~ 0 1639 cm Analysis: Calc'd for C, I·»; jt, /.50 Z Fouad: C, 79,76; H, 8.33 2 C.Sj· GH U.V.: “ 225 (e = 14,400), 324 (ε = 26,660) ME: (mol.ior.) 37¾ dl-6a, '/-dihydro-l-hydraxy-S, 5-diae .-hyl-3- (i-iael riyl-4-phenoxybutyl)&i-dr:>fe’iZ0ib,dJpyrua-?<8H}-SiK! is prepare·’ from She corresponding 3-hydroxy15 msthyler.·; derivat ive j ~55 -175’ C, MS: (nijl.Ici.) O' = R » 0.31 L·· -ll;a gel, IC-benzene: >~=tl;yl acetate) a.aiysis; Calc’d for C^HjqG^: c, 76. 82; Ji, 7,44 X Found: C, 76.80; H, 7.572 2', dl-oa, 7-dihydrc-l-hydrcxy-6, e-dimethyl-3-il-wechyl~4-(4-pyridy 1) butyl}-6H-dioancoib,d3pyran-$(8H)-oae is prepared from the corresponding 325 hydroxymethyltne derivative us a glassy soilc. «5; (rraJ.ion) 391 Analysis: Calc’d for C, Found: 0, 73.32; li, 7.62; N, 3.42 2 73.22; ll, 7.47; K, 3.25 2 -32 4 3700 di-ba, 7-Dihydro~l~!iyyl]-4 chromanone, m.p. 185°-187’ C.

IR: (C1IC13) C = 0 1613 cm-1.

TMS MMR: 1·15 (s, one methyl of gem dimethyl), 1.20 (d, J=7ilz, methyl), 1,48 (s, one methyl of gem dimethyl), 2.0-3,1 (rn), 2,85 (t, J=7Hz, CK2Ph), 3.4-3.8 (m, -CdjOCRj-), 6.35 (bs, Aril), 6.63 (be, ArH), 7.30 (s, Ph), S..10 (d, J=>2Hz, C-30 3) and 12,3 (s, phenol).

MS: m/e 406 (M®), 391, 376, 363, 315, 302 (1002), 287, 285 and 272. —32, a. *3700 EXAMPLE 4 1C dl-6a3-7,10,10aa-Tetrahydro-l-hydroxy-6,6-dimethyl-3-(1-methyl-4phenylbutyl l-eK-dibenzo/b.d/pyran-giSHj-one A solution of dl-6«,7-iiihydiO-l-hydroxy-6s6-din;e.thyl-3-(l-[i!ethyl4-phenylbutyl)-6H-dibenzo/b,d7pyran-9(8H)-one (0.97G g.) in tetrahydrofuran (7 ml.) is added to a rapidly stirred solution of lithium (0.1 g.) in liquid ammonia (35 ml.) (distilled through potassium hydroxide pellets). The reaction is stirred for 15 minutes and then solid ammonium chloride is added to discharge the blue color. Th.e excess ammonia is allowed to evaporate and the residue is diluted with water (35 ml.) and acidified with concentrated hydrochloric acid. The water solution is extracted with dichloromethane (3 ?; 25 ml.) and tha dichlorometnane extracts dried over IS sodium sulfate and evaporated to yield 0.98 g. of a crude oil which was purified via column chromatography to yield 0.39 g. of dl-6ae-7,iO.iOaatetrahydro-1-hydroxy-6,6-dimethy1-3-(1-methyl-4-phenylbutyl)-6Hdibenzo /b.d/pyran-9(8H)-one, m.p. 20-^-205¾. «· 1-2.35 (M,ll,!ri‘;sthvi·. ethylene, remaining protons), 1.55 (S,6,gem dimethyl), 2.35-3,5 IR: (CHClg) C--C 1535 cm*1 and dl-6a3,7,10,1Oa 3-tetrahydro-1-hydroxy-6,6-dimethy1-3-(1-methyl4-phenylbuty)-6H- dibenzo #>,d/pyran-9 (SH)-one as a solid foam.

IR: «0 1690 cm'1, OH 3275 an' NMR:S™j| G.35-2.12 (M.ll «-methyl.ethylene, remaining protons), 1.35, 1.4 (25,6,gem dimethyl), 2.25-2.95 (M,7,«-me’.hylsriGS, benzylic-methylene, methinyl), 6,1-6.35 (M,2,aromatic), 7,l(bd.S,, 1,hydroxyl), 7.25 (S,5,aromatic). -2 37 0 0 dl-6ag-7,10,1 Oaa-tetrahydro-1 -hydroxy-6,6-dimethyl -3-(1 -methyl 5-phenylpentyl)-6H-dibenzoZb,^pyran-9(8H)-one, m.p. 159°-163° C.: -CH^-iCHgJ^-CHCCHgJ-Ar, benzylics, remaining protons/, 3.9-4,4 (S,T,phenolic hydroxyl),.

IR: (KSr) C=0 1695 cm1 Analysis: Calc'd for CZ7H34O3: C, 79.76; H, 8.43% Found: C, 79.49; H, 8.43% and the corresponding cis-diastereomer: dl -Sai ,7,10,1Oap-tetrahydro-1-nydroxy-6„6- dimethyl-3(l-methy1-5-phenylpentyl)-6H-dibsnzo /b,d/pyran-9(8H)-one; m.p. 91°-130° C.

IR: (KBr) C=0 1709 cm1 15 MS: (mel.ion) 405. dl-Sa ,7.10.10aa-tetrahydro-1-hydroxy-586-dimethyl-3-(2-phenylathyl)-6H-dibsnzQ/fc,^Zpyran-3(8H}-aneD a.p. 206°-209° C.: IS: (KBr) OH 3260 cm1, C=0 17:0 cr/1 NMR: 6^§l. 1.05-1.45 (2S,6,gem dimethyl), 2.75(bs,4,ethylene), 1.1=3.1 (M,z„rsmaining protons), 3.75, 4.0 (2d,l,10aa proton), 6.2 (d,2, aromatic), 7.15 (S,5,aromatic), 8.8 (S,ljhydroxyl-DgO overlay).

MS (mol ion) 350 dl-6ag,7,10, 10aa-i;gtrahydro-l-hydroxy-6,6-dimethyl -3-(l-methy13- phenylpropyl)-6H-dibenzo/b,d/pyran-9(8H)-one, m.p 165° C.: IR-. (KBr) OH 3176 cm1, C-0 1695cm1 and dl-6ap,7,10,1Oag-tetrahydro-1-hydroxy-6,6-dimethy1-3-(1methyl-3-phenylpropyl)-6H-dibenzo /b,d/pyran-9(8H)-one as a solid foam: IR: (CHCl,) C=0 1685 cm1, Off 3250 cm1 1.35, 1.45 (2S,6,gern dimethyl), 2.8 (bd,s,4,ethylene), 30 1.75-3.6 (M,8,remaining protons, 6.3 (M,2,aromatic), 7.25 fe,6, aromatic,hydroxyl. - 34 4 3 0 Ο til7,4.0,j.C.'m-i.et.i'«iiyJiu-l-b/'li-'.’sy“i·, u-diiii.:i,iiyl-3-(i-ihutii^ 1-4phenoxybutyi) i>il-dil>i>.nzo[b,u Jpyran-9 (SH)-one: M.P. lfiO’-l/S’ C.

MS: (mol.ioii) 403 Rj 0.53 (silica gel, 8~benzene:2—athyl acetate) TMC NMli; 7.41-6.67 (multiplet,6,phenolic Oli, Cglij); 6.3 (S,2, aromatic Uj 5^)5 4.33-1.56 (Ms, 15, remaining methylene and methine protons) 1.47 (8,3,00.); 1.27 and 1.17 (D,3,!!e); 1.12 (S,3,CH3).

Analysis: Calc’d fcr C,6«3,«4: C, 76.44; H, 7.39 % Found: C, 76.61; 11, 7.90 % dl-5aC,7,10,lOaa-tetrahydro-l-hydroxy-δ,6-dimethy1-3-[1-methy1-4(4-pyridyl)butyli-6R-dibenao(b,dJpyron-5(8H)-one: M.P. 6Ο’-7Ο’ C.

Rj - 0,4 (-jilicu ^el, ethyl acetate) 1151 -. noj., lc , .

KM; iff] 0.33-1. 73 (11,15, aeti./l, methylene), 1.73-3.0 (M,8,lme thine, remain ir.,; protons), 3.97-4.2 (bd. ϋ,Ι, aliphatic), 6.27 (S, 2, aromatic), 7.03, 7.13 (D,2,pyridine aromatic), 7.35 (S,1,hydroxyl), 3.42 (M,2,pyridine aromatic). ci--un . 7,l(l,103a-tetrahydro-l-hydroxy~6n-aethyl-3-(l-aethyl-4phenylbutyl)-6H-diber.3o'b,4]pyren-9f6H)-one, m.p, 1G3’-167° C. (pre-softening at 1403 0,) KMR: ϊ·2 (S>,3,S-methyl, J=7Hz), 1.4-1.8 (K,3,6-methyl),3.1ChClj 4.0, 4,0- (2M,methinyl ether, J=8 and l-'dlz), 6,2-6,4 (11,2,aromatic), 6.825 7.4(M,6,aromatic, phenolic), 1.2-2.6 (11,15. remaining protons).

JR: (KBr) 0-0 1709 cm1.

Analynin: Calc’d for C^H^O : C, 79.33; H, 7.99 7. found: C, 79.43; H, 8.03 7.

MS: (mol.ion) 378. '337 OC dl-όίΐί, 7,10,10aa-tetrahydro-l-hydroxy-6, b-diraathyi-3- [ l-methyl-2- ( phenylethoxy)ethyl]-6U-dibenzo[b,d]pyran-9(8H)-one (a solid glass): TMS NMR: 1.13 (s,one methyl of gem dimethyl), 1.24 (d,J=7Uz,met 1.50 (s,one methyl of gem dimethyl), 1.6-3.2 (M), 3.2-3.8 (M), 4.05 (t-l,onc p ton), 4.30 (Μ,σηο proton), 6,33 (s, two ArH), 7.30 (s,Ph) and 7.70 (s,phenol' MS: (mol.ion) 408 (M®, 100%), 392, 375, 304, 287, 286, 274 and 2'. ° 0.57 (silica gel, ether) and the corresponding, cis-isomer: dl-6a8,7,10,lOag-tetrahydro-l-hydroxy-6,6-dimethy1-3-El-msthy1-2-(5 phenylethoxy)ethyl]-6H-dibenzo[b,d]pyran-9(8H)-one, m.p. 127°-130° C.: we NISI: 1.20 (d,J=7Hz,methyl), 1.32 and 1,39 (s,gam dimethyl), 1.6-3,8 (M)j 6.25 (s, too ArH), 7.07 (s, phenol) ana 7.28 (s,Ph).

MS: (mol.ion) 408 (M®, 1002), 393, 391, 325, 316, 304, 287, 286, 274, 273 and 245.

R- = 0.50 (silica gel, ether).

EXAMPLE 3 dl-6a3,7,8,9,10,10aa-Hexahydra-lhyuroxy-6,fc-dimethyl-3-(l - me thy 1___4 - pheny rputyl)-6H-diiienzoib,dl-pyean-9l)-ol_ ι3700 •ν r ΪΌ a solution of dl-6a3, 7,10il0aa-tetrahydro-l“hydroxy-5,6-dineth;fl-5 3-(1 - ,:iethyl-4 - phenylbutyl)-6H-dibenzo[b,d]pyran-9{BH)-one (0.25 g.) in ethanol (2G0 mi.) stirred at room temperature under nitrogen is added sodium borohydride (0.5 g,). Tr.e reaction is stirred for 30 minutes and acidified with 6S hydrochloric acid, then diluted with water (50 al.) and extracted with ether (3 x 50 ml.). The combined ether extracts are dried over sodium sul10 fate and concentrated under vacuum to yield 0,2S g. of a mixture of 9-0H ttaud B-iso»ers. Column chromatography yield? 9.087 g. of dl-6aS,7,8,9,10, iOae-bexahydro-l-hydruxy-ij, 6-dimethyl -3-(1 * ss thy 1-4 - pheny lbutyl)-6H-dibenzoib,d)pyr»i-93-ol, .n.p. 1S6’-158' C, after crystallization from etherchexane {1:2;·.

MS: (mol.ion) 394 Analysis: Cal A* -iir C^R^O^t C, 79.13; H, 8.69 X Found: C, 78.94; H, 3.79 % The following compounds are prepared by means of the above procedure: el-Cas,7,3'10,19aa-hax«shydro-l-hydroay-6,6-diaethyl-3-(l-methyl5-phenylpentyl)-6K-dibenzo[b,d]pyran-93-al: XMS-. 1.0, 1.4 (28,5,gem dimethyl), 1,2 (D,3,a-niethyl, J » 7 cps), 0,8-4,0 (M, 1.8,remaining ptotonei, 4,1-7(,7 (M,2,p.u_aolic~0H and alcoholic Oli), 6.1, 6.2 (2D,aromatic, J » 3 cps), 7.0-7,3 (M,5,aromatic).

Analysis: Calc’d for G, 79.37; K, 8.88 7.

Found: C, 79.58; H, 8.92 X dx-tai', 7,3,9,10,10aa-hexahydro-l-hydroxy-6,6-dimethyl-3-(2-phenyl~ ethyl)-6K-dibenzoib,d]pyran-98-ol; m.p. 213°-2154 C.: - 36 «37ϋ0 IR: (KSr) OH 3367 ca1, 3125 cn-1 TMS ' NitR: oCDC1 1.0, 1.35 (2S,6pgem dimethyl), 2.85 (3,4,ethylene), 3.85 (bs,l,hydroxyl-DjO overlay), 3,6 (M,l,10aa proton), 0.8-3.6 (ii,8,remaining protons), 6.2 (2d, 2,aromatic), 7.2 (S,5,aromatic), 8.75 (S,l,hydroxyl0,0 overlay).

MS: (mol*ion) 352 dl-6aS j 7,8,9,10, lOsa-hexahydro-l-hydroxy-S, 6-dimech.yl-3- (I- methyl— 3 -phenyipropyl)-6H-dibenzo(b,d)pyran-98-ols m.p. 171°-172“ C.: NMR: 1·15' 1·25 W,3,methyl), 1.35 (3,6,gem dimethyl), 1.6-1.95 (M,2,methylene). 2.15-2.7 (M,3,baasylic-methinyl and methylene), 1.0-3,8 (M,10,remaining protons and hydroxyl), 6.1, 6,25 (2d, 2,aromatic), 7,2 (S,5,aromatic).

Analysis: Calc'd for C^H^s C, 78.91; H, 8,47 2 Found: C, 78,57; H, 3.50 2 dl-Saa-7,8,9,10, lQa~hexahydro-l-hydroxy-6a-iiiethyl-3“(l - methyl-4 phenylbutyl)~6H-diben2o(b,d]pyran-93~al.

This product is obtained as a mixture of the diastereomeric alcohols. The mixture, s foam, is separated into two components by preparative layer chromatography on silica gel plates using 5% methanol in chloroform as eluting solvent.

The diastereocisric mixture exhibits maxima in the infrared region (in chloroform) at 3827 and 3333 cm-1 (OH).

From 60 mg. of the foam, 10 mg, of component A is isolated; R^ = 0.65. Its !2!r. spectrum is provided below.

