CA1095909A - 9-hydroxyhexahydrobenzol¬c| quinolines and intermediates therefor - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
1,9-Dihydroxyoctahydrobenzo[c]quinolines (I), 1-hydroxyhaxahydrobenzo[c]quinoline-9(??)-ones (II), and 1-hydroxy-tetrahydrobenzo[c]quinolines (?V) useful as CNS
agents, especially as analgesics and tranquilizers, as hypo-tensives, as agents for the treatment of glaucoma and as di-uratics; intermediates therefor (III) and derivatives thereof having the formulae:

, , (I) (II) and (III) (IV) wherein R is hydroxy, alkanoyloxy having from one to five carbon atoms and hydroxymethyl;
R1 is hydrogen, benzyl, benzoyl, 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 hetero-cyclic ring (piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group); R4 is hydrogen, alkyl having from 1 to 6 carbon atoms and -(CH2)z-C6H5 wherein z is an integer from 1 to 4;
R5 is hydrogen, methyl or ethyl; R6 is hydrogen, -(CH2)y-carbalkoxy having from 1 to 4 carbon atoms in the alkoxy group wherein y is 0 or an integer from 1 to 4; carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; -(CH2)x-C6H5 wherein x is an integer from 1 to 4; and -CO(CH2)x-1-C6H5;
Ro is oxo, methylene or alkylenedioxy having from two to four carbon atoms;
R' is R or Ro;
z is (a) alkylene having from one to nine carbon atoms; (b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) is alkylene having from one to nine 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 hydrogen, methyl, wherein W1 is hydrogen, chloro or fluoro; pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cyclo-alkyl wherein the substituent is

Description

This invention relat~s to certain no~7el benzo lc~
quinolines and more particularly to l,9-dihydroxyoctahydro-benzo~c]quinolines, l-hydroxyhexahydrobenzo~c~q~inol1ne-9 (8H)-ones and l-hydroxy-tetrahydroben20[c~quinolines and derivatives thereof useul as CNS agants, especlally as analgesics and tranquilizers, as hypotensives in mammals, including man, as agen~s for the treatment ~f glaucoma and as diuretics; and to intermediates ~h~refor, and to processes for the preparation of the aorementioned compounds.
Included among such active compounds and inter-mediates are compounds having the formula:
1 1 .

f~z w . xx wherein A is selected from th~ group consi ting of:

~''' ~

: .
. . .
.
: . .

: ' :
.. , . , ,.. , . . . i r~
~2--alkylen 6 ~ 6 R

~1 IV I, J~ V', ~)\ VI ', J~

~\ R5 ¦ 6 R5 1 6 ~/

and the ketal~ and thioketals of the aompounds wherein A
i9 III' wherein tha ketal moiety has from two to four 5 carbon atoms, and th~e pharmaceutically acceptable acid addition salts of the compounds wherein A is I' or II', wherein -O-alkylene-O- is alkylenedioxy having from two to four carbon atoms, and wherein R, Ro, R', Rl, R2, R3, R4, R5, R6, R7, Z and W are as defined above. Some of the above compounds may also be depicted as shown in Formulae I, II, III, IV, V, VI and VII below.
An acceptable alternative n~menclature for the herein described compounds of Formulae I-IV is based upon replacement of the root "Benzo[c]quinoline"
15 with "phenanthridine". Thus, d,l-trans-5,6,6a~,7,8,9, lO,lOa~-octahydro-l-acetoxy-9~-hydroxy-6~-methyl-3~5-phenyl-2-pentyloxy)benzo[c]quinoline becomes d,l-trans-5,6,6a~,7,8,9,10,10aa-octahydro-1-acetoxy-9~-hydroxy-.

, , 6~-methyl-3-(5-phenyl-2-pentyloxy) phen~nthridins .
Despite the current availability of a numb~r of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an ag~nt useful for the control of broacl levels of pain and accompanied by a minimum of sicle-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain`and is known to ~xhibit various undesirable side-effect:s. Other, more potent analgesic agents such as d-propoxyphene, codeine, and morphine, possess addictive lizlbilityO The need for improved and potent analgesic agents, is, therefore, evident~
The analgesic properties of 9-nor-9~-hydroxy-hexahydrocannabinol and of other cannabinoid structures, such as ~a-~etrahydrocannabinol (~8-THC) and its primary metabolite, ll-hydroxy-~3-THC, have been reported by Wilson and May, Absts Papers, Am. Chem. Soc , 168 Meet , ~EDI 11 tl974), J. Med. Chem. 17, 475-476 (1974), and J. M~d. Chem., 18, 700-703 (1975).
_ UOS Patents 3,507,885 and 3,636,058, issued April 21, 1970 and January 18, 1972, respectively, describe various l-hydroxy-3-alkyl-6H-dibenzo-(b,d]pyranS having at the 9-position substituents such as: oxo~ hydrocarbyl, and hydroxy or chloro, hydrocarbylidene, and intermediates therefore.
U.S. Patent 3,649,650, issued March 14, 1972, discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo ~b,d]pyran derivatives having at the l~position an ~-dialkylaminoalkoxy group active as psychotherapeutic agentsO
German Specification 2,451,934, published May 7, 1975, describes l,9-dihydroxyhexahydrodibenzo~b,d]
pyrans and certain l-acyl derivatives thereof having at the 3-position an alkyl or alkylene group, as hypotensive, psychotropic, sedative and analgesic agents, The precurso hexahydro-9H-dibenzo~b,d]pyran-9-ones used in their pre-paration, and which are reported to have the same utility as the corresponding 9-hydroxy compounds, are described .

in German Specification 2,451,932, publ,ished May 7, 1975.
U.S. 3,856,821, i~sued December 24, 1974, describes a series of 3-alkoxy substituted dibenzo[b,d]
pyrans having antiarthritic, antinflammatory and central nervous system activity.
sergel et al., J. Ch~-m. Soc~ 286-287 (1943) investigated the replacement o~ the pentyl group at the 3-position of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-l-ol by alkoxy ~butoxy, pentyloxy, hexyloxy and octyloxy) and found that it led to biological inactivity. The hexyloxy derivative was reported to ex~ibit feeble hashish activity at 10 to 20 mg,/kg The remaining ethers showed no activity in doses up to 20 mg./kg 3 In a more recent study, Loev et al,, 30 Med, Chem., 16, 1200-1206 ~1973) report a oomparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo~b,d]pyran-l-ols in which the 3-substituent is -OCH~CH3)C5Hll; CH2CH(CH3)C5Hlli or CH ~CH3)C5Hll. The eth~r side chain containing compound was 50~ less active in central nervou~ system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as the compound in which oxygen is replaced by methylene, Hoops et al., J. Org. Chem., 33, 2995-2996 (1968) describe the preparation of ~he 5-aza analog of ~6a~lOa)-tetrahydrocannabinol referred to therein as 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3-n-pentylphenanthridine, but report no utility for thecompound. Beil, in "Psychomimetic Drugs", edited by Efron, Raven Press, New York, 1970, page 336, reports the compound was "completely inert in animal pharmacology."
Hardman et al , Proc. West. PharmacolO Soc., 14, 14-20 (1971) reports some pharmacological activity for 7,8,9,10-tetrahydro-1-hydroxy-6,6/9-trimethyl-3-n-pentyl phenanthridine, a 5-aza ~6a~l0)a~tetrahydrocannabinolO

; .

~ J~

Mechoulam and Edery in "Marijuana", edited by Mechoulam, Academic Pregs, N~W York~ 1973, page J.~7, observe that major structural change in the ~rahydro-cannabinol moIecule seem to result in steep reductions in analgesic activity.
Paton, in Annual Review of Pha~macology, I5, 192 (1975~ presents generalizations on structure-~ction relationships among cannabinoids. ~he presence of the gem dim~thyl group in the pyran ring is critical for cannabinoid activity and subst:itution of N ~or O in the pyran ring removes activity.
It has now been ound that certain benzo~c]
quinolines; namely, l,9-dihydroxyoctahydro-6H-benzo~c]
quinolines (I), l-hydroxyhexahydro-6H-benzo[c]quinoline-9~8H)-one~ (II) and l-hydroxy-tetrahydroquinolines (IV) ara effective as CNS agents, especially as analgesics and tranquilizers, as hypotensives, which are non-narcotic and ~ree of addiction liability, as~_~ents for the treat-ment of glaucoma and as diuretics. Also included in this invention are various derivatives of said compounds which are useful as dosage forms and intermediates thereforO The above-named compounds and their derivatives have the Formulae I, II and IVo Compounds of Formulae III
and IV are precursors to compounds of Formulae II and I, H~ ~R (I) ¦

Z-W ~ , ~Z_W~II) ~III) R ~ ~ U ~ \z-W
_~ 6 wherein R is selected from the group consisting of hydroxy, alkanoyloxy having from ~ne to five carbon atoms and hydroxymethyl;
Rl is selected from the group consisting of hydrogen, benzyl, benæoyl, alkanoyl having from on to five carbon atoms and -C0-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in ~he alkyl group;
R4 is selected from the group consisting o hydrogen, alkyl having from 1 to 6 carbon atoms and -(CH2)z-C6H5 wherein z is an integer from 1 to 4;
R5 is selected from the group con3isting of hydrogen, methyl and ethyl;
R6 is selected from the group consisting of hydrogen, -(CH2)y-carbalkoxy having from one to four carbon atoms in the alkoxy group and y i3 O or an integer from 1 to 4; carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl ha~ing from one to six carbon atoms; -~CH2)X-C6H5 wherein x is an integer from 1 to 4; and -CO~CH2)x_l C6~5;
Ro is selected from the group consisting of oxo, methylene and alkylenedioxy having from two to fsur carbon atoms;
R' is selected from the group consi~ting of R and Ro;
Z is selected from the group consisting of ~a~ alkylene having from one to nine carbon atoms;
~b~ -~alkl)m-X-~alk2)n- wherein each of ~alkl) and ~alk2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms ~L~39~9 in ~alkl) plus (alk2) is not greater than nine; each of m and n is O or l; X i9 selected ~rom the group con-sisting of o ~ S ~ so and SO2; and W is selected from the group consis~ing of hydrogen, methyl, pyridyl pipexidyl, ~ wl wherein Wl is selected from the group consisting of hydrogen, f~CH~) ~
~luoro and chloro; and -C~ C~-W2 wh~rein W2 is ~ _~cH2)bJ
selected from the group consisting of hy~rogen and ~ r Wl; a is an integer ~rom 1 ~o 5 and b is o or an integer from 1 to 5; with the proviso that the sum of a and b is not greater than 5; and the ketals of compounds of Formulae II, III and IV whe~ein the ketal moiety has from two to four carbon atoms.
Also included in this invention are phar-maceutically acceptable acid addition salts of compoundsof Formulae I and II. ~epresentative of such ~alts are mineral acid salts such as ~he hydxochloride, hydrobromide, sulfate, nitrate, phosphate; organic acid salts such as the citrate, acetate, sulfosalicylate, tartrate, glycolate, malonate, maleate, fumarate, malate, 2-hydroxy-3-naphtho-ate, pamoate, salicylate, stearate, phthalate, succlnate, gluconate, mandelate, lactate and methane sulfonate.
According to the present invention there is provided a process for the preparation of a compou~d having ( Q ~ ~1 6~ \ Z-W
or a pharmaceutically acceptable salt thereof, wherein Q is ~D95~0i9 EI~R
or . wherein R is hydrogen or an acyl group selected from alkanoyl groups having from ona to rive carbon atoms; Rl is hydrogen or an acyl group selected f rom benzoyl, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2:R3 wherein p i~ O or an integer from 1 to 4; each of R2 and R3 when taken in-dividually is the same or different and is hydrogen sr 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, said ring being piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylpiperazino having from one to four carbon atoms in the alkyl group; R~ is hydrogen, alkyl having from 1 to 6 carbon atoms or -(CH2)z-C6H5 whsrein z i5 an integer from 1 to 4; R5 is hydrogen, methyl or ethyl;
R6 is hydrogen, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to YiX carbon atoms;
-(CH2)X-C6H5 wherein x is an integer from 1 to 4, or -CO(CH2)X l-C6H5; Z is alkylene having from one to nine carbon atoms, or -~alkl)m -X-(alk2)n - wherein each of (alkl) and (alk2) is the same or diferent and is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alkl~ plus (alk2) is not greater than nine, each of m and n is O or 1, and x is O, S, SO or SO2; and W is hydrogen, methyl, pyridyl, ~ Wl wherein Wl is hydrogen, fluoro or chloro;
which comprises reduction of a compound of the formula:
Q