TMS - 7.0-7.5 (M, 5, aroma tic), 6.2, 6.3 (2D,2,aromatic), 1.2 “3 (D,3,a-aathyl, J 7 Ha), 0.8-4,5 (tt,22,remaining protons). - 37 43700 Component Β, 42 ag., R„ «· 0.75, is similarly isolated. Its NMR spectrum ls provided below, TMS “ 7.0-7.5 (M,5,aromatic), 6.1, 6.3 (2D,2,aromatic) , 1.2 (D,3,ο-methyl, J 7 Hz), 0,8-4.5 (M,22,remaining protons). dl-6a 1,7,8,9,10,10aa-hexahydro-l-hydroxy-6,6-dimethyl-3-(1-wethyl-'-p:..eaoxybutyl)-bii-dibenzo[b,ilJpyran-98-ol, m.p. 144!'-146 C. ' Rt “ 0.31 (silica gel, 9-ether:l-hexana) Analysis: Calc'd for C26H3404; C, 76.06; Ii, 8.35 5! : Found: C, 75.85; H, 8.22 7, 1C NMR: 6.75 (M,6,phenolic OH + C.1^); 7.95 and 7.80 (BS,2, aromatic H2 * H4); 4.17-1.00 (M,26,non-aromatics including 1.42 [S,Me], 1.28 and 1.17 [D,Me], 1.10 is,CHg], methylene, methine and hydroxyl). , di-6a?.,7,3,9;l'i,10aa-!!e/-!'iiydro-l-hydroxy-6,6-dinethyl-3-(l-methyl4-pa<:noxybutyl)-6H- Rf 0.37 (allies gel, 9-ether:l-hexane) M3: (mol.ion) 410 dl- 6a?., 7,8,9,10,10aa-hexahydro-l-hydroxy-6,6-dime thy 1-3- [ 1-me thy ΙΑ- (4-pyridyl)butyl j-e!i-dibenzo[b,d]pyran-9i5-oi: M.P. 17'j°-190° C.

P.( - 0.19 (silica gel, 9-benzene:l-i.j.ethanol) KMR: 8.50-8.45 (0,2,pyridine aromatic); 7.32 (S,l,phenolic hydroxyl); 7.12-7.07 (D,2,pyridine aromatic); 6.26 (BS,1,benzene aromatic); ti.10 (B5,l,benzene arcmatic); 4.60-3.30 (M,3,methine + OH [singlet 3.83]); 5..80-0.80 (M,26,alkyl, including singlet at 1.44 [Me], doublet 1.24-1.17 (CHg) singlet 1.12 [Ciigj and remaining methylene and methine absorptions). 437 0 0 dl-6aB,7,10,10aa-tGtrahydro-l-hydroxy-6,6-dimethyl-3-[l-methyl-2-(2phcnylathosy)ethylj-6n-di.benzo[b,djpyran-9(8!l)-one is converted to dl-6ap,7,8, 9,10,10na-hcxahydro-l-hydroxy-6, δ-dimethy 1-3-[l-w.ethy 1-2-(2-pheny le thoxy) ethyl 611-dibenzo[b,d]pyran.-98-ol (a solid): III: (CHClJ OH 3597 and 3333 cm1.

TIIS NMR: 5cdg^ 1.02 (s', one methyl of gem dimethyl), 1.20 (d,J=7Hz,meth 1.37 (s, one methyl of gem dimethyl), 1.6-4,2 (M), 6.19 (bs, ArH), 6.30 (bs, ArH) and 7.2? (s,?h). dl-6ai3,7,10,10afs-tetrahydro-l-hydroxy-6,6-dimethy 1-3-[l-methyl-2-(210 phenylethoxy)ethyl]-6H-dibenzo[b,d]pyran-9(8II)-one is converted to dl-6ag,7,8, 9,10, lOag-hexahydro-l-hydroxy-6,6-dimethyl-3- [l-methyl-2- (2-phenylethoxy )eti!yll-6ir-dihenzo[b,d]pyran-9g-ol, a.p. 93^-105° C.

IR: (CHCip OH 3534 ana 3279 sm1.

. NMR: - 1.12 (M,three methyls)5 1.73 (M), 2.32 (M), 2.82 (t,J=7H bUuX^ J Cll2?h), 3,0-4.1 (Μ), 6.13 W9J«2H2,ArH) 5 6,30 (d,J=2Hs#AxH) # 6.90 (bs,phsnol) and 7«25 (s,Ph).

MS: (mol.ion) 410 (ii ® ) and 105. -3Sq_- EXAMPLE 6 dl -5-Hydroxy-2,2-dinethyl-7-i2-· Heptyloxy)A-chroraanone To a solution of 5,7-dihydroxy-2,2-dimethy 4-ehromanona (18.5 g. 87.1 nM) and potassium hydroxide (2.44 g., 43.5 inM) in li,;i~dimethylfortnafflide (53 nl.) is adieu '.ith stirring 2-bronoheptar.e (15. 77 g., 38.0 ιώί). The mixture is heated for four days at 100° C., cooled to room temperature and chea adieu to a mixture of aqueous sodium hydroxide (110 ml. of IN), water (45 ml.) and chloroform (150 ml.). The mixture is agitated and the chloroform layer separated. The aqueous layer is extracted with more chloroform (150 ml.).

The combined chloroform layers are wished with 12? sodium hydroxide (2 x 100 kJ.) dried ever sodium sulfate and concentrated ro an oil. The unreacted 2brocoisepeana is removed by distillation and the residue purified by silica gel chromatography to give 5.90 2,. (22. 12) of the title product as an oil.

NMR (COClj) 5 - 12.4 (one proton -singlet, hyd:oxylic), 5.7 and 6.0 (two one proton dounlets, .. 3 Rz., aromatic protons), 4.1-4.7 (one proton multiplet, ether methir.e), 2,7 (2 proton singlet, C-3 methylene), 0.7-2.0 (22 ptotnn multiplet for the remaining protons, gem dimethyl appearing as a singlet at 1.5.).

In like manner, dl -5-hydroiy-2,2-di>iiiithj’'l-7-[2-(5-phenyl)pentyloxy ]-4-chromt::ooe is prepared by substituting 2-brcma-5-phenylpentane for 2bromoheptane, m.p. 83’~84° C. c-thylene), 1.5 (S, b, gem dimethyl), 2.7 (S,2,e-n“thylene), 2.5-2.9 (M,2, banzylic methylene), 4.1-4.7 (M,l,machine), 5.9-6.1 (M,2,aromatic), 7.1-7.5 (M,5,aromatic), 12.2 (S,l,phenolic) .

MS: (mol.ion) 354 Analysis : C, 74.55; H, 7.39 2 Found: C, 74.68; Η, 7.4ό X 70 dl-5-hydroxy-2,2-dimethyl-7-(l-methyl-3-phenylprspoxy)-4-chromanone is prepared from 2-bromp-4-phenylbutane as an oil: Tl·!? KMR; 1.25, 1.35 (d,3,methyl), 1.4 (S,6,gem dimethyl), 1.62.4 (.Ϊ-I,2,methylene), 2.6 (S,2,benzylie methylene), 2.85 (S,2,3 e-methylene), 1 4.05-4.7 (tf,l,methinyl), 5.9 (fid, 2, aromatic), 7.25 (S,5,aromatic). dl-5-?.ydroxy-2s2-dinathyl-i-cyelo:iazyioxy-4-chruaanoae is prepared from bromccyclohexane: M.P. 72°-75° C, IS (KBr) C=0 1620CD1-1; 011 3390 ca-1 MS: (mol.ion)290 ' TM? im: 5“^ 1-2.1 (M,10,CsH10-cyclohe:^l), 1.4 (S,6,gem dimethyl), 2.65 (S,2,e-methylene), 4.0-4.45 (M,i,eycloha:tyl methinyl), 5.S5-6.05 (H,2, aromatic), 11.9 (S,hydroxyl, 0,,0 overlay).

EXAMPLE 7 dl-5-Hydroxy-3-Hydroxyffisthylene-2,2-l:irieLhyl-7-(2- Hepfcylcxy)4-Gliromanone To the sodium hydride obtained by washing 9.23 g. (192 eM) of 502 5 sodium hydride in mineral oil dispersion with pentane is added dropwise, over ;; 33 minute period, a solution of dl-5-hydroxy-2,2-dimathyl«'7“(2-heptyloxy)4-chroaanone (5.90 g,, 19.2 »M) and ethyl formate (34,9 ml,, 432 mM). After the addition is complete, ether (475 cl.) is- added -rad the resulting mixture refluxed. After 18 hours, the reaction mixture is cooled to room temperature and acidified with IS hydrochloric acid. The organic layer is separated and the aqueous layer is further axtraetoi with erfctr (3 x 125 ml.). The combined trier extracts aro dried over sedrus cuifste ar.d concentrated under vacuum tc yield 6,41 g, (>1002) of 51 -5-hydr0xy-3“hydroxyraetfcylen6-2,2-dimethyl-7(2- heptyloxy)-4-ehromeni'ne a;. oil.

T'iS KIR '2 a tone broad singlet proton, hydroxylic), 11.8 LDvi (one proton singlet, phe;.

I vinyl), 6,1, 6.0 (2 one proton doublets, J “ 332, aromatic), 4.8-4.2 (one proton multiplet. mithiue), 2,1-0.7 (20 proton au’tiplet for the remaining protons).

In like manner, appropriate reactants of Example 6 are converted tot dl-5-hydroxy-3-me tl.ylenfc-2,2-di«.et!:yJ2-(5-phenyl) pen tylozy]-4chromanone, an oil.

KKR: ό™*, 1.3 (i),3,a-methyl, d = 7 Hi), 1.3-2.0 (M,4, ethylene), 1.4 (S,6,gem dimethyl), 2.3-2.3 (bd..T.Z-benzylic methylene), 4,125 4.7 (M,1,methine), 5.3-6.0 (M,2,aromatic), 7.0-7.4 (M,6,aromatic and vinylic), .0 (S,l.phenolic), 13.3 (bd,S,l,hydroxylic); dl-5-hydroxy-3-hydro:^rmethylene-2,2-dimethyl-7-[2-(4-phenyl)- . butyloxyj-4-chromanone, an oil; dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-cyclo:iaxyloxy-4- , chromanone; IS (KBr) C=0 1620 cm-1; OH 3420 cm-1 MS: (nol.ion) 318 MMR: 1,1-2.3 (lijlO^^H^Q-cyclohexyl) , 1,55 (S,6,gam dimethyl), 4.1-4,5 (K, l-cycioliexyl-wethinyl), 5.9-6.1 (H, 2, aroma tie), 7,l-7.5(d,l,iaethiayl), 11.6 (S,I,hydroxyl, D^O overlay). dl -5-hydro5y-3-hydroxymethylene-2,2-diinethyl-7“(l-tnechyI-3- ' phenoxypropyl)-4-chromanone, sn oil (from reactant of Example 1.): 1 R?n 0.42 (silica gel, 18-benacncsl-ethyl acetate) Ms: (mol.icn) 36S EXAMPLE 8 dl -6a, 7-Dihydro-l-Hydrojty-6, S-Dimethyl-S--(2 - heptyloxy)_oli-Olbonzo- [b,djpyran-9(S; i) -One____ To a solution of dl -5-hydroxy-3~hydroxyraer.hylene-2,2-dimethyl-75 (2 - heptylox-y)-4-chromanon^ (5.17 g,, 15.4 mM) and aathylvinyl ketone (2.27 al., 27.9 mM) in methanol (23 ml.) is added triathyIgpniae (0.54 ml.). The reaction is stirred tor 16 hours at rcoat temperature and then diluted with ocher (250 a],.). The resulting ether solution is extracted with 102 sodium carbonate (6 x 30 ml.), dried over sodium Sulfate, and concentrated under vacuum to yield 6.11 g. of an oil. The residue is refluxed with ethanol (45 ml.) and 23»' potassium hydroxide (45 ml.) for 16 hours. Thereafter, the reac•icn solution is cooled, acidified wi“L 6B hydrochloric acid and extracted with iichioromethane (3 x 106 bL .,. The organic phase is dried over sodium sulfate end evaporated to yield 5.j g, of a dark solid. The solid is tri15 Curated in not ether to yiaiu 1.00 g. of the title compound, m.p. 185°-189° C 1,26 g. of further matal is obtained vie silica gel chromatography of the mother liquor. The total yield is 42.32.

;T'K (CCMj) : 11.2 (one broad proton singlet, phenolic 011), 7.9 (eno broad proton .irglat, vinyl), 6.2, 5.9 (two one proton doublets, J “ 3Hz aromatic protons), 4.6-4.0 (one proton multiplet, machine ether), 3,0-0.6 (25 proton multiplet, remaining protons).

IK iRbv) C - 0 1600 ca'1.

Analysis: Calc’d for C, 73.71; H, 8.44 % Found! 0, 73.41; H, 6.37 ΐ OT I CH3ci‘2°H = 242 mu (ε = 26,800). max The following compounds are similarly prepared from appropriate iaactrnts of ’dRaaclc 7: - 43 y dl-6a,7-dihydra-l-hydrojry-S, 6-dimethy l-3-(i-me!:hyl-4-ph£nylhutoxy)· 6H-dibenzoib,d]pyran-9(8H)-one; m.p, 140°-163° C; τυς HMP.: =cdC1 1.3 (D,2,a-methyl, J = 7 Hz), 1,1-2.3 (M, 15,remaining 3 protons), 2.3-3.0 fbd,T,2,benzylie-Btethylene), 4.1-4.7 (M,1,methine), 5.95 (0, 1, aromatic,.I = 2 Hz), 6.3 (D,l,aromatic, J - 2 Hz), 7.2-7.4 fit, 5, aroma tic), 8.0 (D.l,vinylic, J = 2 Hz).

IR: (X3r) C = 0 1563 cm-1 Analysis: Calc'd for C^H^O^: C, 76.82; H, 7,44 n Found: C, 76.74; H, 7.43 % MS:(aol.ion) 406 dl -6a, 7-dihydro-l-hydroxy-6,6-dimethy1-3-(l-’-iethyl-3-phenylbutoxy)6H-dibenzo[b,dJpvtan-9(8il)-one; M.P. 163° C. •ng MMR: 1-2, 1.3 (d,3,methyl). 1,45 (S,6,gem dimethyl), 1.65-2.2 c 3 i (.‘•,2,methylene), 2,3-2.95 (M,4,methylent,benzylie methylene), 4.1-4.6 (M,l, cethinyl), 5.9, 6.15 (2d,2,aror>.ati···.;, 7.15 (S,6,aromatic, hydroxyl-D^O overlay), 7.95 (6S,1,olefinic proton).

MS: (mol.ion) 392 dl -6a, 7-dihydro-I-hydro:cy-6,6-dimethy l-3-eyclohexyloxy-6H-dibenzOf'n, d ]py ran-9 (8H) -one; M.P. 259°-254° C.

IR (K3r) CO 1590 ca-1; OH 3390 cm-1 HMR: -,.,,120 1.05-3,0 ChlSjC^U^-cyclohexyl, 6a-methinyl, 7tsthyiene, 8-i-r.ethyler.e), 1.45 (S,6,geo dimethyl), 4.0-4.4 (M, 1,methinyi), .3-6.I (2d,2,aromatic), 7.1-7.25 (d,1,olefinic proton), 7.3 (S,1,hydroxy1D^O overlay). .*37 00 dl-6a, 7-dihydro-l-hydroxy-6,6-dinsthyl- J- (1-methy 1.- 3-piieno!7ypropyl)- 611-dibenzo [b, d ] py ran-3 (811) -one, a light yellow solid: M.P. 203-206° C. M'3; (nol.ion) 392 Analysis: Calc'd forC25U28°4! C’ 76,S0; H, 7.19 '!<, Found: C, 76.33; u, 7.12 % $37 00 EXAMPLE 9 dl-6aE 7,10,10aa-Tetrahydro-l-Kydroxy-6,6-Dim2thyl-3(2-lieptyloxy)-6H-biben2ofb,d}pyran-9(8il)-0ne A solution of dl~6ag,7-dihydro-l-hydroxy-6,6-dimethy1-3-(2- heptyl5 oxy)-6H-dibenzo[b,d]pyran-9(Sii)-one (1.2 g., 3.3 mM) in tetrahydrofuran (9 al. is added dropwisa to a rapidly stirred solution uf lithium (25 mg.) in liquid 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 ammonium chloride is added to discharge the blue color. The 10 excess ammonia is allowed to evaporate and -the residue was diluted with water (45 ml.) and acidified with 10« hydrochloric acid. The aqueous solution is extracted with dichloromethane (3 x 50 ml.) and the dichloromethane extracts dried over sodium sulfate and evaporated to yield 1.30 g. of a crude semisolid which is purified via column chromatography to yield 0.614 g. (50.93) of product, n.p.l41°-14&° C, after reeryutallization froti chloroform/hexane.

NMR (CDCl^) 6 - 8.2 (one proton singlet, phenolic OH), 5,8-6.3 (2 proton multiplet, aromatic), 3.9-4.6 (2 proton multiplet, methine ether and C-10 equatorial). 0.3-3.2 (26 proton multiplet, remaining protons).

IR (KBr) C = 0 1737 cm1. >0 MS (m/e) 360 (Mi), 261 (M-99).

Analysis: Cclc'd for C2?H 04.· C, 73.30; H, 8.95 7.

Found: C, 73.05; H, 8.82 7. and'the corresponding cis-isomer: dl-6a/J,7,10,10,l0a£-tetrahybro-1-hydroxy-6,6-dimethyl-3(2-hepty1oxy)-SH-dibenzo <£b,dJpyran-9 (8H)-one, m.p, 141°-146° C. (from ether/hexane).

IR: (KBr) c=0 1718 cm'' MS (m/e) 360 (I'f), 261 (M-99) Similarly, the following compounds are prepared from products of Example 8: - 46 ΰ° d1-6a ,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimetbyl-3-(1-methyl4-pheny1butoxy)-5H-dibenzo/b,d/pyran-9(8H)-one; m.p, Ί22°-Ί25° C.

NMR: δ 1.3 (D,3,α-methyl, J = 7 Hz}, 1,1-3.0 (K, 16, remaining protons), 2.3-3.0 (bd.T,2,benzylic methylene), 4.1 (bd.D, 1, C-10 equatorial, J = 14 Hz), 4.1-4.7 (M,1,methine), 5.95 (D,1.aromatic, J = 2 Hz), 6.1 (D,1, aromatic, 3 = 2 Hz), 7,2-7.4 (M,5,aromatic), 7.9 (S,l,phenolic).

IR: (KBr) C = 0 1709 cm-1 Analysis: Calc'd for ϋ,,θΗ^Ο^: θ» 75.44; Η, 7,90 % io Found C, 76.22; H. 7.79 % and the corresponding cis-isomer: dl -6a8,7,10,1Gag-tetrahydro-1-hydroxy-6,6-dimethyl -3-(1-methyl4-pheny1butozy)-6H-dibenzo /b,d/ pyran-9(8H)-one, m.p. 141°-142° C.

IR: (KBr) OO 1707 cm! MS: (mol.icn) 408 Analysis; Calc'd for C,76,44; Η, 7.90:) Found: C, 76.58; % 7.0 dl-6ag,7,’0,10ώ. ifetrahydro-l-hydroxy-6,6-dimethyI-3-(1-methyl-320 pheny]propoxy)-6H-dibenzo Zb,d7pyran-9(8H)-cne: M.P. 160° C.

NM«:S ¢£¢- 7.2,1.3 (d,2,-methy]), 1.4 (S,6,gem dimethyl), 1.652.9 (M,11,remaining protons), 3.9-4,5 (M,2,10ax-proton, methinyl), 5.9-6.1 (2d,2,aromatic), 7.2 (S,5,aromatic), 7.9 (S, 1,hydroxyl-0,,0 overlay): MS: (mol.ion) 394 dl- 6 aa, 7,10,1Oax-tetrahydro-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy6H-dibftnzo/b,d/pyran-9(8H)-one: M.P. 215°-21S° C.

IR (KBr) C=0 1695 cm'1; OH 3225 cm-1 3o MS: (mol.ion) 344 NMRS™^ 1.0-342 (M,18,C5H10-cyclohexy1, 6aB,7,8,10,10aaprotons), 1.5 (S,6,gem dimethyl), 3.9-4.3 (M,l,cyclohexy1-methiny1), 5.9, 6.05 (2d,2,aromatic) 8.9 (bs.l.hydroxyl^O overlay). - 47 •s 3 7 ί) Ο dl-6aS,7i10,lQaa-tecrahydro-l~hydraxy6,,6- M.P. 167°-170° C.

MS: (mol,ion) 394 Analysis: Calc’d for ^2^0200^: C, 76.11; II, 7.66 7, Found: C, 75.93; li, 7.63 7.

NMP, 7.87 (S,3,phenolic proton), 7.42-6.07 (il,5,C,Hr)* 6.33 (S,2,aromatic 11, + 11,.), 4.42-1.OC (M,22,non-aromatics—including triplet centered at 3.90 for -CH?-0-, singlet at 1.48 fee CH^, doublet centered at 1.27 for CK3, singlet at 1.13 for Cil^ and 11 other «ethylene, taethine protons) - 48 43700 EXAMPLE 10 01-683,7,8,9,10,10aa-Hexahydro-l-Hydroxy-6,6-Dimethyl-3__(2 - lleptyloxy)-611-llibenzq[b,d]nyran-93-ol_ To a solution of dl-6a6,7,10,10aa-tetrahydra-i-hydroxy-6,6-dimethyl3-(2-heptyloxy)-6-!l-dibenzo[b,d]pyran-9(8H)-one (0.60 g., 1.66 mM) in ethanol. (18 ml.), stirred at room temperature under nitrogen Is added sodium borohydride (275 mg.). The reaction is stirred for 30 minutes ond poured onto a mixture of ice (35 ml.), 10% hydrochloric acid (35 ml.) and ether (200 ml.).

’The ether layer is separated and the aqueous layer extracted with additional ether (2 x 100 ml,). The combined ether extracts are dried over sodium sulfate and evaporated to an oil. Crystallization from hexane yielded 305 ag. (50.3%) of product, m.p, 107/-104^ C.

NKS - 7.5-6.7 (one broad proton singlet, hydroxylic), 6.1-5.

CDL12 (two broad proton singlet, aromatic), 4.5-0.5 (31 proton multiplet, remaining protons).

IP. (KBr) OH T90 cm Analysis: Calc'd for 0^: C, 72.89; H, 9.45 2 Found: C, 72.52; 11, 9.13 2 Similarly, the following are prepared from appropriate tetrahydro compounds: dJ-6a!i ,7,8,9,10,10aa-hexahydro-l-hydroxy-S,6-Jiraethyl-3- (l-methyl4-pheny3butoxy)-6!i-dibenzo[b,d]pyran~98“ol, an amorphous solid.

IR: (KBr) OH 3390 cm'3 MS: (mol.ion) 410 TMC NMR: 6. , 1.3 (P,3,a-:,iethyl), 1.0-4.5 (M,24,remaining protons), .8-6.0 (M,2,aromatic), 6,8-7,3 (M,5,aromatic). _ 49 ^•ΓίίτΦο -Ο I dl -6aS, 7,3,9 j 10,10aa-hexahy dro-l-hydroxy-6, δ-ti ime ihy 1-3- (1-sie thyl3-phenylpropoxy)-6H-dibenzo(b,d]pyran-98-ol, an amorphour solid.

MS: (mol,ion) 396 dl -6a3,7,8,9,10,lOae-l-hydroxy-S,6-ditnathy l-S-cycloheiqi-Ioxy-SKdibenzofb.dJpyran-gS-ol: M.P. 214--216° G.

IS (KBr) OH 3365 cm1; 3125 em1 PS: (mol.ion) 346' :;:s: 5 ‘ 1.0-3.0 (11,23,C-H.^-sycltaheicyl,gem dimethyl, 7,8,9a,10 protons), 3.5-4.15 (li,2,6a3,10aa protons)5 4.35-4.7 (M,l,cyclohexy1-uethinyl) <..85-5.05 (bdrl.hydroxyl-D^O overlay), 6.,1-6.45 (K,2»axo dl -6a,5,7,8,9,10 ^Qa-j-uexahydro-X-hydroxy-b ,6-diaathyl-3- (l-r:othyl3-phendxypropy1)-6fi-dibe»zc[b,d}pyran-98-ol: M.P. 151--152° C.

Rj = 0,25 (silica gel, 9-ethersl-hexane) IS: (at.· 1. ion) 396 Analysis: Calc'd for : C, 75.72; H, 6.14 X Found: C, 75.79; H, 3.39 7. dl-6a j, 7,8,9,10, lOaci-hexahydro-l-hydroxy-G, 6-dimftthyl -3-(l-me thyl3-?h’enoxypropyl)-6i:-dibanzo[b,d]pyran-9a-ol; an oil.

Sj “ 0.35 (silica gel, 9-ether:l-hexane) MS: (mol.ion) 396 EXAMPLE 11 The following compounds are prepared according to the procedures of Examples 1-5 from appropriate (3,5-dihydroxy)phenyl compounds of the formula 3,5-(HO)ar‘d tlie appropriate acid of formula k^RjC=CU-COO!i.

H OtI OH HI 1 ^Z-HR*'* avO gl R,, *» η 5 Z w CH3 Cil -(ch2)6-C6!!5 11 H -(ch2)7-C6U5 CKjCH3 -2)8-C6H5 CH3 II -CK(CH )(Cii?>cC6K5 Ojdj C^K,. -CH(CH3) (CH?),-C6U5 Ά ch3 ~ai(cup(Cii., g-C6!l5 H H -CH (Cl!.. ) 'i'll,),- 4-i'f’ il. 6 A CH3C2i!5 -C(CH,J2(CH2)3- CJb. 6 □ CH, ch3 -'C-iPj-CH (Cll3)- C,Hr 6 5 CH3 H -c;-;(cii3) (ch2)2ch(ch3)· c ,:u t? C2.ls H -CH(CH3)(CH2)3- 4-C1CJL 6 4 c2h5C2U5 -CHfCH )(CH2)4- 4-C1CJL 6 4 A -ch(ch3)(ch2)2- 4-ClC6ll4 H H -CH(CH3)(CH2)~ 4-ClC£H4 ch3 A -CH(CH,)(CK2)- 4-FCJL o 4 CH, Cii, -CH(GH, )(011,),- 4-pyridyl Ii II -(Cll,)3 2-pyridyl g,h5 li -(ch2)3 3-pyridyl ch3 A -(Cil2)3 4-pyridyl H AS -(Cll2)3 2-piperidyl H L -(CH2)3 4-piperidyl n> 3 H -(ch2)4 2-pyridylC2H5 11 -(οη2)4 4-pyridylC2H5C2H5 -(ch2)4 3-piperidyl ck3 A -(ch2)4 4-piperidyl H Η -(ch2)2C6h5 H 11 -Cil (CH 3) (Cli2)2-4-V4 «3 H -ClKCHj) (Cll2)2- 4-cic6;i4C?5CZK5 -ck(ch3) (CH2>2-CA H {ll(Ctl3)(Cli2)3-GA 3370 a ch3. CU3 -CH2CH(CH3)CK2- 2-pyrjdyl ti It -CH2CK(CH,)CH2- 4-piperidyl c2:i. li -ca(cii3)CH(cH3)cii2- 3-pyridylC2n5 4“5 -CH(CH3)ai(cu3)CH2- 4-pyridyl II tt -CH(CH3)CH(Cii3)CH2- 3-piperidyl r·; 3 c?. -CB(CH3) cnt,)2- 2-pyrldyl ch3C2!!5 -ch(ch3)(ch2)2- 3-pyridyl ch3 ca3 -ch(ch3) (C1I2)2- 4-piperidyl H ir _gi(ck3)(ch2)3_ 3-pyridyl CH3 Cii3 -CiKCHpCClipy. 4-piperidyl ch3 Clt3 -CH(CH3)CH(C9K,.)CII2- 4-pyridylC2U5 Ctt3 -CH(C2H5)CCH2)2- 4-nyridylC2H5 li -CH(C2H5)(CH2)2- 2-piperidyl H H -CH(C2H3)(CHz)2- 4-piperidylG!3 ti -CH,CII(C2H5)CH2- 3-pyridyl A CK3 -Ctt(C2H5) 2) 3- 3-pyridyl ®3GS Ό: (Ο,Ης/ 4-pyridylC2!!5 2 5 «2 4 2-pyridyl H H “CH (C2i’s)CH (C2K-} CB2- 4-pyridyl 11 H -GI{C2H55 CH (C2ti3) eil2- 2-piperidyl CK3 ch3 “(CH,)3®(Cit3)-C6H5 CH3 ®3 C!l„ JCiI3 -(Gi2)3CK(CH3)- 4-pyridyl H -(ch2>3ch(cu3)-C6Hil σπ3 ®3 “(CH2)3CH(CH3)-CAl CH^cil3 -cii(ai3$ (cH,)?cit(cii3)-C6nS ch3 H -CH(CH3)(CH2)2CH(CK3)-Cfi!illC2H5 -C3;CK3)(CHz)2CH(CH3)- 4-piperidyl ch3 ®3 -ch(ch3) (ch2)3-cAi H Tl “CH(ch3) (ctt2)2ciKai3)-C6K11C2K5C2U5 -(ciwC6i:ll ®3 H “(CH2)r θ6!’11 ®3C2I!5 -2)8-C6U11 - R4R5 z w CH3 ch3 -(ch2)2-C4H7 CIi3 ch3 -CH7CH(CH3)eH2-c5i!9 H ch3 -CH2CU(CH3)CH2~C5K9 5 ch3 ch3 -CH(CH3)(CH2)2-C'7U13 11 11 -CH(CH3)CH(CiI3)Cll2-C6I!ll cii3 ch3 ~CH(CH3)(CH2)3-G5H9 a3c:!3 ~cra2)4-C6H5 ck3 ch3 -CC!i2)2CH(C2H5)- c6hs 10 CH3 ch3 -C(CH3)2-C6K5 H ch3 -CH(CH,) 011,011 (0,11,.)-C6H5 HCR3 -CH(CH3)CH2-C5H9 li Cli3 -CH(CH3)CK2-C3U5CA H -CH(CH3)CH(CH3)-C6H11 15 Cll3CH3 -CH(CH3)(CH2)4-C5H9 CH, ch3 -011(¾) (ch2)2-C6U5 ¢370( Τ' EXAMPLE 12 Compounds of tha following formula are obtained from appropriate reactants of Preparations K anti V and appropriate acids of formula R4R,.C=CHCOOH by the procedures of Examples 1-4 (R^ and 11,. - ii, CH. or £,11,.): S Reduction of the keto compounds with sadiua borohydride according ι to the procedure of Example 5 affords the corresponding 9-hydroxy compounds (both isomers formed; tha g-form predominates), The sulfoxide and sulfone , compounds of Examples 15 and IS are reduced in life- manner to the corresponding 9-hydroxy compounds. ,>37θ° EXAMPLE 13 dl-5-Hydroxy-2,2-dimethyl-7-(l-raethyl~4-plienylbutoxy)-4-chromanone A nixture of 5-phenyl-2-pentanol (16.4 g., 100 mM), triethylamine (28 ml., 200 mM) and dry tetrahydrofuran (80 ml.) under a nitrogen atmosphere is cooled in an ice/water bath. Methanesulfonyl chloride (8.5 ml., 110 mM) in dry tetrahydrofuran (2b mi.) is added dropwise at ouch a rate that tilts tempera ture holds essentially constant. The mixture is allowed to warm to room temperature and is then filtered to remove triethylamine hydrochloride. The ' filter cake ia washed with dry tetrahydrofuran and the combined wash and fil10 trate evaporated under reduced pressure to give the product as an oil. The oil is dissolved in chloroform (100 ml.) and the solution washed with water (2 x 100 ml.) and then with saturated brine (1 x 20 ml.). Evaporation of the solvent affords 21.7 g. (89.72) yield of 5-phenyl-2-pentanol mesylate which is I used in the next step without turther purification.