1~
~ OR

R4~

~9~

g wherein Rl, R4, R5, R6, W and Z ar~ as defined above, eit~er by:
a) catalytic hydrogenation to produce a compound wherein Q is H OH; or X
b) by reduction with an alkali metal in liquid ammonia to produce a compound wherein Q is ~ and if necessary subsequent reducti.on with a metal halide to produce a compound wherein Q is H / OH ;
,>
and when necessary to produce a compound wherein one or more of R and Rl is other than hydrogen acylating a product of the reduction;
and when necessary to produce a compound wherei~
R6 is other than hydrogen reacting a product obta~ned as above wherein R6 is hydrogen with formaldehyde or an alkyl or acyl halide and then when necessary reacting the product obtained with an alkali metal complex hydride to produce a compound wherein R6 is alkyl or ~C~2)n-C6H5.
Compounds having the Formulae I, II and III
above contain asymmetric centers at the 6a- and~or lOa-positions. There may be additional asymmetric centers in the 3-position substituent (-Z-W), and 5-, 6- and 9-positions. Diastereomers with the 9~-con~iguration ~5 are generally favored over the 9~-isomers because of greater (quantitatively) biological activity. For the same reason, the trans~6a,10a)diastereomers of compounds of Formula I are generally favored over the cis (6a,10a~
diastereomers. As regards compounds of Formula II, when one of R~ and R5 is other than hydrogen, the cis-diastereomers are preferred because of their greater biological activity. As regards Formula IV compounds, asymmetric centers exist at the g-position and in the 3-position substituents. Among the enantiomers of a . . ~, ~1~95~9 yiven compound, one will generally be favored over the other and the racemate because of its greater activity. The enantiomer favored is determined by the procedures described herein. For example, the 1-enantiomer of 5,6,6a~,7,8,9,10,10aa-octahydro-1-acetoxy-9~-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline is favored over the d-enantiomer and the raaemate because of its greater analgesic activity. For convenlenae, the above formulae depict the racemic compounds However, the above formulae are considered to be generio to and embracive of the racemic modifications of the oompounds of this invention, the diastereomaric mixtures, the pure enantiomers and diastereomers thereof. The utility of the racemic mixtures, the diastereomeric mixtures as well as of the pure enantiomers and diastereomers is determined by th~ biological evaluations described below.
Further, various intermediates useful in the ~``
preparation of compounds of Formulae I, II, III and IV
are al o included in this invention. The intermedlates have the formulae 5 6~ ~V) ~6 (VI) and o ~-W
7 (VII) ~959~9 ~11--wherein R4 ~ R5 ~ R6 and Z-w are as defined above;
R7 is selected from the group consi~ting of hydrogen and formyl; and Yl is selected from the group consisting of hydrogen and hydroxy protecting groups, partlcularly methyl, ethyl or benzvl.
Asymmetric centers may exist in intermediates V, VI and VII at the 2-position and in the 7-position substituent (-Z-W) and, of course, at other positions e.g. in the l-position substituent. The 2- and 7-positions in Formulae V-VII correspond to the 6- and the 3-positions, respectively, of compounds having Formulae I, II, III and IVo Favored, because of their greater biological activity relative to that of other compounds described herein, are compounds of Formulae I and II wherein R
and Ro as defined above;
Rl is hydrogen or alkanoyl;
R5 is hydrogen, methyl or ethyl;
and each of R4 and R6 is hydrogen or alkyl;
Z and W have the values shown below:
Z M n W
_ alkylene having from 5 to 9 - - H or CH3 carbon atoms alkylene having from 2 to 5 - - C6H5, 4-FC6H4, 4-25 carbon atoms ClC6H4, 4-pyrldyl -(alkl)m~~~alk2)n 1 1 { C H , 4-FC H4, 4-0 1 { ClC6H4, 4-pyridyl -talkl)m~~(alk2)n 1 1 { H or CH3 0 1 { H or CH3 1 0 { H or CH3 Preferred compounds of Formula I are those favored compounds described above wherein R represents hydroxy and which have the trans-configuration, Pre-ferred compounds of Formula II are those wherein Ro is oxo~
Especially preferred are those preferred ... :
- ' : `, .

.

compounds of Formul~e I and II wherein:
R is hydroxy (Fo~mula I only);
Rl is hydrogen or acetyl;
R5 is hydrog~n;
R4 is methyl or propyl R6 is hydrogen, me~hyl or ethyl:
when Z is alkylen~ havin~ ~rom 2 to 5 carbon a~oms w is phenyl or 4-pyridyli when Z is -(alkl)m O-~alk2)n- wherein m is O and n is 1, (alk2) n is alkyl~ne having from four to nine carbon atoms, w is hydrogen or phenyl; and when Z is alkyle~e having ~rom five to nine carbon atoms, W is hydrogen.
Additionally, the avored and preferred classes of intermediates of Formulae III, IV, V, VI and VII are those compounds having said formulae which serve as intermediates for the favored and preferred compounds of Formulae I and II.
Compounds of Formulae I and II wherein R6 i9 other than hydrogen, alkyl and -(CH2)X-C6H5 also serve as intermediates for Formulae I and II compounds wherein R6 is hydrogen, alkyl or -(CH2)x-C6H5.
The compounds of this invention of Formula V
are prepared from appropriately substituted anilines, e.g a ~ 3-hydroxy~5-~Z~W-substituted)-anilines (VIII1 or derivatives thereof in which the 3-hydroxy group is protected by a group (Yl) easily removabl to regenerate the hydroxy group. Suitable protective groups are those which do not interfere with subsequent rPactions of said 3-(protected hydroxy)-5-substituted anilines and which ~an be removed under conditions which do not cause undesired reactions at other sites of said compound or of proucts produced therefrom. Representative proteotive groups (Yl) are methyl, ethyl, benzyl, substitu~ed benzyl wherein the ;ubstituent is, for example, alkyl having from 1 to 4 carbon atoms, halo (Cl, Br, F, I), and alkoxy having from one to four carbon atoms, The exact chemical structure of the protecting group is not critical to this invention since its importance resides in its ability to per~orm in khe manner described above.
The selection and identlication 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 sequence. It should, therefore, b0 a group which is easily removed to permit r~storation o the hydroxy groupsO Methyl is favored as a protecting alkyl group since it is easily removed by treatment with pyridine - hydrochloride. The benzyl group, also a favored protecting - 15 group, is removed by catalytic hydrogenolysis or acid hydrolysis.
When Z is -~alkl)m-X-~alk2)n , Yl p benzyl or a substituted ben~yl group since it can sub-sequently be removed without detriment to the Z group.
The protected aniline derivative (VIII) is then converted to a compound of Formula IX by known technology as described herein, An abbreviated reaction se~uence (Flow Sheet A) for preparing repre~entative compounds of Formula V
beginning with a 3-~protected hydroxy)-5-~Z-W-substituted) aniline ~VIII) wherein -Z-W is OCH3 is given below:

ig~9~

Flow Sheç~t A
l OCH 3 ~ R4 2 _ > ~ /COOR

(VIII) ( IX) or ~ H2 . / \R4-COCH2COOR

/fCH3 ~NacNsH4 1CH3 COOR
) ClCC2HS ~O~ ~

~CH ~ ( 3 ) PPA ) ~ ~ R4 cOOC 2H 5 / ( R5 H ) \~V-A) ¦ /HBr- (X~
¦ HBr-~ HOAc HOAC
OH ,C~

~ j~ KOH ~ ~
H I R4 W- ~alk2) n~ 1~ R4 H H
(V-B) (V-C) ~. .
Y .

-: :.