A mixture of 2,2-dimethyl-5,7-dihydroxy-4-chromanone (2.08 g., 10 nM), potassium carbonate (2.76 g., 20 mM), N,N-dimethylformamide (10 ml.) and 5-phenyl-2-pentanol mesylate (2.64 g., 11 mM), under a nitrogen atmosphere, is heated to 80^-82° G. in an oil bath for 1.75 hours. The mixture is cooled to room temperature and then poured into ice/water (100 ml.). The aqueous solution is extracted with ethyl acetate (2 x 25 ml.) and the combined extracts washed successively with water (3 x 25 ml.) and saturated brine (1 x j ml.). The extract is then dried (MgSO^), decolorized with charcoal and evaporated to give che product as an oil which crystallizes upon seeding with pure product·, m.p. 60°-32° C, Yield quantitative. ϊη like manner, the following compounds are prepared from appropriate 2,2-RZiRj-5,7-dihydroxy-4-chromanones and appropriate alkanols. The necessary alkanol reactants not previously described in the literature are prepared from appropriate aldehydes or ketones via the Wittig reaction of Preparation C. - 55 437 m *s . cm ο -Ρ Ο 3 σν cn «η 3 3 3 ο ο ο a CM rt iJ OH •-η ιη 3 CM CM 0 3 η -fi ; > cn R cs a ςκ η — 3 cm ο ο ο ο ο ο ο in S . Η CM r*i gM OOO m «η κ rs cm ο o ; rt rt rt rt X X X X rt rt rt Ό rt rt rt 3 rt rt T3 X X >1 •rt •rt Mr X X X rt X X rt < Ό Ό •u μ μ •4- 3 ST 3 Ό T3 μ •a •a μ 3 •rt •r« •rt ϋ a 3 Ό 3 »rt •rt •rt o •μ rt ti 35 v£ μ μ μ to to O O M3 μ μ μ to μ μ to M3 O X X th •rt •n O . rt jn O x X X ♦rt X X rt U rt Pl to to Pr Pr to O to to to to to to to C. to O' A 1 1 CM 1 CM J < 1 1 <- sr Po 0 1 sr 1 CM 1 cn I i sr I CM i ϊ 1 I sr CM CM CM N rl <*j M <-*>. CM z-%. .—·» r’« CM cm rs CM CM CM CM SJ £S K CM 33330003 Ο Ο ΟΟ^'-'^υ η n «? λ m n <*» X*S X*f «·*% - Z·» »-* χ-* X CM ts CM CM CM CM CM . z-% λ z-s m m in n cn cn Mt TmG β ο CM r-i CM g ΚΖ χ-% κΡ G OSOOOOOOOR ^133333 3 »*χ lux ^r *-χ ν_ζ X-’ νχ ο Ο ο Ο ο Ο ο Ο «Ρ -Ρ Ρ _Ρ ο Ο ο ο rt rt ,_· rt rt X X X X T3 3 3 3 3 rt rt rt rt rt μ μ μ μ U jn jn m _jn m m tn X X X X X 3 3 3 w cn Pf to c. to P. Po ’ΰ Po 0 0 rr· 1 i I ( t O 0 o 0 0 0 O 0 CM CM CM PM sr CM cn Κ 3 ο ο sr Ζ*\ -Ρ ο 4-Χ CM Χ*Ύ cn ο S cm jn CM Ο Ο 3 νζ ο ζ“> CM cn r S 0 «η Ο 3 CM Ο Μ CM · Ο 3 ο ; CM Ο cn κχ 3 3 Ο Ο CM CM CM I CM Ν 3 3 3 ' 33000: ο ο vx v> I CM CM 3 >>» G jn στ σ» cn o en cm > x> 3 χ^ χ*·'· CM CM Ο O CM CM U SJ CM 3 3 J O 3 3 Ο O X» v-/ O O ffl CM rt 3 3 R 3 . CM 3 3 O O333OOO XOWRVOOOO 3 cn o rt rt rt S 6 u S cn cn cm 3 3 OQO3 $3700 β.

I sr it a a sfl D r> V u u un m in χ 32 J sp sO V u CJ • *-> vz t 1 n cn cn cn δ s i CM CM tt W ' CJ CJ ! I I I I I CM CM m \p cn so cn /-\ zs Z*» ZS z*. z·*» m m t Ν Ν Ν Ν N a Nixassajuo a-SuoSo'-'CJ S> SvZ S-Z Sz· s-/ CJ CJ I I I I I I' I I cni tt I cn m x cn cn «η en m $ $ 5 5 tt tn tt m eM tt CJ CJ tt cn cn ri tt tt x CJ CJ CJ tt cncncncnmcntt 32 δ δ δ 5 δ tf4 δ 5 5 χ SO tn tn cj X 4* sO sO t ο υ mt Mf Mf tt tt Ό sO CJ in CJ r-i tt U φ sO | I «J •c mt “io »4 m cj tn tn r* cn cn ή * Is. 3! X !S X XXXI to ι cn cn mj· sr m tn so < U CJ CJ CJ CJ CJ in m tt tt I \0 \© l CJ CJ co co tt tt tn m o o tt SO SO CJ o o cj ο o χ1 ?r ?c a J’·’ x uN a B a 3auMBxaBBuaQ«N m *n cn cn m tt fncncncncncncncnje SB S uN uN t 3 a 3 3 u* S 5 5 BBS □ S o'1 3 70 EXAMPLE 14 The products of Example 13 are converted to compounds having the formula below by the procedures of Examples 1-5. 0-(alk2)-W EXAMPLE 15 dl-6ag, 7,10,10aa-'fetrahydro-l-hydroxy-6,6-dimethy 1-3-(1methyl-3-phenylsulfinylpropyl)-6H-di benzo [h,d]py ran-9 (8!t)-one Equimolar amounts of m-chloroperbenzoic acid and dl-6aP,7,10,10aa5 tetrahydro-l-hydroxy-6,6-diraethyl-3~(l-methyl-3-phenylthiopropyl)-6H-dibenzo [b,d]pyran-9(8H)-one are reacted together in a .nixture uf chloroform and ace tic acid (2:1) at room tenperature for one hour. The organic phase is washe with water, dried (MgSO^,) and evaporated to dryness to give tha product. t Iii like manner the thio others of Example 12 are oxidized to the corresponding sulfoxldes of formula ‘5 3 7 0 0 EXAMPLE 16 dl-6ag, 7,10,10aa-TeCrahydro-l-hydro::y-6; G-dimethy 1-3-(1methy 1-3-phenylsulfony Ipropy l)-6H-dibenzo[b,d]pyran-S (811)-one The procedure of Example 15 is repeated but using two equivalents of m-chloroperbenzoic acid as oxidizing agent per mole of thio ether reactant.

Similarly, the thio ethers of Exampia 1.2 are converted to their corresponding sulfonyl derivatives to give compounds of the formula: - 60 437 00 EXAMPLE 17 (-)-Trans 3-(1-methyi-4-phenylbutyl)-Sa,7)8,19a-tetrafeydro-6,6,9trimethyl-6K-dibcasa(b,,djpyran-l- B -ol To a stirred solution of (+) p-fflantha-2,S-die*-l-ol (4.9 g., 0.0322 5 cole) act’ 5-(l-cfithyl-4-phaaylbutyl)-re?.oroinol (3.2 3., 9.032 mala) in dry methyl ana chloride (200 sil.) is added anhydrous magnesium sulfate (4 g., 'j.332 mole). The ni-ztura is stirred ur.cur a nitrogen, atmosphere and cooled to ' ' C. Freshly distilled uoron trifluoride etherate (2 al., 0.016 male) is then adds! dropwise over a 5 minute period, The reaction mixture iss stirred for 1.5 hours at 0° C. and anhydrous sodlr-a biaaraoaate (10 g., 0,119 mole) is added. Stirring is c-xitinued until the dark color fades. The reaction mixture is til;..?··. .j?.c cvcpoiated to give 11,7 g. <33,62) of ε resinous prodThe prelect js ;.ur?.fiec vii. coloaa chromatography on an activated tnag > ’3a . i1.· it·;.·., avail ole frit. H <1 3 S Ifsaufacturing Chemists, 290S Highland Avenue, Cincinnati, Gilt, una*·. t - tradeKarh Fioi-isii'1. to give 3.4 g. * (277.1 ·;£ tha desired v c mixture Of epticaiiy active diastariomers.

N’tiR e*’. i.i (Isl.C^-metlyl), 1,3, 1.4( (23,6,gea dimethyls), 1.71 (S,3,C&-iiB5hyi;, 3.7-i.b fM,12,remaining protons), 3,0-3.6 p.-eisij, 3.05 fiji.-ydrsx/l.C./l overlay?, 6.1 (S^.C^-proton, aromatic), 6,4' (.••i^jCj-nrctoajf.sccdtic.^r-proion), .1-7.5 (M,5,aromatic protons), ik? (mal. ion) 390 It is converted rc tha spticn.1?-’ active 0aS,7,i'l,10co-Setrahydro-lhydrvxy-2-Cl-irethyl-4-pbenyr3utyl)-6,6-diaiethyl-6K-dibe!iso[b,d]pyrsn-9(8H)-one diesteriotiers cccordin,; to the procedure cf Wildes eta!., J. Org. Chem., 36, 771-j (1971. (c - l.o, c:;ci.,) = -100.8“.

-J 6i i *3700 EXAMPLE 18 dl -6a3,7,10,10aa-tetrahydro-l-(4-morpholinobutyryloxy)-6,6dinethyl-3-(l-methyl-4-phenylbutyl)-61[-diben2o[b,d)pyran9(8H)-one hydrochloride To a stirred solution of dl -6a8,7,10,10aa-tetrahydro-l-hydroxy-6,6dimethyl-3-(l-mathyl-4-phenylbutyl)-61[-dibenzo[b,d]pyran-9(8H)-one (0.52 g., 1.28 mM) in dry methylene chloride (25 al.) is added 4-aorpholinobutyric acid hydrochloride (0.268 g., 1.28 mM). The mixture is stirred at room temperature under a nitrogen atmosphere. A 0.1 M solution of dicyclohexylcarbodiimide in .0 . methylene chloride (12.8 ml,, 1.28 mM) is added dropwise and the mixture stirred for 24 hours. It is filtered and evaporated to give the title1 which is purified by column chromatography on silica gel. 4 3 7 0 0 ex;j-?p;.e 19 The procedure of Example 18 is repeated but using the appropriate dl - 6a3,7,10,lOas-tetrahydro-6,6-R,8^-3-(Z-K)-SH-dibenro[h,d)pyran-9(8H)-ones of Examples 4, S and those produced as penultimate products in the procedures of Examples 11, 12 and 14; and the appropriate alkanoic acid or acid of lormula KOOC-(CE,) HCl to produce esters of the formula τ. ρ λ. a wharain .<· 2 ar.d if ss defined in Exttiplas 4, i, 11, 12 and 14 and R^ ia -COCd, -cca.cd, -CC2) -cocci2;2:;H2 ¢. .:. i. -cu(c;2).,.«;'c2a5)2 3 2'3ca3 .. ·» ’Λ u 3? ,} -co:kc4h9)2 -co:;(c2h5)2 - v. .Ί 2 *CGCHj-piperidino -COC.^-pyrrolo -COCH?-(K-methyl)pi?esiaino -CfKCiL).,-morpholino -•CO(C!i0)2-(H-i>utyl)pipsrldlno -Co(CR?)3~ py rro iid i no -CO(C2H4)-(8-erhyl)piperidino -CO-piperidino -CO- (H-me thy 1) piper idi.no -CO-morpholinc -CO-pyrrolo Basic esters are obtained as their hydrochloride salts. Cat«»fui i.cctralization with sodium hydroxide affords the Irs·' ester. - 63 i -W 4370 EXAMPLE 20 dl·· 6aS, 7,8,9,10, 10aa-liexahy dro-1- (4-morpholinobu ty ryloxy) 6,6-dim.ethyl-3-(l-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran-98ol hydrochloride The title product of Example 5 is esterified according to the proce dure of Example 18 to produce the above-named ester salt.

In like manner, the remaining products of Example 5 arid those of Examples 3, 4, 8-12, 14-17 arid 21 are converted to esters having the formula shown below wherein R^, R^; Z and W are as defined in said Examples and R^ bai the values given below: *1 -COC113 -CO(CH2)2CH3 -CO(ra2)3CH3 -COCH2WH2 -COCK2N(C!l3>2 -C0(CH2)2K™cd3 -CO(CM2)2M(i-C3H7)2 -cora2!5(c4Hg)2 -CO(CK2)4M(C2HS)2 -conh2 -COK(C«3)2 -C0NHC2K5 -C0M(C4K9)2 -C0CH2“Pyrrolo -COCK2-pyrroli dino -COCH2-morpholino -COGH2-(N-methyl)piperidino -COCH,-(N-butyl)piperidino -CO (CHO 2~piperidino -CO (CH2)2-(N-isopropyl)piperidino -COCCHpj-pyrrolidino -CO (CHj)^- (N-ethy l)piperids.rio -CO-piperidino -CO-(H-mathyl)piperidino -CO-morpholino -CO-pyrrolo .. 64 '00 EXAMPLE 21 dl-6a, 7-Dihydro-l-hydroxy-o. a-diniethyi-j-(l-itie£hyl-4i>henyibutyl)-6Ii~tliben20ii-»'lj9y~ari--S(8lI)- A) di- Ethyl 5-Hydroxy-4-methyl-7-(l-methyi-4-phenylbutyl)coumarin-35 propionate______________ Λ mixture of 2-(3,5-dihydroxyphenyl)~5-i5henylpentane (33 g., 0.13 M) . (Preparation C) diethyl α-scetoglutarate (32.2 g., G.14 I·!) and phosphorous oxychloride (20 g., 9, 3 M), protected fro-a atmospheric moisture, is stirred at room tenipcm^ure. After 10 days, the mixture is dissolved ia chloroform, washed three timts with water, dried (Na^SO^), and evaporated. The residue is subjected to silict gel chromatography (eluents - 5 banzar.e:! ether) to yield 27 g, of the desired ester, a.u. a. £10» hexane. Further reerys talli· /.ation from ethyl acetate/hexane ?ffords an analytical samples m.p. 78°-85°C.

Analysis: Calc’d for C.,J!^OgS C, 73.91= II, 7.16 7.

Ji founds C, 3.82; E, 7.13 7. y,:.s j -ι,ι-?·;'; 422 l) dl- 7,lO-fiih*4-hyarosy· ·. - ·“-mathyl-*-phenyIbucyl)-Sli-dibenso[b,dJy -yi·-6,4'S3:-.:1c,a- . ____,__________ To the sod;or hydride powder obtained by -/ashing 10.0 g. (0.21 mole) IS of rCS sodium hydrins in mineral oil dispersion with dry hexane is added 20.6 g. (¢.049 tale; c ? 'he cuter of part A of this (-xau.pla and the two powders are (aired thoroughly- Tha reaction flash ia cooled to 15M7’ C. sad dimethyl sulfazidi: '230 mi.) is tdded directly into the reaction flask. After stirring for aa additional ho· -r '-.ϊ If “-17’ C., the raacrio:; is kept overnight in the refrigerator. After warming to room temperature the reaction mixture is poured into a rapidly stirred mixture of 600 ml. of ice and water and 40 ml. of coneescrrctd hydrochloric acid, more ice being added as needed to keep the 'mixture cold. The slurry thus produced is stirred for an additional hour - 65 i -53700 and is then decanted. The residual gum is heated on the steam bath with excess • concentrated sodium bicarbonate solution and, while still warm, the resultant solid is filtered. The filter cake is washed with bicarbonate solution and water and recrystallized from ethyl acetate/hexane to give 4.5 g. of cyclized S product, m.p. 163°-164° C. Further purification is achieved by recrystalliza-; cion from methanol; m.p, 166“-167° C.

Analysis: Calc'd for (-24Η24θ4' C, 76.57; H, 6.43 Z Found: C, 76.50; H, 6.56 % MS: (col.ion) 376 C) dl-7,8,9,10-Tetrahydro-l-hydroxy-3-(l-methyl-4-phenylbutyl)spira[6ll-dibenzo[b,d]pyran-9,2-[l,3]dioxolan]-6-one A solution of 0.031 mole of the cyclized product of part B of this. example in benzene (500 ml.) containing ethylene glycol (10 ml.) and p-toluene·* 1· sulfonic acid (10 mg.) is heated overnight under reflux (Dean-Stark trap).

The solution is cooled, poured into water containing excess sodium bicarbonate I and the organic phase separated, dried (Ka^SO^) and evaporated to yield the ' desired ketal.

I D) dl-6a,7-Dihydro“l~hydroxy-6,6~dimethyl~3-(l~methyi-4-phenylbutyl)~ 6H-dibenzefb,dlpyran-9 (8H)-one.

A slurry of 0.175 mole of the above produced ketal in ether (1.5 liters) is added over 90 minutes to the Grignard reagent prepared from magnesium (44.6 g.,1.84 g-atoms) and methyl iodide (110 ml., 251 g., 1.77 moles) in ether (1.8 liters). After refluxing for 2 days the reaction is treated care1 fully with IS hydrochloric acid (200 ml.), and then with ill hydrochloric acid (740 ml.); The mixture is stirred vigorously for 1 hour and then the ether layer washed once with water and once with 5% sodium bicarbonate. Tlie ether layer is dried (Sa^SO^) and concentrated to yield the desired unsaturated ketone. If desired, it is purified by crystallization and/or column chromatography (see Examples 3 and 8). *3700 ϊα like manner, the remaining l-(2-W-sub3tiuuted)-3,5-diliydroxybenzenes of Preparation G and those of Preparations D, Ε, K, M, Q, R and T are converted to the corresponding dl-6a,7-dihydro-I-hydroxy-6,6-diiaethyl-3(Z-U)-6U-dibenzo[b,dlpyran-9 (811)-ones.

EXAMPLE 22 dl-6ao ,7,10,1 'Jaa-Ie trahydro-l-hydroxy-G, 6-dine thy 1-3- ¢1ae thyl—'>-pher.ylbuty loxy J-0H-dIbenzo[b,d]pyran-9 (811)-one, _________Ethylene Katal___ ___ Λ solution o£ dl-6a8,7,10,10aa-tetrahydro~i--:'!ydroxy--6,6-diii’eehyI-3- (l->cethyl-4-phenylbutyloxy)-6K«-dibenzo[b,dJpyran-9(8H)-one (60 mg., 0.145 mM), ethylene glycol (0.5 tel.), benzene (10 ml.) and ?. crystal of p-toluenesulfonici acid is hasted at reflux for three hoars. Ihe reaction mixture is then cooled end .-'-ceni.ratt.·'.. The concentrate is shaken up in chloroform and the chlorophase washed first with sodlvK bicarbonate and then with water. It is then dried and ecneen..·-; '.< give the ke'.al cs a light brown oil a 1 (63 S'g,).

Repetition of this procedure but using propylene glycol, trimethyl-’ sne glycol and tetraiazthylar.e glycol, in place of ethylene glycol, affords the corresponding ketals, Ay , : of this proesduie tiie ketone products of Examples 3, 4, 8, 9, 11, 12, 14-16, 13, 19 and 21 are converted to the corresponding ethylene, tritu.thyiei.e and tstramethylene ketals. 370 EXAMPLE 23 dl-5-Hydroxy-2,2-dlm3thyl“7-(2-heptylmercapto)-4-chroaanone To a solution o£ 5-hydroxy-7-mercapto-2,2-dimethyl-4-chromanone (19.7 g., 87.1 mM) and potassium hydroxide (2.44 g., 43.5 mM) in Ν,Ν-dimethyl formnmide (58 ml,) is added with stirring 2-bromoheptane (15.77 g., 88,0 mM), ·. The mixture is heated for four days at 100° C., cooled to room temperature and then added to a mixture of aqueous sodium hydroxide (110 ml. of IN), water (45 ml.) and chloroform (150 ml.). The mixture is agitated, the phases separated and the aqueous layer extracted with more chloroform (150 ml.). .0 The combined chloroform layers are washed with IN sodium hydroxide (2 x 100 ml.) dried over sodium sulfate and concentrated to sn oil. The unreacted 2-bromoheptane is removed by distillation and the residue purified by silica ! gel chromatography to give the title product.

The following compounds are similarly prepared from appropriate .5 reactants of the formula Br-ialkgJ^-tJ frot. tke appropriate 5-hydroxy-7-mercap to-2,2-R^Rj-subs tituted-4-chromanoae; .Λ- Λ a η CH3 1C21!5C2H5 1 0 ch3 ΟΠ- ο 1 H ch3 1 ch3 CH3 1 ch3CH3 1 H ii 1 -CH(CH3)(CtI2)4- CH3 -CH(CH3)(ch,)4~ CH3 -CK(CH3)(CH2)3-CA -CH(CH-)(CH,)-- •5 2 ώC6H5 -CH(CH3)(CU2)2-C6H5 -CH(CH3)(CK2)3- 4-pyridyl -ch(ch3)(ch2)3- 4-pyridyl *3700 R4R5 n (alk2) w CHj ch3 1 -CH -G6H5 ck3 CIL j 1 -Cch,)4- r ’I 6 5 ch3 CJiz 5 1 -(ch2)7- c6ii5 rrj Ch., 1 -c(ch3)2(ch,)5 CH3 C!!3 il 1 -C(CIi3)2(Cii2)5- CH, ch3 '••r »> i. -CIl (CH3)Ct! (Ctt3) (ch?)4-CIC Ή CH^ 1 -CH(CHj)CIi(CH.j) (Clip,- GH^ CK3 CIL, j. -(ch2)3- 3-pyridyl οϊλ '.: 1 -(CH2)3- 4-pyridyl H CH, 1 ~CH (CH -Λ) CH2“ 2-pyridyl tJ K 1 4-pyridylC2!!5 CH. .,. 1 -CH(CH3)(CH,)?- 4-piperidylCK3 ch3 0 — CJU 6 □ CHj at3 0 r* jj ^6nil !i 'J3 0 — 4-KC,H, 6 ·♦ c,u5 ri 0 4-cic6h4 'CC J --C6K5 rv J0 % H r 9 ..... r* 1« V<»»c ύ □ CIL· J 9 ΰC4i!7 Cxi-, J CH. 3 —C5H9 ch3 H 0 —C7i!13 CH. J 0 — 2-¾)¾ CFL· jj CH j 0 — 2~{e,n,)e[;H0 © j .io C.I3 0 — 4-(06Η5)ε6Η5θ CH.r4 ΰ __33C7!i12 H fi r ‘j — 4-(C6k5)C6Hw Cii3 -½ 0 — 4-pyridyl rf*·»! ~“3 Cit, G — 4-piperidyl £3700 EXAMPLE 24 dl-Gap, 7,10, lOan-Tetraliydro-l-acc toxy-6,6-dime thy]-3- (1-me thyl4-plienylliutoxy)-6H-d.i benzo [b, d ] pyran-9 (SH)—on e.

Pyridine (15 ml.), acetic anhydride (15 ml.) and dl-6ap,7,10,10ac5 tetrahydro-l-hydroxy-6,6-dimethyl-3-(l-methyl-4~pIienylbutoxy)-6H~dibenzo[b,dJpyrnn-9(8H)-one (4.06 g.) are combined at 0° C. and the mixture, stirred for a half-hour at 0° C. The reaction mixture is poured onto ice/water and acidifiec with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2 x 100 ml.), the extracts combined and washed with brine. The extrac is then dried (MgSO^) and evaporated to give a colorless oil which is crystallized from ether-pentane. Yield = 1.69 g.j m.p. 95°-96° C.

Analysis: Calc'd for c> 74.64; 11, 7.61 Z Found: C, 74.55; 11, 7.59 Z Evaporation of the mother liquor gives a second crystalline fraction which if: digested in hexane. Yield “ 1.74 g,; m.p, 94°-96° C.

By means of this procedure but using the appropriate alkanoic acid anhydride and the appropriate.dl-6a8,7,10,10aa-tetrahydro-6,6-R^,Ry3-(Z-W)-6Hdibenzo[b,d]pyran-9(8H)-ones of Examples 4, 9, 11, 12 and 14 as reactants, affords 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 affords the corresponding 9-hydroxy derivatives. A mixture of the 9a- and 9?·-isomers is produced. ΙΎΛΜΡΤ.Ε 75 dl-6aR,7,8,9,10,10;r.x“!iexi!liy[hO-l,9-(!i.-!Ctit'.o:iy~&,6-dti]iethyl~ 3- (1-ine rliy l-Mp!ic’iiyl!m!:yl)-6ii-'c! i !ienxo[b, c! j pyran__ A solution of dl-6a6,7,6,9,10,10aa-hexahydro“l“hydroxy-6,6-dimethyl 5 3“(I-nethyl~4~piienyibutyl)-6!!~dibenzo[b,djpyran~9f)-ol (2,0 ¢.} in pyridine (20 ml.) ls treated at 10° C. with acetic anhydride (20 mi.) and the mixture stirred for IS hours under nitrogen. The reaction mixture is worked up according to U.e procedure of Example 24.

In like manner, the 1,9-dihydroxy compounds of Examples 5, 10-12, 14 and 15 are converted to their diacetoxy, dipropionyloxy, dibutyryloxy and divaleryloxy esters. —- fa? ir 370 0 EMiFLE 26 dl-6ap,7,10,10aa-Tetrahydro-l-(4-H-piperidyl-hutyroxy)-6,6' dimethy 1-3-[2-(5-phciiyl)pcntyl0xy]-6!l-dibenzo[b,d]pyran9(8H)-one hydrochloride A mixture of dl-6ap, 7,10,10a a half-hour and filtered. The filtrate is evaporated to an oil which is washed with ether (3 x) and evaporated to yield 1.78 g. (97%) of dl-6aS,7,10. 10aa-tetrahydro-l-(4~N-piperidyl-butyroxy)-6,6-dimethy1-3-[2-(5-phenyl)psntyi oxyj~6I!-dibenzo[b,d]pyran-9(8H)-one hydrochloride as a solid, white foam.

IR: (KBr) NH ® 2667, 2564, 0 = 0 1779 and 1730 cm_i.

MS (mol.ion): (M®-HC1), 407, 262, 247, 154, 98 and 91. c PREPARATION A 2-Bromo-5-phenylpentane To phosphorous pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyi-2-pentsnol (3,2 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C and was then allowed to warm to room temperature. Water (SO ml.) is added, the mixture stirred for one hour and the methylene chloride 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 ks a light yellow oil. 1»£R: 1.6 (D, 3, methyl, J = 7Hz), 1.6-2.0 (M, 4, ethylene) 2.3-3.0 'ba. T, 2, benzyllc-aethylene), 3,7-4.2 (H, j i, aethiae), 6.9-7.4 (!!, 5, aromatic). -70PREPARATION Β 2- (3,5-Dimethoxyphenyl)-5-phenylpentane A solution of l-bromopropylbenaene (51.7 g.) in ether (234 ml.) is added dropwise over a 2-hour period to a refluxing mixture of magnesium (7.32 g.) In ether (78 ml.). The reaction mixture is refluxed for 30 minutes longer and Chen a solution of 3,5-dimethoxy-acetophenone (50 g.) in ether (78 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenched by addition of saturated ammonium chloride (234 ml.), the ether layer Is separated and the aqueous phase extracted with ether (3 x 200 ml.). The combined ether extracts are dried over magnesium sulfate and concentrate) under vacuum to yield 81 g. .of an oil. Forty grams of the oil is hydrogenated in a mixture containing ethanol (300 ml.), concentrated hydrochloric acid (2 ml.) and 52 palladium-on-carbon (5 g.). The catalyst is filtered off and the ethanol removed under vacuum. Ths residue is distilled under vacuum yielding 28 g. of 2-(3,5-dimethoxypheiiyl)-5-phenylpentane (b.p. 0.125 mm., 1S4°-159° C.).