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

i9~

R in the above flow sheet represents alkyl having from one to six carbon atoms. (R5, for the purpose of illustration in the overall Flow Sheet, is represented as hydrogen. However, in the sequen~e VIII ' X or VIII -~ V-~, R5 can be hydrogen, methyl or ethyl~) The 5-substituen~ of Formula VII compounds can be group -Z-W desired in compounds of Formulae II
or I, or a group readily convertible to said group.
When the Z moiety of group -Z-W is -~alkl)m-X-(alk2)n-wherein X is O or S and each of m and n is 0, the5-substituent, when W is hydrogen, is -XH (i.e., OH or SH) or a protected -XH group of the Formula -X-Y1 wharein Yl is as defined above When, of course, -Z-W is ~alkl)m-X-(alk2)n-W wherein m is 1, n is o and W is hydrogen, the 5-substituent becomes -(alkl)m-X-H The -XH group is advantageously protected in the manner described above.
The appropriate 3-hydroxy-5-substituted anilines discussed above are reacted, preferably in the form of derivatives in which the 3-hydroxy group (and 5-hydroxy group if one is present) is protected as mentioned above in order to achieve satisfactory reactions, with an alkyl ~-ketoesterr e.g., an alkyl acetoacetater in the presence of acetic acid to provide the corresponding ~-~(3-protected hydroxy)-5-substituted anilino]-~-(R4)-acrylate (IX). The reaction is generally conducted in a reaction-inert solvent such as benzene or toluene at temperatures of from about 50C. to the reflux tem-perature of the solvent under conditions which result in removal of by-product water. Benzene and toluene are efficient solvents when the reaction is conducted at the reflux temperature, since they permit azaotropic removal of by-product water. Other means of water removal - or effective removal of water - such as molecular sieves can be employed, as can other solvents which permit azeotropic removal of water.
Favored protecting groups for the 3-hydroxy-- : .
~, 59~

5-substituted aniline reactants are methyl, ethyl and benzyl groups since the ether~ are easily prepared, afford satisfactory yields o~ compounds of Formulae IX
and X and are conveniently removed.
The alkyl ~-ketoestex, preferably one in which the alkyl group has from one to six carbon atoms, is generally used in excess to insure maximum conversion of the aniline reactant to the corresponding alkyl ~-anilino-~-(R4)acrylate ~IX). rren to twenty percent excess of alkyl ~-ketoester is usually sufficient to achieve satisfactory conversions. Acetic acid i9 used in catalytlc amounts to facilitate reaction.
The alkyl ~-anilino-~-~R~)-acrylate ~IX) is then reduced to the corresponding alkyl-3-[(3-protected hydroxy)-5-substituted anilino]-3-~R4)-propionate ~X) by, for example, sodium borohydride-acetic acid and catalytic hydrogenation. A preferred catalyst is platinum dioxide since it conveniently p~ts the raaction to be carried out at low pressures, i.eO, at pressures under 50 p s i. Other catalysts such as noble metals, e.g., platinum, palladium, rhodium, supported or unsupported, can be used along with pressures of hydrogen ranging from about atmospheric to superatmospheric, e.g., 2000 p.s.i. In addition to such catalysts which are heterogeneous catalysts, this step can be carried out using homogeneous catalysts such as Wilkinson's catalyst, tris(triphenylphosphine)chlororhodium ~
Of course, when the protecting group or groups are benzyl or substituted benzyl, catalytic hydrogenation will result in their removal. For this reason, methyl or ethyl groups are preferred as protecting groups for the 3- and/or 5-hydroxy groups of Formula VIII reactants Alternatively, compounds of Formula X can be prepared directly from compounds of Formula VIII by reaction of Formula VIII compounds with an alkyl 3,3-R~R5-acrylate in acetic acid. The reaction is conveniently carried out by reacting equimolar quantities of the alkyl :
. :', ~L~39596:~

3~3-R4R5-acrylate and disubstituted aniline ~VIII) in from 0.1 to 2 equivalents of glacial acetic acid a~
temperature ranging from Oc. to the reflux temperature.
Alternatively, compounds of Formula V-B may be prepared directly by condensation of equimolar quantities of VIII with the appropriate substituted acrylic acid (~4R5C=CH-COOH) in pyridine hydrochloride at 150-200C.
In addition, when the R4,R5 groups are both alkvl, treatment of VIII and ~he alkyl ~4,R5 acrylate in a reaction-inert solvent, e.g~ tetrahydro~uran, with mercuric acetate followed by reduction with sodium borohydride gives X.
Direct conver ion of compounds of Formula VIII
to compounds of Formula x is also conveniently achieved by treati1lg ~ 3,5-~diprotected hydroxyàniline hydrochloride with an excess of an alkyl acetoacetate, eOg. ethyl acetoacetate, in the presence of sodium cyanoborohydride in a solvent such as methanol.
The alkyl 3-anilino-3-(R4)-propionate (X~ is then cyclized to the corresponding 2-(R4)-quinolin-4-one (Formula V-A or -B) by means of a suitable cyclizing agent such as polyphosphoric acid (PPA), hydrogen bromide-acetic acid, sulfuric acid, oleum ~fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid-formic acid and others known to those skilled in the artO
In a modification of this ~on~ersion, the alkyl 3-anilino-3-(R4)-propionate (X) can be converted to the corresponding acid by, for example, saponifioation of the ester followed by acidification, prior to cyclization.
The ether protecting, or blocking, groups on the 3-(and 5-)hydroxy groups can be removed at the time of cyclization through the use of hydrobromic acid in acetic acid as cyclizing agent and deblocking agent.
Hydrobromic acid 48% aqueous, is generally used since it affords satisfactory cyclization and deblocking. The reaction is conducted at elevated tempe~atures and j ~5~

desirably at the reflux temperature. However, when Z
is (alk ) X-(alk ) - cycl~zati~n conditions such as polyphosphoric acid or trifluoroacetic acid must be used to avoid cleavage o the ether or thioether linkage.
Alternatively, the protecting group (or groups) ca~ be xemoved subsequent to the cyclization reaction Hydrobromic acid-acetic acid is also a favored agent for deblocking at this stage of the overall synthesis.
The reaction is carried out as described above.
Other reagents such as hydriodic acid, pyridine hydrochloride or hydrobromide c:an be used to remove protecting ether groups such as methyl and ethyl groups.
When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydro-genolysis. Suitable catalysts are palladium or platinum, especially when supported on carbon. Alter~atively they can be removed by solvolysis using trifluoroacetic acid.
Of course, when group -Z-W contains ~ulfur, acid debenzylation is used rather than catalytic debenzylation.
A favored method for the transformation of compounds of Formula X to compounds of Formula V which affords satisfactory yields and permits use of relatively mild conditions comprises conversion of Formula X compounds to N-carbalkoxy derivatives wherein the N-carbalkoxy 25 group has from two to five carbon atoms by reaction with the appropriate alkyl or benzyl chloroformate. The N-carbalkoxy or carbobenzyloxy derivativa of Formula X
is then cyclized by means of a polyphosphoric acid to the corresponding N-carbalkoxy or carbobenzyloxy derivative of ~ormula V compounds. The N-substituted derivatives of Formula X compounds can, if desired, be hydrolyzed to the corresponding 3-(N-substituted)-3-~protected hydroxy)-5-substituted anilino]-3-~R4)-propionic acid prior to cyclization. Polyphosphoric acid generally produces maximum cyclization and is a preferred cyclizing agent.
Compounds of Formula V in which the hydroxy group or groups are protec~ed and in which the nitrogen s9~i~