NMR: δ^χ 1.25 (d,3,ct-CH3), 1.3-2.1 (M,4,ethylene), 2.2-2.9 (M, 3,ben2ylic-methylene, methinyl), 3.45 (S,6,methoxyl), 6.2-S.7 (M,3,aromatic), 7.2 (S,5,aromatic). _ PREPARATION C 2- (3, S-Oihydroxyphei'iylj-S-phenylpentane ?. mixture of 2-(3,5-dimethoxyphenyl}-S~phenylnenCane (22 g.) and ! pyridine hydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hours I with vigorous stirring. The reaction mixture is cooled, dissolved in 6’J hydrochloric acid (200 pi.) and diluted with water to 600 ml. The aqueous solution is extracted with ethyl acetate (4 x 100 ml.), tha ethyl acetate ' extracts dried over sodium sulfate and concentrated under vacuum to yield g, of crude product. The product is purified by silica gel chromatography to yield 19.2 g. cf 2-(3,5-dihydroxyphe.nyl)-5-pr.enylpentane as an oil, «rya idS: ϊςζ,,'ΐ 3.1 (d,3,a-asthyl), 1,35-1.65 (M,4,ethylene), 2.2-2.8 (ri.i0,santylie-..-et:.ylerie; methinvl), 6. 1-6.5 (M,3,aromatic), 5.65 (bd.S.,2, hydroxyl), (,s’,53aronatie). following the proc es cf Preparations SandC, the compounds listed 15 belc» ars prepared by s toting the appropriate l-brcaoalkylbenzene for 1b r c-mop ropy ib an 2 ar. e i 2- (3:5- (d inydroxyphenyl )-6-phenylhexane— I.l (D,3,a-nethyl; J-? cps), 1.0-1.9 Cd(Cl,)-Arl, 2.2-(.3 (M,3,henzylic methylene, methinyi), 6.0 (bd.S.,2,phenolic 20 Ci!), 6.2-6. *{M, 3,aromatic), 7.1-7.4(.1,5,aromatic). 1- (3,5-dihydroxyph2r.y 1 )-2- taenylethane— m.p.: 7?.“~77° C. 2- (3,5-;ii!iydroxyphenyl-4-phenylbutane (an oil)— KlR: til·!, 1.1, 1.25 (d,2,methyl), 1.45-2.0 (K.’.siethylene), 2.15-2.7 (KjJjbenzylic-nethylene, methinyi), 6.3 (S,3,aromatic), 6.85 (S,2, hydroxyl-DgO overlay), 7.1 (S,5, aromatic). - 72 '·3?θ0 The following compounds are prepared in like manner from Cha appropriate alcohol and 3,5-dimethoxybenzaldehyde or 3,5-dimethoxyacetophenone by the methods of Preparations A, B and C: OH -.z-w z w CH(CH3)CH2C5n9 ch(ch3)(ch?)? csH0 CH(CI13)CH2C3«5 CH(CH3)CH(CH3)cAi CH(CH3)(CH2)3C6U11 ch(ch3)(ch2)4C5K9 ch(ch3) (ch2)5C6H11 CH(C2H5)(CK2)2cAi(CH2>3C5U9 GH(C2H5)(CH2)3C6H5 C(C1I3)2CA (αφΖίC6H5 (CH2)2CH(C2H5)C6H5 CH(C-H3)CH2CU(C2H5) c6h5 _ 73 ¢370° HREFARATIOli Ο 1-(3,5-Dlhydroxyphenyl)-2-methyl-4-phenylbutane A solution of n-butyl lithium (29 ml. of 2.2M) is added dropwise Co ( 3,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g. ) in tetrahydrofuran! ( 290 ml.) with stirring and the resulting deep red solution is stirred for > -ins-half hour. Benzyl acetone (9,4 g,) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic add and concentrated under reduced pressure. Tha residue is extracted with methylene chloride and the extract evaporated to give crude 1-(3,5diffiathoxyphenyl)-2-asthyi-4-phenyl-3.-butene as an oil. It is purified by chroma tography on silica gei (400 g.) aati elution with benzene, field: 10 g. os an oil. 1.95 2.3-3.1 (11,4), 3.S iS,6), 6.15-6,6 (M,3), 2j *' ί—’ Λ <*/·' ’ » ~ 1 * -> - -- * The 1-(2,5~dimethcxyphanyl)-2-methyl-4-phenyl-l-butene (9.4 g.) thus prepared is dis£a?.v-.-.u 1:: ethanol (250 nl.) and catalytically hydrogenated at 45 p.5,1, io the presence of palladlum-on-charcoal (1 g. of 10%) and concentrated hydrochloric acid (1 ml.). Yield: 9.4 g. of 1-(3,5-dimethoxyphenyl)2-Keihyi-4~phefyl.buU nw as κι cil.

RS; A*L °·9 (d·35’ 1·35~ί.95 (M,3), 2.2-2.9 (Μ,4), 3.75 (S,6), J‘3 6.35 It is demethylated according to the procedure of Preparation C to. give 1- 3,5-di bydroxyphe3yl)-2-methyl-4-phenylbutane.

The 3,5-di®eci»oxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 3,5-dit!iethoxybenzyl bromide (12 g.) and triphenylphosphine (14,2 g.) in acetonitrile (200 ml.) for one hour. The reaction mixture is ther. cooled and the crystalline product recovered by filtration, washed with ether and dried (20 g.); m.p. 269°~270,J C.

“ PREPARATION Ε 2-Methy1-2- ( 3,5-dihydrosiyphenyl) -5-phenylpentane To a solution of the Grignard reagent prepared from 2-phenylbromoethane (5.5 g.), magnesium (0.8 g.) and dry ether (60 ml.) is added a solution.' of 2-methyl-2-(3,5-dimethoxyphenyl)propionitrile (2.75 g.) in dry ether (20 ml.)» The ether is distilled off and replaced by dry benzene (50 ml.) and the mixture refluxed for 48 hours. It is then decomposed by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour. The mixture is , then extracted with ether, the extract dried (KgSO^) and concentrated to an oil. Distillation of the oil in vacuo affords 2-methyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentanona; b.p. 168° C./0.2 msi. (Yield: 2.32 g., 60%) The thus-produced pentanone (58 g.) is dissolved in ethanol (400 ml.) and treated with sodium borohydride (10 g.) at room temperature. The reaction mixture is stirred for 12 hours and is then cooled and neutralized ,5 with 6S hydrochloric acid. The ethanol is removed under reduced pressure’ , and the residue extracted with ether. Tha extract is dried (MgSO^) and eoacentrated to give 2“aeehyl-2>-(3s5-tiiHethoxyphenyl)-5-phenyl-3-pentanol as an oil (52 g,, 882 yield).

The pentanol (16 g.) is taken up in ether (100 ml.) and reacted JO with powdered potassium (2.5 g.) in ether (200 ml.). Carbon disulfide j ; (equimolar to the potassium) is added and the mixture stirred for a half I hour. Methyl iodide (9.0 g«) is then added and tha reaction mixture stirred for 6 hours. The resulting suspension is filtered and the filtrate concentrated under reduced pressure. The residue is taken up in ethanol ( 150 ml.), Raney nickel added ( 25 s·) and ^be mixture refluxed for 18 hours. ; Evaporation of the alcohol and distillation of the residue gives 2-methyl2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentene. _ 75The pentene derivative is catalytically hydrogenated according to the procedure oi Preparation D and the resulting 2-methyl-2-(3,5-dimethoxypiienyl)-5-phenyl-3-pentane demethylated via the procedure of Preparation C to give the product.

PREPARATION F 3, S-Dibenzyloityacetophenone Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3,5-dibenzyloxybenzoic acid (175 g., 0.532 M) in ether (250 al.) tetrahydrofuran (1400 ml.) maintained at 15°-2O° C. After stirring an additional 0.75 hour at 10°-15° C., water (600 ml.) is slowly added keeping the reaction temperature below 20° C. The aqueous layer is separated and extrac ted with ether (3 x 250 ml.). The organic phases are combined, washed with ,0 saturated sodium chloride solution (4 300 al.), dried over sodium sulfate, and concentrated under vacuum to give an oil which slowly crystallized from isopropyl ether. The crude product is recrystallised from ether-he2:ane to yield 104.7 g. (592) of product; m.p. 59°-61° C. 77PREPARATION G Ethyl 3-(3,5-Dibenzyloxynhanyl)crotonate (Wittig Reaction) A mixture of 3,5-dibenzyloxyacetophenone (43.2 g., 0,13 mole) and carbethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heated under a nitrogen atmosphere at 170’ C. for 4 hours. The clear melt is cooled to room temperature, triturated with ether and the precipitate of triphenyl phosphine oxide removed by filtration. The filtrate is concentrated under vacuum to an oily, residue which is chromatographed over silica gel (1500 g.) and eluted witi' benzene:hexane solutions of increasing benzene concentration beginning with 40:60 and ending with 1002 benzene. Concentration of appropriate fractions gives an oily residue which i? crystalii2cd from hexane. Yield: 40.2 g. (772); m.p. 73=-75° C.

Analysis; Caic’d for C’ H, 6.51 2 found: Cs 77.72; H, 6.60 2 ' In like manner, ethyl 3-(3,5-dimethoxyphenyl)crotonate is prepared frcm 3,5-diffiathoxyacetc;haiione (51.7 g.) and carbethoxymethylene triphenylphcsphorane (200 g.). Yield 61.8 g., 862, b.p. 146°-ΐ62β C. at 0.3 mm. _ 78 .*37 00 \ .. Λ PREPARATION Η 3-(3 ,5 -Dibenzyloxyphenyl)-l~butanol A solution of ethyl 3-(3,5 -dibensyloxyphenyl)crotonate (24.1 g., 60 mM) in ether (250 ml.) is added to a mixture of lithium aluminum hydride (3.42 g., 90 mM) and echer (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled. Water (3.4 ml.), sodium hydroxide (3.4 al. of 6N) and water (10 m3.,) are then added successively to the reaction mixture. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil - 2.4 g. (982).

Rg ·= 0.25 [siliea gel: benzene(lS):ethyl acetate(l)].

MS: (mol.ion) 362.

Analysis: Calc'd for θ2ήΙ!οβθ3! C, 79.53; H, 7.23 2 Pound; C, 79.37; H, 7.11 2 In like manner, ethyl 3-(335-dimethoxyphenyl)crotonate (60.4 g.) is ' reduced to 3-(3,5-dimethoxyphenyl)butanol (48.0 g.( 902).

I ' PREPARATION I 3-(3,5-Dibengyloxyphenyl)butyl Tosylate Tosyl chloride (11.1 g., 58.1 tali) is added to a solution of 3-(3,50 dibenzyloxyphenyl)-l-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C.

! The reaction mixture is held at -35° C. for 18 hours and is than diluted with ! cold 2N hydrochloric acid (1500 ml.) and extracted with ether (5 x 250 ml.).

Tne combined extracts 3re washed with saturated sodium chloride solution (4 x 250 ml.) and then dried (Na^SO^). Concentration of the dried extract affords ' the product as an oil. It is crystallised by treatment with ether-hexane. Yield: 24.63 g. (842).

Analysis: Calc'd for C^H^O^S: C, 72.06; H, 6.24 2 Pound: C, 72.05; H, 6.29 2 _ 79PREPARATION J 3-(3 , 5 - DibenzyIoxyphenyl)-l-pl;enoxybutane A solution of phenol (4.56 g., 48.6 nit) in dimethylformamide (40 ml is added under a nitrogen atmosphere to a suspension of sodium hydride (2.32 5 ' g., 48.6 mM of 207 previously washed with pentane) in dimethylformamide (70 ml.) at 60“ C. The reaction mixture is stirred for one hour at 60°-70° C., after which a solution rf 3-(3 , 5 -- dibenzyloxyphenyljbutyl tosylate (23.93 g. 46.3 ml·!) in dime thyl forsanide (80 ml.) is added. The reaction mixture is stirred at 80° C. for a half hour and is then cooled to room temperature, di10 luted with cold water (2500 ml.) and extracted with ether (4 x 400 ml,). The combined extracts are washed successively with cold 2N hydrochloric acid (2 x 330 al.) and saturated sodium chloride solution (3 x 300 ml.) and then dried (Na,SO^). Reaovnl of the solvent under reduced pressure affords the The oily rcii.iue is dissolved is benzene and filtered (100 Concentration of the filtrate under reduced prod: :t as· an oil. Yield: 14.86 g. (732). •silica gel, benzene).

MS: (eol.icn) 438 Analysis: Calc'd for £39^39^3· C, 82,16; ll, 6.89 2 20 Found: C, 82.07; li, 6.84 % Repetition of Procedures G through J, bet using the 3,5-dibenzylox; derivatives of benzaldehyde, acetophenone or propiophenone, the appropriate carbethoxy (or carbomethoxy) alkylidene triphanyl phosphorane; and the appropriate alcohol, phenol, thiophenol, hydroxypyridine or hydroxypiperidine' as reactants affords the following compounds: product as an ou. 15 through silica gel pressure gives the R, - 0.7 _ 80 _ 7ΰΟ OCH2CgH5 h5c6ch2°/ (alfep-X-Calk^-W For convenience, tha various values of U for given values of -(alk2)-X-(aik9)n“ 2re collectively tabulated. n O Μ X & I η CJ fe I £ fe I tf tf rd rH s P X fi ci. cn fe M ui o □ 3 As ρ o fi. fe is Ό fe P .

X \O ft* « Ό fe P Φ fi. fe et rd is Π3 fe P Φ Ct m “A O O *0 J fe •41 P 0 - Ct r* fe et tf ι υ tf is fi.

I tf P 0) fi. fe fi.

I tf tf O is fe S5 c υ vo fe u ι «*> < m vO £ I tf «I o alk, „ alk. * x-S 1 CS 1 tf X yj TJ Ά Αβ ζ_) rd rd Ή P j X X Φ υ I Ό Ό fit »| fe fe •rl P is et J cs bC tf S3 o fe I tf w Ό o fe tf S3 o fe a fe ι rd £ •H P U et *& •H P ω o. •rl fi.

I tf p ο £ cs σι in a rd is •rl P a fi. tf K. Ό u rd o I •rl P is et rd Λ rd a- * Ao tf u 55 Ό * U m fe fe P is et ι tf rd •S' i-l P is tf & •rl P X fi.

I cs •tf vO a fe ι tf tf a I tf S3 O ΐ tf Λ m ·» m m o m tn tn in m tn m m m in tn *fe 55 si 33 23 K 23 32 33 33 S3 r-· \D Ao Ao I Ao Ao vO to S3 vD VO VO \O vO o o a tf u υ υ o o υ u O u CJ rd rd o rd rd rd rd rd o rd rd rd cn cn δ cn S 2« A S C pi rs r> es es o es cs cs cs /S cS 33 S-* U cn a O o o o o es cs cs cS es /“* x—\ xs /*v x*> CS es CS es es 23 S3 « 32 32 CJ 0 u CJ O fe/ fe/ fe* \u/ fe* Z*S /S x·*. s~\ n tn m m tn 23 23 Sj33 . es CS CS cs ΰ U CJ a υ *37θθ alk s3?Ut) PREPARATION Κ 3-(3 i5 -Dihydroxyphenyl)-l-pheno:cybutane A solution of 3-(3 » 5 -diben3yloxyphenyl)-l-phenoxybufcane (14,7 g., 133.5 mil) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 mi.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10Z palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-102 ethyl acetate. The middle fractions' are combined and concentrated to give the title product: 7.8 g. (802), as an oil.

Rj = 0.25 [silica gel, benzene(4), methanol (1)].

MS: (mol,ion) 258 Analysis: Calc'd for C,/H.,0,: C, 74.39; H, 7.02 2 iC id ό Found: C, 74.13; II, 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 comprises stirring a solution of the dibenzyl ether (X = S) in trifluoroacetic acid at room temperature for two hours. The reaction mixture. Is evaporated to dryness and the residue taken up in ether.

The ether solution is washed with water, dried (MgSO^) and evaporated to give the debenzylated compound. _ 85 - PREPARATION L l-Bromo-3-(3,5-Dlaethoxyphenyl)butane Λ solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3,5-dimethoxypheny1)-1-butanol (30.0 g., 5 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room tempera ture and stirred for an additional 30 minutes. The mixture is poured over Ice (200 g.) and the resulting mixture extracted with ether (3 x 50 ml.). The combined extracts are washed with 57 sodium hydroxide solution (3 x 50 ml.) , ; saturated sodium chloride solution (1 x 50 ml.) and dried (Na^O^). Removal ; of the ether and vacuum distillation of the residue affords the title product} g. (55% yield); b.p. 125°-132“ C. at 0.4 mm.

The following compounds are prepared from 3,5-dimethoxybenzaldehyde 3,5-dimethoxyacetophenone and 3,5-dimethoxyproplophenone and the appropriate carbethoxyalkylidene triphenylphosphorane by the procedures of Preparations G, I! and L.

OCH, c(c2h5)ch2 PREPARATION M 4-(3,5-Dihydroxyphenyl)-1-(4-pyrldyl)pentane A mixture of 3-(3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-. pyridinecarboxaldehyde (3.79 g., 35.4 nmoles) in tetrahydrofuran (40 ml.).

The resulting mixture is then added dropwise to a slurry of 502 sodium hydride' (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere , at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° and then concentrated under reduced pressure. The concentrate 1 is diluted with water (200 ml.) and then acidified with SH 1IC1. The aqueous acid solution is extracted with benzene (4 x 50 ml.). It is then made basic and extracted with ethyl acetate (3 x 50 ml.). Evaporation of the combined extracts after drying (MgSO^) affords 4-(3,5-dimethoxyphenyl)-l-(4-pyridyl)1-pentene (7.1 g., 702) as an oil.

Catalytic hydrogenation of the thus-produced pentene derivative according to the procedure given in Preparation D gives 4-(3,5-dimethoxyphenyl)-l-(4-pyridyl)pentane in quantitative yield; m.p. 131°-133° C.

The pentane derivative thus obtained is demethylated by heating a mixture of the compound (7.15 g., 25 mmoles) and pyridine hydrochloride (35 g.) under a nitrogen atmosphere at 210° C. for 8 hours. The hot mixture is poured into water (40 ml.) and the resulting solution made basic with 6N sodium hydroxide. Water and pyridine are removed by distillation in vacuo. Ethanol (50 ml.) is added to the residue and the inorganic salts which precipitate are filtered off. The filtrate is concentrated in vacuo and the residue chromatographed on silica gel (150 g.) using as eluting agents 52 ethanol/benzene (4 liters), 102 ethanol/benzene (1 liter), 132 ethanol/benzene (1 liter) and 16% ethanol/ben2ene (5 liters). The product is isolated as a glassy solid by concentration of appropriate fractions of the eluate. Yield » 5.0 g. (78%).

The 3-(3,5~dimethoxyphenyl)butyltriphenylphosphoniuin bromide is 5 prepared by refluxing a mixture of l-bromo-3-(3,5-dimethoxyphenyl)butane (21.5 g., 78.5 nmoles) and triphenyl phosphine (20.5 g., 78.5 mmoles) in xylene (60 ml.) for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The filter cake ls washed with ether and dried in a vacuum deslcator to give 36,4 g, (86%) yield of product; m.p. 190^-200° C.

Repetition of this procedure but using the appropriate bromo(3,5-dlmethoxyphenyl)alkane and the appropriate aldehyde or ketone affords the J following compounds.

OH z H (ch2)3 2-pyridyl (cn2)3 3-pyridyl (ch2)3 4-pyridyl (ch2)3 2-piperidyl (ch2)3 4-plperldyl (ch2)4 2-pyridyl (ch2)4 4-pyridyl (CH2>4 3-piperidyl (ch2)4 4-plperidyl ch,ch(ch,)ch7 2-pyridyl CH,CH(CHq)CH? 4-piperidyl CH(CH,)CI1(CH3)CH, 3-pyridyl CH(CH,)CH(CH,)ra? 4-pyridyl CH(CH3)CH(C1I3)CH2 3-piperidyl .. 3 7 0 0 ι i' ζ W ch(ch3)(ch2)2 ch(ch3)(ch2)2 CH(CHq)(CH,), 2- pyridyl 3- pyridyl 4- piperidyl Cn(CH3)(CH2)3 ch(ch3)(ch2)3 ck(cu3)ch(c2u5)ch2 ch(c2e5Kch2)2 ClKCgKj) (Cii2) 2 3- pyridyl 4- piperidyl 4-pyridyl 4-pyridyl 2-piperidyl 10 ch(c2h5)(cii2)2 4-piperidyl CH2CH(C2H5)CH2 3-pyridyl CH(C2H5) (CIl2)3 3-pyridyl CH(C2H5)(CH2)3 4-piperidyl CH(C2H5)CH(CII3)CH2 2-pyridyl 15 CiI(C2I!5)CH(C2Hs)CH2 4-pyridyl CH(C2Hs)CH(C2E5)CH2 2-piperidyl (ch2)3CSH11 CH(CH3)(CH2)3 % (“AC3H5 !0 (cap 2C4i!7 CHiCH(CH.)CH„ £ H £C5U9 Cd (CHJ (CH2)2C7H13 CH(CH3)CH(CH3)CH2C6«31C6H5 >5 (CH2)“7C6H5 (CE23g c,h, 6 5 J CH(®3)(CH2)6 c6h5 1 C!i(CH3) (Cii2)? Ρ Π Sa5 ch(ch3)(ch2)3 4-K5n4 30 c(ch3)2(ch2)3 CgHg Cil(CH3) (ch2)3 4-ClCgH^ CH(CH3)(CH2)4 4-ClC6H4 CH(CH3) (CH2) 4-ClCgH4 CH(CH3)(CH2) 4-KC6U4 35 CH(CH3)(CH2)2 *FC&H4 CH(CIip (CU2)2 ^“C1C6‘i4 Ζ J JC6H11 CHCCH3)(Gi9)2Cl!(CH3)CA CH(CH3) (CH2)2CH(C113)cAi CH(CU )(CH2)2CH(CH3) 4-piperidyl CH(CH3)(Ctl2)3cAi CK(Cii9)(CiI9>2Cii(Crf3) All Vll C.lf o U. CJL,υ 11 PREPARATIONΝ 3,5-Dimethoxy-g-methylstyrene Oxide To a solution of dimethylsulfoxonium methylide (69.4 mM) in dimethyl sulfoxide (65 ml.) at room temperature is added solid 3,5-dimethoxyacetophenone (10 g., 55.5 rail). The reaction mixture is stirred for one hour at 25° C,, for one-half hour at 50° C. and is then cooled. The mixture is diluted with water (50 ml.) and added to a mixture of ice water (200 mi.)-ether (250 ml.)—low boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgSO^) and evaporated to an oil.

Fractional distillation of the oil yields e.O g. (/SZ) of 3,5-diEethoxy-amethylstyrsne oxide, b.p. 93°-97° C, G.2 am.

IR (CCL4): 2780, 1595.

CT (952 ethanol): A . ’ CI3X MS (mol.ion): 194 PMR (CDC1-) (60 Mis): 6 0 2.95 (d, J = 6 I1z,2Xh)s 3.81 (S, (d, J » 2 Hs, ArH). 1151, 1058 cm \ : 279 nm (ε = 2068) (1.70 (S, Cil3-), 2,76 (d, J = 6 Hs.^H) Cll30-), 6,41 (t, J = 2 Hz, ArH) and 6.58 Analysis: Calc'd for : 68.02; H, 7.27 2 Found: C, 67.96; H, 7.28 Z _ 91 _ 43-700 PREPARATION Ο ' 2-(3,5-Dimethoxyphenyl)-2-hydroxypropyl-2-plienylethyl Ether A mixture of dry 2-phenylethanol (30 ml., 251 mil) and sodium metal (690 mg., 30 ml!) is heated at 110° C. for 30 minutes, 'lhe resulting Iff solution of sodium 2-pueaylethoxide is cooled to 60’ C., 3,5-dfmethoxy-«-methylstyrene oxide (2 g., 10,3 mM) added and the reaction heated 15 hours at 60° C. The reaction mixture is cooled and added to a mixture of ether and water. The J ί ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenyly ethanol is removed by vacuum distillation (b.p. ”65° C., 0.1 mm.) leaving a 3.5 g. residue, lhe residue is purified via column chromatography on Merck silica gel 60 (300 g.) and eluted in 15 ml. fractions with 60!£ ether-pentane. Fractions 52-88 yielded 2.9 g. (892) of 2-(3,5-dimethoxyphenyl)-2-hydroxy1 propyl 2-phenylethyl ether.

IR (C&4): 3534, 1595, 1202, 1153 cm1.

UV (952 ethanol): λ 278 (ε - 1830), 273 (e - 1860).

C2£X MS: (mol.ion) 316 PMR (CDC13, 60 MHz): δ 1.46 (S, CH3~), 2.86 (S, OH), 2.86 (t, J 7 Hz, -CH2-?h), 3.53 (S, -CH20), 3.71 (t, J - 7 Hz, -CH2O), 3.80 (S, OCHLj) „ 6.38 (t, J “ 2 Hz, ArH), 6.61 (d, J - 2 Hz, ArH) and 7.23 (S, PhH).

* Analysis: Calc'd for C^H^O^: C, 72.12; H, 7.65 2 1 Found: C, 71.92; H, 7.63 2 _ 92 _ PREPARATION Ρ > 2-(3,5-Slmetho:cyphenyl) propyl 2-Phenylethyl Ether To a 0° C. solution of 2-(3,5-dimethoxyphenyl)-2-hydroxypropyl 2phenylethyl ether (550 rag., 1.74 mM) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 ml., 5.22 mM). The reaction is 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 ether (150 ml.) and 152 sodium carbonate (100 ml.). The organic phase is separated and washed with 152 sodium carbonate (3 x 50 ml.), 1 dried over magnesium sulfate and evaporated to an oil. The oil is dissolved 10 in absolute ethanol (15 ml,), 102 palladium-on-carbon (100 mg·).added and the mixture stirred under one atmosphere of hydrogen gas, Nhen hydrogen uptake ceases (26,5 ml., 20 min.), the reaction is filtered through diatomaceous ; earth and the filtrate evaporated to an oil. The oil is purified via prepara·! J five layer chromatography on silica gel plates, eluted twice with 6:1 pentanet 15 ether to yield 211 mg. (402) of 2-(3.5-dimathoxyphenyl)propyl 2-phenylethyl I ether.

IS (CC14): 1600, 1205, 1155, 1109 cm-1.

MS: (mol. ion) 300 PMR (CDC13, 60 MHz) δ 1.22 (d, J => 7 Hz, 01^-), 2.32 (t, J “ 7 Hz, · Cll2Ph), *2.8 (K-C-Ma), *3.6 (-CHg-O-CHj-), 3.75 (3, OCilg), 6.35 (m, ArH) and :, 7.18 (S, PhH). 1. _ 93 _ 4370° PREPARATION Q 2-(3,5-Dlhydroxyphenyl)propyl 2-Phenylethyl Ether A mixture of 2-(3,5-dimethoxyphenyl)propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine (0.4 ml., 4.96 mM) and dry pyridine hydrochloride (4 5 g., 34,6 ml·!) is heated at 190° C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of the aqueous phase, is dried over magnesium sulfate and evaporated to an oil. The oil is purified via preparative layer chromatography on silica gel plates, eluted six times with 30% ether-pentane to yield 65.8 ‘ mg. (37%) of 2-(3,5-dihydroxyphenyDpropyl 2-phenylethyl ether.

IR (CHC13)i 3559, 3279, 1605, 1147, 1105 cm1.

MS: (mol.ion) 272 PMR (CDCi3, 60 MHz) δ 1.18 (d, J - 7 Hz, CH^), 2.80 (t, J - 7 Hz, -CH2Ph),'2.80 (H-C-Me), 3.4-3.8 (-CH^CH^), 6,08 (t, J = 2 Hz, ArH), 6.21 (d, J - 2 Hz, ArH) and 7.16 (S, Phil). lhe following compounds are prepared from appropriate alkanols by the methods of Procedures 0 and P.

HO OH '0 CH, - 94 ι * “ 7 J ϋ (alk2) w -(αφ6- ch3 -(ch2)6C6U5 <CH2>4 ch3 -CH(CH3)CH2 ch3 (Cil2)4 ch3 -(CH2)- 4-¾ 4-pyridyl -<ΏΙ2>2- 2-piperidyl -CH(CH3)CH2- 4-piperidyl -(CH, ),CH(CH,)(CH,),-CH3 -ch(ch3)- cii3 -c(ch3)2- cu3 ,3*°° PREPARATION R 1 4-(3,5-Dihydroxyphenyl)-l-phenoxypentane Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenona; (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phanoxypropyltriphenyl5 phosphonium bromide (7.18 g., 0.13 M) in dimethylsulfoxide (450 ml.) is added dropwise over 1.75 hours to a suspension of 502 sodium hydride (7.89 g., 0.165 I M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at O’-5’' C. After stirring for 4 hours at 0°-5® C. the reaction is allowed to · warn to room temperature and is then carefully stirred into ice water (2000 ml.), 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 500 ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine axlde. Filtration, followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane consisting of 302 to 1002 benzene.

From the middle fractions 51 g. (752) of 4-(3,5-dibenzyloxyphenyl)-l~phenoxy« per.t-3-ene is isolated as an oil; R^ 0.8 (silica gel, 2-henzene:l-hexane); MS (mol.ion): 450.

Analysis: Calc'd for C^ll^Oy C, 82.63; H, 6.71 2 ! Found: C, 82,90; 13, 6.69 2 ; A solution of 4-(3,5-dibenzyloxyphenyl)-l-phenoxypent-3-ene (51 g., I 0.113 M) in a mixture of absolute 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 102 Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields 30.8 g. (1002) of product as a viscous oil, Analysis: Calc'd for Cj^qO^: C, 74.97; H, 7.40 2 , Found: C, 74.54; H, 7.45 2 _ PREPARATION S 3,5-Dimethoxy-6-methylstyrene oxide To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in . tetrahydrofuran (one liter) is slowly added 3,5-dimethoxybefizaldehyde (1.0 mu’?). The reaction mixture is stirred at -73° C. for 3 hours and Chen allowed to warm to room temperature. It is then added to ether-water and the ether . phase separated. The ether phase Is washed with water, dried (MgSO^) and evaporated. Fractional distillation of the residue gives the title product.

PREPARATION T 3-(3,5-Dlhydroxyphenyl)-2-propylbutyl Ether To a solution of sodium butoxide in butanol (0,5 liters of 1M) is added 3,5-diraethoxy-8-methylstyrene oxide (6.33 M). The mixture is heated , for 18 hours at 70° C. and 'is then cooled and added to a mixture of ether- water. The ether solution is.separated, dried (MgSO^) and evaporated to give 3-(3,5-dinethoxyphenyl)-3-hydroxy-2-propylbutyl ether. 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.

Similarly, the following are prepared from appropriate alcohols: OH CK, HO CH, ,CH O-(alk)2-W (alk2) H (alk,,) H ch2 G13 CH(CH3)CH2 ch3 (C.'!2) 5 CU3 CU(C2H5)-(CH2)2 ch3 (Ci'.y) 3C6ll5 ch(c»i3)ch2C6lI5 (ch2)2 4-FC6H4 (CH2)2 4-pyridyl ,37»° PREPARATION U 2-R^R5-5,7-Dihydroxy-4-chromanones The procedure of British Patent 1,077,066 is employed to produce the compounds tabulated below. It comprises reacting the appropriate R^OCH-COOU '-’ich an excess (50%) of l,3,5-trlhydro::ybenB8ne and of polyphos phoric acid (10 to 20 grams per gram of trihydroxybenzene) on a steam bath for three hours. The mixture is then cooled and poured into water. The precipitate is extracted with ether, the ethereal extract washed with sodium hydroxide solution, dried and evaporated to afford the product. Purification is accomplished by distillation of the residue. The following are thus prepared: £ 3 7 ο θ PREPARATION V (4-Halophenyl)cyclohexanols A. 3- and 4-(4-Fluorophenyl)cyclohexanols A benzene solution containing equimolar amounts of 4-fluorostyrene 5 and 2-methoxybutadiene and hydroquinone (1% by weight based on diene) is heated in a sealed tube at 150° C. for 10 hours. The reaction vessel is cooled, the contents removed and concentrated to give 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-(4L0 fluorophenyl) cyclohexanones'.

Sodium borohydride reduction of the ketones according to the procedure of Example 5 affords the keto compounds.