atom is substituted with carbalkoxy are treated with hydrobromic acid-acetic acid ~o give compounds o Formula V-A. When the hydroxy protecting group or groups are benzyl or substituted benzyl, regeneration of the hydroxy groups is accomplished by catalytic hydrogenolysis. A
carbalkoxy group if present on the nitrogen atom is unchanged by thi~ reaction. It: can, if desir~d, be sub-sequently removed by treatment with hydrobromi~ acid-acetic acid or any of a variety of acids or bases.
Removal of the benzyl protectin~ group by treatment with trifluoroacetic acid also removes any N-carbalkoxy group present.
When the -Z-W substituent of Formula V compounds is -XH (X = O or S), and it is desired to have said -Z-W
substituent represent, in compounds of Formulae II or I, a group -X-(alk2)n-W wharein X is O, S, SO or SO2, and W is as previously defined, conversion of group -XH to group -X-(alk2)n-W is conveniently and advantageously undertaken at this point in the overall xeaation sequence~
Thus, tha 7-XH group of Formula V-~ above represented, for the purposes of illustration, as -OH, is transformed by the Williamson reaction with the appropriate bromide ~Br-(alk2)n-W], mesylate or tosylate, t~ group -O- (alk2) n~W (Formula V-C) .
Similarly, whan group -Z-W of Formula V is -(alkl)-X-H, its conversion ~o -(alkl)-X-(alk2)n-W
wherein n is O or 1 and W is other than hydrogen is conveniently undertaken at this Qtage of the reaction se~uenoe via the Williamson reaction.
A variety of groups, such as those included within the definition of R6, can be used in place of carbalkoxy or carbobenzyloxy in this favored method to mask the nitrogen against protonation.
Group R6, if not already present in compounds of Formulae V-A, V-B ar V C, can be introduced prior to formation of the hydroxymethylene derivative (Formula VI) by reaction with the appropriate Cl-R6 or Br-R6 reactant o--accord.ing to known ~roce~ures. O course, ~hen a.n acyl, ' e.g., aoetyl, group R6 is desired in productq o~
Formulae I or II, such cJroup~ are generally intxoduced ~t that point in ~he reaction sequences ~Flow She~t B) S following formation of Formula II compounds whereir. ~6 i~ hydro~en, e.g., by acylation with the appropriate acyl halide accordiny to known procedures.
Compounds of Formula V and, of coursP, of Formula2 V-A, V-B and V-C, are ~onverted by the following illus~rative sequence ~Flow Sheet B) io xepresentative - compounds of Formulae II and I ~5 - H ~n the ilius,r~tion), - - .

.
- " ' ' ' .
. ' -, , ' ' .

.

.

9~

Flow Sheet B
-~ OC2~15 ~

W- R NaH R4 ~ Z-W
(V) . H0 (VI) ¦C~3-CO-CH=CH2 Ba~e, CH30H
1l ,~.` ~

~ ~ ~303 ~ J ~

H ¦ CH0 (III) ~Li~NH3 ~VII) 1+ 1,3-bisformyl ~ derivatlve (VII-At]

R4J~
H H
(I) (II) ~+ cis isomer]

,~

-22~
The quinolines of Formula V are converted to hydroxymethylene derivatives of Formula VI by reaction with ethyl formate and sodium hydride. This reaction, a formylation reaction, produ~es the bis-formylated derivative (VI) in excellent yield. Treatment of the bis-formylated derivative with methyl vinyl ketone gives a mixture of the corresponding mono-N-formylated Michael adduct (VII) and 1,3-bis-formylated Michael adduct, The two products are conveniently separated by column chromatography on silica gel.
The conversion of compounds of Formula VII
to compounds of Formula III is achieved by an aldol condensation of the mono-N-formyl compound of Formula VII. The 1,3-bis-formylated Michael adduct when subjected to the aldol condensation produces a spiro-annelation product (III-A) as the major product. However, VII-A
can be converted to VII by treatmen~ with an equivalent of o Il ¦ H
CHO
(VII-A) (III-A) potassium carbonate in methanol.
In addition to the spiro-annelation product, small amounts of the desired enone (Formula III) and (V) are also produced.
The enone of Formula III is converted by Birch reduction to the compound of Formula II. Both the cis-and trans-isomers are produced. This reduction is conveniently carried out using lithium as the metal.
Sodium or potassium can also be usedO The reaction is conducted at a temperature of from about -35C. to .
.. .

g~

about -80c. The sirch reduction is favored b~cause it offers stereoselectivity resulting in formation of the desired trans-ketone of Formula II as the ma~or product. Catalytic reduction over a noble metal is favored when the cis-diastereomsrs are desired as the major product.
The hydroxy ketones of Formula II (compounds wherein Ro is oxo and Rl is hydrogen) and the dihydroxy compounds of Formula I (R - ORl = O~) appear to be rather unstable. Upon standing they undergo oxidation as evidenced by formation of purple to red colors~
Formation of the colored by-products occurs even when the hydroxy ketone is subjected to sodium borohydride reduction. It has been found that formation of the colored by-products can be prevented by acylation, particularly acetylation, of the l-hydroxyl group (ORl) with acetic anhydride in pyridine, and by formation of acid addition salts, e.g., hydrochlorides. The acetyl derivatives are stable upon standing and even when sub-jected to further reactionO
The aforesaid colored by-products are believed to have a quinonoid structure arising from oxidation of the l-hydroxy group (ORl) to oxo and introduction of a second oxo group at the 2- or the 4-position~ The by-products are themselves active as CNS agents, especlally as analgesics and tranquilizers, and as hypotensives, and are used in the same manner and at the same dosage levels as are compounds of Formulae I and IIo Reduction of the 9-oxo group of compounds of Formula II, and preferably for reasons of stabili~y mentioned above, of the acetylated derivative of Formula II, via metal hydride reduction affords compounds of Formula I wherein the hydroxyl group at the l-position is present as its acetylated derivative. Sodium borohydride is favored as reducing agent in this step since it not only afords satisfact~ry yields of the desired product, but retains the acetoxy group at the ~;~
~.

5~9 -?4-l-position, and reacts slowly enough with hydroxylic solvents (methanol, ethanol, water) to permit their use as solvents. A temperature of from about 0C. to about 30C is generally used. ~ower temperatures, even down to about -70C., can be used to increa~e selectivity of the reduction. Higher temperatures cause reaction of the sodium borohydride with the hydroxylic solvent and deacetylation. If higher t:emperatures are desired, or required for a given reduction, isopropyl alcohol _ 10 or the dimethyl e~her of diethylene glycol are ~ed as solvents. A preferred reducing agent is potassium tri-sec-butyl borohydride since it favors stere~selective formation of the 9~-hydroxy group. The reduction is conducted in dry tetrahydrofuran at a temperature below about -50C. using equimolar quantities of the 9-oxo compound and reducing agent.
Reducing agents such as lithium borohydride or lithium aluminum hydride require anhydrous ~onditions and non-hydroxylic solvents, such as 1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of ethylene glycol Alternately, and more desirably, compounds of Formula III, especially those wherein the l-hyd~oxy group is protected as an ester or benzyl ether, are converted to compounds of Formula I by catalytic hydrogenationO
A convenient procedure compriqes catalytic hydrogenation over palladium, e.gO palladium-on-carbon, or other noble metal, supported or unsupportedO
The acetylated derivatives of Formula I thus produced are converted to the corresponding hydroxy derivatives by cleavage of the acetyl group by standard methods The isomeric 9-~- and 9-~-hydroxy compounds having Formula I are produced in the above-described reducing steps. Treatment of the keto oompounds of Formulae II-IV with the appropriate alkylene glycol or alkylene dithiol having two to four carbon atoms in the presence of a dehydrating agent such as p-toluenesulfonic : ` ' ' .

&~

acid, or other acid, used in ketalization (oxalic, adipic), affords the corresponding ketals or thioketals (Fahrenholtz et al., J. Am Chem. Soc~, 89, 5934 ~1967]), Compounds of Formula I wherein R is hydroxymethyl are prepared via the Wittig reaction of the corresponding 9-oxo compound of Formula II with methylenetriphenyl-phosphorane or other appropriate methylide. The reaction is conducted under relatively mild conditions to produce the corresponding 9-methylene compound.
Hydroboration-oxidation of the 9-methyle~e compounds then affords the hydroxymethyl derivative. Borane in tetrahydrofuran is favored for the hydrobora~ion step since it is commercially available and gives satisfactory yields of the desired hydroxymethyl compound. The reaction is generally conducted in tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The borane product is not isoalted but is directly oxidized with alkaline hydrogen peroxide to the hydroxymethyl compoundO
Compounds of Formulae I and II, including those wherein each of R4 and R5 is alkyl, are also prepared by the sequence of Flow Sheet C below:

g O Flow She~t C
ketal i z.:ti~n ~

Z-W . ~ Z-W
U III (R4, R5 = ~) + II-A

~ R4~ oi : / 6 III-C ~`i R5S,,il IV-B

~ ~Z W ~Z-W

IV-A

Z-W

The first step of this sequence compri6es con-version of the previously described enones ~Formula III, Flow Sheet ~) to the corresponding ketals by reaction with an appropriate alkylene g].ycol ~e.g., ethylene glycol) in the presence of approximately equivalent amounts of p-toluenesulfonic acid or other aoid commonly used for ketal formation as dec;cribed above in benzene with azeotropic removal of water. A mixture of two ketals is obtained; II-A, the reduced form, and IV-~, the oxidized form. Formation of IV-A is favored by addition of agents such as air, Pd/C, sulfur or 2,3-dichloro-5,6-dicyanobenzoquinone to the reaction mixture, The exclusion of oxidizing agents from the reaction mixture or the addition of reducing agents to the reaction mixture favors formation of II-A.
Deketalization of Formulae II-A and IV-A
compounds by procedures known to those skilled in the art affords compounds of Formulae II and IV These latter compounds are then converted to compound of Formulae I and IV by the procedures of Flow Sheet B
The reduced Formula II-A compounds are oxidized (dehydrogenated) by a variety of oxidants, including iodine, by standard techniques to produce Formula IV-A
compounds.
The heteroaromatic system of compounds of Formula IV-A readily adds organometallic reagents to the azomethine bond. Organolithium reagents, e g. methyl and ethyl lithium, react with IV-A to produce adducts of Formula III-B. Oxidation of the thus-formed adduct by various oxidizing agents, conveniently air, aromatizes the adduct to give Formula IV-B substituted in the 6-position. Further reaction of the 6-substituted IV-B
compounds with organolithium reagents affords the 6,6-disubstituted products of Formula II-B
The addition of the second group (R5) to the 6-position, particularly when R5 is laryer than methyl, is facilitated by activation of the azomethine bond by ~5~g9 -2g-quaternization. Activation is conveniently achieved by reaction of Formula III-~ with an alkyl halide (e.g.
methyl or ethyl iodide~/ or an aralkyl halide, desirably an aralkyl bromide [C6H5~CH2)XB] such a~ benzyl bromide to give Formula III-C compounds substituted in the 5-position. The thus-activated aompounds readily react with an excess of organolithium or Grignard reagents ~see Hoops, et al , J. ~. Chem., 33, 2995-6, 1968) to provide trisubstituted Formula II-B compoundsO
- lO Hydrolysis of the ketals of Formulae II-B and III-C
affords the corresponding enones which are converted to Formulae II and I compounds by proceduras described above. Of course, when R6 of Formulae III or III-C
compounds is benzyl, lithium-ammonia reduction of the enone also cleaves the benzyl group.
A furthPr procedure for introduction of alkyl groups at the 6-position with ultimate production of compounds of Formulae I and II is that of Flow Sheet D:

~9s~

Flow Sheet D

X OH X OH

' ~-W O~z-W
R6 l X IV-A El IV-C

~¦~ R6 X
1''''' 1 0~ 0~

Z-W I IV-E

6 X~IV-D 1 R4MgX

r /
0~0 H R4 gX

4~
~N Z-W
R5~ l II-B

~, ,~,.

- , ., ~ ~

::
- ' ''' ~ ' ~59~

The 6-oxohexahydrobenzo~c]quinolines of Formulae IV-C and IV-E are prepared from compounds of Formula IV-A and IV-D by reacting them with sodium or potassium hydroxide at elevated temperatures, e.g. at about 200-300C Quaternization of the nitrogen of IV-A, by reacting IV-A with methyl or ethyl iodide, benzyl bromide or other aralkyl halide, permits the reaction with sodium or potassium hydroxide to be carried out under milder conditions. The intermediate adduct formed is easily oxidized with mild o~eidizing agents, including air, to the oxo compound of Formula IV-E but which, of course, as a result of the quaternization reaction, bears a substituent (methyl, ethyl, aralkyl) on the nitrogen atom.
An alternative procedure comprises treating IV-A with a peracid, e.g. m-chlorope~benzoic acid, peracetic, to form the corresponding N-oxide which is ~ then reacted with acetic anhydride in an N-oxide rearrangement to give IV-C ~Boekelheide Rearrangement)~
Other methods known to those skilled in the art can be used for the conversion of N-oxides to lactams.
Compounds of Formula IV-C or IV-E are then treated with an excess of an appropriate Grignard reagent, e.g. methyl or ethyl magnesium bromide, to give the corresponding 6,6-dialkyl compound II-B~
The 3-hydroxy-5-(Z-W-substi~uted)anilines are prepared from corresponding 5-(Z-W-substituted)resorcinols via the Bucherer Reaction which comprises reacting the appropriate 5-(Z-W-substituted)resorcinol with aqueous ammonium sulfite or bisulfite. The reaction is conducted in an autoclave at elevated temperatures, e.g. from about 150 to about 230C. The aniline product is isolated by acidifying the cooled reaction mixture and extracting the acid mixture with, for example, ethyl acetate~ The acid solution is neutralized and extracted with a suitable solvent, e.g. chloroform, to racover the aniline product.
Alternatively, the aniline product is isolated by extracting the cooled reaction mixture with an appropriate , . ' :: :

solvent followed by column chromatograph~ of the crude product.
The 5- ( Z-W-~u}:~stituted) resorcinols, if not known, are prepared from 3, S-dlhydroxybenzoia acid.
~he procedure comprises esterifying 3,5-dihydroxyb~nzoi~
acid in which the hydroxy group~ are protected ~e~g~, as methyl, ethyl or benzyl e~hers); or alternatively, amidating the 3,5-~di(protected hydroxy)~benzoic acid~
The overall abbreviated sequence is illustrated 10 below (Flow Sheet E):
OH Flow she~!t E Y
~''~ ~ ~