In like manner, the corresponding 3- and 4-(4-chlorophenyl)cyclohexanols are prepared from 4-chlorostyrene, .5 b. 2-(4-Fluorophenyl)cyclohexanol This compound is prepared from cyclohexane oxide and p-fluorophenyl ’ lithium according to the procedure af Huitric et al., J. Org. Cham., 27, 715-9 (1962), for preparing 2-(4-chlorophenyl)cyclohexanol. _ 99 _ I 0° PREPARATION W ' (2-Halophenyl)cycloalkanols The procedure of Huitric et al., J. Org. Chem., 27, 715-9 (1962) is employed but using the appropriate cycloalkylene oxide and p-halo (Cl or F) phenyl lithium reactants to produce the following compounds: >~X Cl Cl 5 Cl 100 PREPARATION X -lly droxy-7-mercap to-2,2-g Imethy 1-4-chromanone A mixture of 3,5-dihydroxyphenyl methyl sulfide (5.85 g.) and 3methylcrotonic acid (4.5 g.) is heated to 125® C. under nitrogen and boron ericluoride etherate (8.7 ml.) added. The mixture is refluxed for one hour and is then cooled. Water (10 ml.) is added, followed by 6N sodium hydroxide (40 ml.). The mixture is heated on a steam bath for five minutes, then, cooled and acidified with 6N hydrochloric acid. It is extracted with ether (3 x 100 ml.) and the combined extracts washed with 102 sodium bicarbonate (1 x 25 ml.) and water (1 x 25 ml.) and then dried (Na^SO^). Concentration of the extract ; under vacuum affords dl-5~hydroxy-2,2-dimathyl-7-methylmercapto-4-chromanone.

It is purified by silica gel chromatography..

I The methyl mercapto compound thus produced is hydrolyzed by refluxing overnight with excess 482 hydrobromic aeid. Concentration of the reaction L5 mixture affords the title compound. It is purified hy silica gel chromatography, The following compounds are similarly prepared but replacing 3me thylerotonic acid with the appropriate acid of the formula R^RjC^CH-COOH: H CH3 H H ch3 c2h5 101 PREPARATION Υ Alkylation of 3,5-Dihydroxyphenylmercaptan A soluticn of 3,5-dihydroxyphenylmercaptan (3.5 g., 0.01 mole) in absolute ethanol (50 ml.) is made just alkaline with sodium ethoxide. The appropriate bromide of formula Br-falkp^-W (0.01 mole) is added and the mixture refluxed for 3 hours. It is then concentrated under reduced pressure and! the residue extracted with ether. Evaporation of the ether affords the product.

The following compounds are thus prepared; OH ! 1 -OTiffl3)(CH2)5- ch3 1 -8H(CH3)CH(CH3)(CH2)4-cfl3 1 -c(ch3)2(ch2)5- ch3 1 -(ch2)8-CH3 1 -(CH2)4- ch3 1 -ch2-C6H5 1 -(CH2)-C6H5 1. -CH(CH3) (CH2)3- c6h5 1 -CH„-C3H5 1 -ch2C5H9 1 -ch2-cAi 1 -2)2-C5H9 1 -(ch2)3-C5H9 1 -(ch2)5-C6H11 1 -(ch2)4-C5H9 1 ~(cii2)3ch«:?h5)-CAl 1 -(ch2)7-C5H9 102 ϊ 37 η (alk2) w 1 -Cch2)4-C7H13 1 -<σφ2-C7H13 1 -(cii2)5- c4h7 1 -2>5-C3H5 1 -(Clip- 2-piperidyl 1 -2)3- 4-piperidyl 1 -(CH.,)- 2-pyridyl 1 -2)3- 3-pyridyl 1 -(ch2)4- 2-pyridyl 1 -CH(CH,)(CH,),- 2-pyridyl 1 -Cil(CH,) (CH,),— 4-pyridyl 1 -CH(C,HS) (Cli,),- 4-piperidyl 1 -(ch2)4-4-*C6H4 1 -CH(CH,)(C1I,),- 4-cic6h4 1 -CU(CH,)(CH,),-4-FC6H4 0 —C6«5 0 — 4-κο6η4 0 — 4-clcsii4 0 —C3H5 0 --C5H9 0 Vll 0 —C7H13 0 — 4-pyridyl 0 — 2-piperidyl 0 — 2-pyridyl 0 — 2-(C6H5)C3H 0 4-(C6H5)C6H. 0 — 3-(CfiHs)C7H. 0 -- CH3 - 103 χ ΡΡ»Ε?.Λ RA.'f ’ OH 2 d1-2-(3,5-J)ibenzyloxyphenyl)-2-liydroxy-l-(2-phenylethoxy)propane To a 20° C. solution of dimethylsulfoxonium methylide (0.184 mole) in dimethylsulfoxide (185 ml.) is added 3,5-dibenzyloxyacetophenone (51.0 g., i 0,153 mole). After stirring 1.5 hours at 20° C., the reaction is 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 sulfate and evaporated to an oil. A solution of the thus produced crude 1(3,5-dibenzyloxyphenyl)-l-methyloxirane (0.153 mole) in dimethylsulfoxide (100 ml.) is rapidly added to a 20° C. solution of sodium phenethoxide (0.306 mole) in dimethylsulfoxide (150 ml,, made by the slow addition of • 35.5 ml. [0.306 mole] of phenethnnol to a slurry of 7,34 g, [0.306 mote] sodium suydri.de in 150 mi. dimethylsulfoxide). The reaction is slowly heated over a * half-hour period to 70° G., stirred 30 minutes and cooled to 20° C. The reaction is diluted with 200 ml. ice water and added to ether (2 1,) and ice water (1 liter). The organic phase is washed with cold water (2x11.), dried over magnesium sulfate and evaporated to an oil. This crude oil is purified via column chromatography on 1.5 kg. of silica gel, and eluted with 60% ether-nentane to yield 30.0 g. (42«) of dl-2-(3,5-dibenzyloxyphenyl)-2-hydroxy-1-(2phenylethoxy)propane, as an oil.

IK.· (CilCij) OH 3534 cm-1. » (t, J-2Uz, C-4 Aril), 6.76 (d, J=2llz, C-2,6 Aril), 7.25 (s, ArH) and 7.43 (s.Arll), (3) MS: m/e 468 (H®), 453, 377 and 335 (100%). 103^ PREPARATION ΛΑ d 1-2-(3,5-Diliydroxyphenyl)-l-(2-phenylethoxy) propane To a 0Λ0. solution of dl-2-(3,5-dibenzyloxyphenyl)-2-hydroxy-l-(2phcnylethoxy)propane (29.0 g., 61.9 mmole) in pyridine (50 ml., 0.619 mole) slowly added phosphorousoxy chloride (5.65 ml., 61.9 mmoles). The reaction allowed to warm to 20°C. and is stirred at 20°C. for 20 hours. The reaction added to a 0°C. solution of 3.3N NaOH (300 ml.) and the resultant mixture ex tracted with ether (3 st 500 ml.). Each extract is washed with saturated potassium carbonate (1 x 500 ml.) and water (3 x 500 ml.). The combined organ extract is dried over magnesium sulfate, silica gel and then decolorized (ca bon) and evaporated to an oil. This oil Is purified via column chromatograp I on silica gel (200 g.) eluted with 602 ether-pentane to yield 17 g. (612) of an oil (mixture of olefins). To a solution of this mixture of olefins (3.62 in ethanol (10 ml.) and ethyl acetate (10 ml.) is added solid sodium bicarbo (300 mg.) and 102 Pd/C (1,2 g.). This mixture is stirred 6 hours under one atmosphere of hydrogen. The reaction is diluted with ethyl acetate and filtered through diatomaceous earth. The evaporated filtrate is purified via column chromatography on silica gel (200 g.) eluted with 802 ether-pentane t< yield 2.0 g. (922) of dl-2-(3,5-dihydroxyphenyl)-l-(2-phenylethoxy)propane a! an oil.

IR: (CHCip OH 3571, 3279 cm-1.

TMS NMR: 1.10 (d, J=7Hz, methyl), 2.80 (t, J=7Hz, -Ciy’h), 2.90 (M, methine), 3.5 (m, -CH2O-CH2-), 6.10 (t, J=2Hz, C-4 Aril), 6.20 (d, J= 2Hz, C-2,6 Aril), 6.5 (broad m, hydroxyl) nnd 7.19 (s, Aril).

MS: m/e 272 (Μ®), 181, 168, 151, 138, 137, 123 105 (1002) and 91. fc —I C.S

Claims (38)

1. WHAT WE CLAIM IS:

1. A canpound having the formulae wherein R Is hydrogen or alkanoyi having from one to five carbon atoms; Rj 1s hydrogen, alkanoyi having from one to five carbon atoms or 5 -CO-iCHgJp-NRgRg wherein p is 0 or an Integer from 1 to 4; each of Rg and Rg when taken Individually 1s hydrogen or alkyl having from one to four carbon stofcs; or Rg and Rg when taken together with the nitrogen to which they are attached represent piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylp1peraz1no having from one to four 10 carbon atoms 1n the alkyl group; each of R<, anti Rg 1s hydrogen, methyl or ethyl; R q is oxo or alkylenedioxy having from two to four carbon atoms; - 104 W·] wherein W-j 'θύ Z is (a) alkylene having from one to nine carbon atoms; or (b) -(alk·]) m -X-(a1k2) n -wherein each of (alk]) and (alk 2 ) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk]) plus (alkg) is not greater than 9; each of m and n is 0 or 1; and X is O,S,SO or SOgS and W is methyl, pyridyl, piperidyl, is hydrogen, fluoro or chloro; or -CH ^ H Z^ a cH-W, wherin W, is ., ^(CHpJb/ 6 * hydrogen or Vfez ”1’ a is an integer from i to 5 and b is 0 or an integer from I to 5; with the proviso that the sum of a and b is not greater than 5; with the proviso that when W is methyl, Z is -(alk-j) m -X-(alkg) n -.

2. A compound according to claim 1 of the formula I.

3. The trans isomer, in respect of the hydrogen atoms on 6a, 10a positions of a compound according to claim 2, wherein each of R and R] is hydrogen.

4. A compound according to claim 3 wherein R^ is methyl; Rg is hydrogen or methyl; Z is alkylene having from I to 9 carbon atoms and W is W]where W] is as defined in claim

5. A compound according to claim 4 where Rg is methyl; Z is alkylene having from 1 to 9 carbon atoms, W] is hydrogen and OR has the β-configuration. - 105 - 4

6. The compound according to claim 5 wherein Z is -CH(CH 3 )-(CH2)3~ and wherein the methyl-substituted end of the Z chain is attached directly to the aromatic ring.

7. The compound according to claim 5 wherein Z is -0Η(0Η 3 )-(0Η 2 )^5 and wherein the methyl-substituted end of the Z chain is attached directly to the aromatic ring.

8. A compound according to claim 4 wherein Rg is hydrogen; Z is alkylene having from 1 to

9. Carbon atoms, is hydrogen and OR has the g-configuration. 10. 9. The compound according to claim 8 wherein Z is -CHfCHgJ-fCHgJg-, and wherein the methyl-substituted end of tiie 2 chain is attached directly to the aromatic ring.

10. The compound according to claim 8 wherein Z is and wherein the methyl-substituted end of the Z chain is attached directly to 15 the aromati·. ring.

11. A compound according to claim 3 wherein R^ is methyl; Rg is hydrogen cr methyl; Z is alkylene having from 1 to 9 carbon atoms; W is 4-pyridyl and OR has the s-configuration.

12. The compound according to claim 11 wherein Rg is methyl and Z is 20 -CHiCHgHCHgJ.-and wherein the methyl-substituted end of the Z chain is attached directly to the aromatic ring.

13. The compound according to claim 11 wherein Rg is hydrogen; and Z is -CH(CH 9 )-(Cii2)j-, and wherein the methyl-substituted end of the Z chain is attached directly to the aromatic ring. 25

14. A compound according to claim 3 wherein each of R^ and Rg is methyl; Z is -(alk 1 ) ra -X-{alkg) n -wherein alk 1 , alkg m, n ana X are as defined in Claim 1; W is a-configuration. —'

15. A compound according to claim 14 wherein Z is -(alk^) -0-(alk2) n 30 wherein a1kp alkg, m,n and X are as defined in claim 1.

16. A compound according to claim 15 wherein m is 0 and n is 1.

17. , A compound according to claim 15 wherein m is 1 and n is 0 - 106 od

18. The compound according to claim 15 wherein each of in and n is 0.

19. The compound according to clain 16 wherein -(alk 2 )is -CH(CHg)and wherein the methyl-substituted end 5 of the (alk 2 ) chain is attached directly to the 0 atom.

20. The compound according to claim 16 wherein -(alk 2 )- is -CH{CH 3 )-(CH 2 ) 2 -,and wherein the methyl-substituted end of the -(alk 2 )-chain is attached directly to the 0 atom.

21. The compound according to claim 17 wherein -(alk-j )10 is-CH(CH 3 )-(CH 2 ) 3 -, and wherein the methyl-substituted end of the (alkp chain is attached directly to the aromatic ring.

22. The compound according to claim 17 wherein -(alk^is -CH(CH 3 )-(CH 2 ) 2 -, and wherein the methyl-substituted end of the -(alk-j)-chain is attached directly to the 15 aromatic ring. - 106a-

23. A compound according to claim 3 wherein each of R^ and Rg is methyl; Z is -(alk]) m -X-(alk 2 ) n - wherein alk], alk 2 , m,n and X are as defined in claim 1; W is methyl and CR has the β-configuration.

24. A compound according to claim 23 wherein Z is -(alk,)^-05 ialk 2 ) n - wherein alk]. a1k 2 , m and n are as defined in claim

25. A compound according to claim 24 wherein is is 0 and n is 1.

26. The compound according to claim 25 wherein (alk 2 ) is -CH(CH 3 )-{CH 2 ) 4 -, and wherein the methyl-substituted end of -(alk 2 ) -chain is attaenel -a the atom. 10

27. A compound according to clain 1 of the formula 11.

28. The trans isomer is respect of the hydrogen atoms on 6a,10a positions of a compound according to claim 27 wherein R Q is oxo; is methyl; Rg is hydrogen or methyl; Z is alkylene having from 1 to 9

29. 30. The compound according to claim 28 wherein Rg is methyl; Z is -CH(CKgHCI! 2 } 4 ~ wherein the methyl-substituted end is attached directly to the benzopyran system; and W is /dy

30. 31. The ccs^eund according to claim 28 wherein R g is methyl; Z is -CHiCHgJ-JCHgl-j-wherein the methyl-substituted end is attached directly to the aromatic ring and W is 4-pyridyl.

31. 32. The trans isomer in respect of the hydrogen atoms on 6a, 25 10a positions of a compound according to claim 27 wherein R Q is oxo; each of and Rq is methyl; Z is -(alk]) m -0-(alk 2 ) n -wherein alk], alk 2 , m and n arc defined as in claim 1 and W is methyl, 4-pyridyl or wherein W, is hydrogen. - 107

32. 33. A compound according to claim 32 wherein m is 0 and n is 1.

33. 34. A compound according to claim 32 wherein m is 1 and n is 0.

34. 35. The compound according to claim 33 wherein -(a1k 2 )- is -CH(CH 3 )-(CH 2 ) 3 - wherein the methyl-substituted end is attached 5 to the 0 atom and W is methyl.

35. 36. The compound according to claim 33 wherein -(a1k 2 )- is -CH(CH 3 )-(CH 2 ) 3 -wherein the methyl-substituted end is attached to the 0 atom and W is 4-pyridyl.

36. 37. The compound according to claim 33 wherein -(alk 2 )- is 10 -CH(CH 3 )-(CH 2 ) 2 -wherein the methyl-substituted end is attached to the 0 atom and W is · A compound according to claim 1 of the formula III. A compound according to claim 38 wherein R Q is oxo. A compound as claimed in Claim 1 and as hereinbefore J5 described in any one of the Examples 3 to 5, 8 to 12„ 14 to 22 and 24 to 26.

37. 41. A process for producing analgesia in a non-human mannal which comprises administering to the mannal an analgesic producing quantity of a compound of formula I as claimed in any one of claims 20 1 to 26.

38. 42. A process for producing analgesia in a non-human mammal which comprises administering to the mammal a compound which has analgesic activity and has the formula (II) as claimed in anyone of claims 1 and 27 to 37.