OH ~ (XII) HO Z-W loyl olIV) ` Y10~--C- Z ' -W
(XIII) ~01

2 Z-W
(VIII-A) .
~, , .
, ;- ~ . .

~9s~

The starting material, 3,5-dihydroxybenzoi~
acid XI is converted to a compound of Formula XII wherein Y2 represents an alkoxy group, desirably methoxy or ethoxy for ease of preparatlon, or an amino group; and Yl is a hydroxy protecting group, by methods described in the literature~
The diprotected benzoic acid ~erivative XII
is then converted to a compound of Formula XIV by known technology. In one procedure XII i8 hydrolyzed to the corresponding acid (Y2 = OH), or lithium salt, ~nd reacted with the appropriate alkyl lithium to produoe an alkyl disubstituted phenyl ketone ~Y2 ~ alkyl). When methyl lithium is used, the r~sulting acetophenone derivative is treated with a Grignard Reagent (W-Z'-MgBr).
The intermediate adduc~ 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 (Yl = methyl) or catalytic hydrogenolysis ~Yl - benzyl), or by treatment with an acid such as trifluoroacetic acid, hydrochloric, hydrobromic or sulfuric acidsa Acid debenzylation is, of course, used when the group -Z-W aontains sulfur.
~ further method for converting compounds of Formula XII to those of Formula XIV comprises reaction of a ketone of Formula XII (Y2 - alkyl) with the +ppropriate triphenyl phosphonium bromide derivative [(C6H5)3P-Z-W]Br in the presence of a base (e.y., sodium hydride~. The reaction proceeds via an alkene which is subsequently catalytically hydrogenated to the corresponding alkane (Z-W) and deblocked to the dihydroxy compound XIVo Of when -Z- is (alkl)m-X-(alk2)n the catalytic hydrogenation also results in cleavage of the benzyl ethers.
Alternatively, conversion of structure XII
compounds to those o~ structure XIV can be achieved by .' ~
,. ...

, ~s~

the s~quence XII ~ XIII ~ XIV. In thi~ sequence, the diprotected benz~nide ~XII, Y2= NH2) is converted to the ketone (XIII, z' = Z less one CH2 group) by reaation with the appropriate Grignard reagent (BrMg-Z'-W) followed by reaction with methyl or ethyl-magnesium halide to form the corresponding carbinol. De~hyd~ation of the carbinol, e.g " with p-toluenesulfonic acid, affords the correspond-ing alkene which is then catalytically hydrogenated (Pd/C) to the alkane (XIV). The ether groups are deblocked (converted to hydroxy) as described aboveO
When Z is aikylene, Yl is desirably alkyl having from one to four carbon atoms or benzyl. The function of group Yl is to protect the hydroxy groups during sub-sequent reactions. It is 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 af 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 pro~ecting group are determined by employing such a group in the above-illustrat~d reaction sequence~ It should, there~ore, be a group which is aasily removed to permit restoration of the hydroxy groupsD Methyl is favored as a protecting alkyl group since it is easily removed by treatment with pyridine hydrochloride~ The benzyl group, i-f used as a protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.
~ alkl)m X~(alk2)n~' ~1 is preferably benzyl or a substituted benzyl group since it can sub-sequently be removed without detriment to the Z groupO
Formula VIII-A compounds can, alternatively, be prepared from 3-amino-5-hydroxybenzoic acids via the procedure of Flow Sheet F below Compounds of Formula VIII-A wherein -Z-W is alkylene-W or -(alkl)-X'-(alk2)n-W wherein (alkl), (alk2), W and n are as defined above and X' is O or S, are obtained by thè following sequence (Flow Sheet F):

~a~9~9~9 Flow Sheet F
(AC - acetyl) Yl ACNP~ (C6P5) ~P'CPCOOC2P5 ~b COOC2P5 ~R' = H, alkyl) l 1 ~ R"

AcNH ~ CH ~C 2~c~ OH
/ R"
C H5N/TosYl ~Br3 ~ 5 ~ Chloride ~

AcNH ~ CH `CH2-OTS ~ CH~ 2`CH Br R" AcNH R"
~-(alk2) -X'H ~C6H5~3P
Yl Yl AcNH ~ CH 2`CH2-X' ~ fH 2~CH 2- P ( C 6 H 5 ) 3 acidR" (alk2)n R" Br R"-C-~CH2)v-W
~ ~ Yl OH

,~3~ < 2 ~--CH~ 2`CH--C- ( CH ~ -W
AcNH Z-W H AcNH l l 2 v R" R"
(VIII-A) ~ `~,, ~s9~

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. The amino group is pro~ected by acetylation according to standard procedures. In the given illustration, the vaLue of R" as methyl or ethyl permits formation of a compound having alkyl sub-stitution on the carbon atom (~) adjacent to the phenyl group. Substitution of a methyl or ethyl group at other sites, e.g., the ~-carbon atoms of the ~lkvlene group, is achieved by choice of the appropriate carboalkoxy alkylidene triphenylphosphorane, e.g. ~C6~5)3P=CtR")-COOC2H5. The unsaturated ester thus produced is reduced to the corresponding saturated alcohol by rea~tion with lithium aluminum hydride The presence of a small amount of aluminum chloride sometimes accelerates this reaction, Alternatively, when Yl is other than benzyl (e.g. methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium-carbon, followad 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 the appropriate HX'-(alk2)n-W reactant, and finally removal of the protecting groups (Yl~ affords the desired compound VIII-Ao When X' i9 sulfur, the protecting group Yl is methyl.
A variation of the above sequence comprises bromination of the alcohol rather than converting it to a tosylate or mesylateO Phosphorou~ tribromide is a convenient brominating agent. The bromo derivative is then reacted with the appropriate HX'-(alk2)n-W in the presence of a suitable base (Williamson reaction)D
The bromo compounds also serve as valuable intermediates for increasing the chain length of the alkylene moi.ety in the above sequence to give compounds wherein Z is -alkylene-W. The process comprises treating the bromo derivative with triphenyl phosphine to produce the corresponding triphenylphosphonium bromide. Reaction of the triphenylphosphonium bromide with the appropriate aldehyde or ketona in the pre~ence of a base such as sodium hydride or n-butyl lithium affords an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated cornpound.
In this variation, the value of the protecting group (Yl) selected depends upon the partiaular sequence followed. When the vertical sequence on the right is used, benzyl is the preferred protecting group by reason of the catalytic hydrogenation step. Methyl is the pre~
ferred protecting group when the left vertical sequence is followed, since it is conveniently removed by treat-ment with acid as described herein.
Compounds of Formula II whereln -Z-W is -(alkl)m-X-(alk2)n-W and X is -SO- or -SO~- are obtained by oxidation of the corresponding compounds in which X is -S-O Hydrogen peroxide is a convenient agent for oxidation of the thio ethers to sulfoxides. Oxidation of the thio ethers to corresponding sulfones is conveniently accomplished by means of a peracid such as perbenzoic, perphthalic or m-chloroperben20ic acid This latter peracid is especially useful since the by-product m-chlorobenzoic acid is easily removed.
Esters of compounds of Formulae II - IV wherein Rl is alkanoyl or -CO-~CH2)p-NR2R3 are readily prepared by reacting Formulae II - IV compounds with the appropriate alkanoic acid or acid of Formula HOOC-(CH2)p-NR2R3 in the presence of a condensing agent such as dicyclohexyl-carbodiimide, Alternatively, they are prepared by reaction of a Formula II - IV compound with the appropriate alkanoic acid chloride or anhydride, eOg., acetyl choride or acetic anhydride, in the presence of a base such as pyridine.
Esters of Formula I compounds in which each of the R and Rl groups is esterified are prepared by acylation according to the above-described proceduresO

Compounds in w~ich only the 9~hydroxy group is acylated are obtained by mild hydrolysis of the corresponding 1,9~
diacyl derivative, advantage being taken of the greater ease of hydro~ysis of the phenolic acyl group. Formula I
compounds in which only the l-hydroxy group is esterified are obtained by borohydride reduction of the corresponding Formula II ketone esterified at the 1-position. The thus-produced Formula I compounds bearing l-acyl~9-hydroxy substitution or l-hydro~y-g-acyl substitutisn can then be acylated further with a different acylating agent to produce a diesterified compound of Formula I in which the ester group at the 1- and the 9-positions are different.
The presence of a basic group in the ester moiety (ORl) in the compounds of this invention permits formation of acid-addition salts involving said basic group. When the herein described basic esters are pre-pared via condensation of the appropriate amino acid hydrochloride (or other acid addition salt) with the appropriate compound of Formulae I - IV in the presence of a condensing agent, the hydrochloride salt of the basic ester is produced. Careful neutralization affords the free base. The free base form can then be converted to other acid addition salts by known procedures Acid addition salts can, of course, as those skilled in the art will recognize, be formed with the nitrogen of the benzo[c]quinoline system. Such salts are prepared by standard procedures~ The basic ester derivatives are, of course, able to form mono- or di-acid addition salts because of their dibasic functionality~
The analgesic properties of the compounds of this invention are determined by tests using thermal nocioeptive stimuli, such as the mouse tail flick procedure, or chemical nociceptive stimuli, such as measuring the ability of a compound to suppress phenylbenzoquinone irritant-inducad writhing in mice. These tests and others are described belowO

`` ~

lCi~S~

Test~ Usin~ Thermal Nociceptive Stimul a) Mouse Hot Plate Analqesio Te~tinq The method used i5 modified after Woolfe and MacDonald, J. Pharmacol. Exp . Ther., 80, 300-307 (1944).
A controlled heat stimulus iq applied to the feet of mice on a 1/8" thick aluminum plate. A 250 watt reflector infrar-ed heat lamp is placed under the bottom of the aluminum plate.
A thermal regulator, conneatecl to thermistor on the plate surface, programs the heat lamp to maintain a constant temperature of 57DC. 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. At 0.5 and 2 hours after treatment with the test compound the mouse is observed for the first "flicking" movements of one or both hind feet, or until 10 seconds elapse without such movements. Morphine has an MPE50=4-5.6 mg./kg. ( c.).
b) Mouse Tail Flick Anal~esic Testin~
Tail flick testing in mice is modified after D'Amour and Smith, J. Pharmacol. Ex~. 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 tail lies flat o~ier a concealed heat lamp. At the onset of testing, an aluminum flag over the lamp is drawn back, allowing the light beam to pass through the slit 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 MPE50of 3.2-5.6 mg.~kg, (s.c.).
Test Using Chemical Nocice~tive Stimuli Suppression of Phenylbenzoquinone Irritant-Induced Writhin~
Groups of 5 Carworth Farms C~-l mice are pretreat-ed subcutaneously or orally with saline, morphine, codeine or the test compound. ~ty minutes ~if ~reated s ~ utan~ously~ or ~ ` .

~S~(~9 fifty minutes (if treated orally) later, each group is treat-ed with intraperitoneal injection of phenylbenzoquinone, an irritant known to produce abdominal contractions. The mice are observed for 5 minute!s for the presence or absence of writhing starting 5 minutes after the injection of the irritant. MPE50's of the drug pretreatments in blocking writhing are ascertained.
Results of the above~ tests are recorded as percent maximum possible effect (% MPE). The % MPE of each group is statistically compared to the % MPE of the standard and the predrug control values. The % MPE is calculated as follows: test time - control time % MPE cutoff time - contr~I~~l~e x 100 In the tables below, the analgesic activity is reported in terms of MPE50, the dose at which half of the maximal possible analgesic effect is observed in a given test.
The compounds of the present invention are active analgesics via oral and parenteral administration and are conveniently administered in composition formO Such com-positions include a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be adminis-tered in the form of tablets, pills, powders or granulescontaining 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 may also be administered in the orm of oxal suspensions, solutions, emulsions, syrups and elixirs which may contain flavoring and coloring agents. For oral administration of ~he therapeutic agents of this invention, tablets or capsules ccntaining from about 0.01 to about 100 mg~ are suitable for most applications.
3s The physician will determine the dosage which ~C~95~

will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient and the route of admin~stration. 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 o~ the above procedures, the analgesic activity of several compounds of this invention and of cer-tain prior art compounds are determined.
The following abbreviations are used in the tables:
PBQ = phenylbenzoquinone-induced writhing; TF -tail flick; ~P = hot plate.

9~

o n ~ ~ ~
O O O t~l tY~ ~ ~ O
~ O ~ ~7 A

,, ~ ~ ~
~ o ~ ~ ~ o ~ ~ ~r ~ o ~ ~
r~ o Ln l` o o o ~l ~ ~ o o ~ _, d -' o o o o o ~> g~ !

P~ 5~
~ 1 ~1 ~ ~ U~, ~ ~ ~
T ~ T T T 1.~ T ~ T T T ~ ~
û
~a o ~ + ~ $ ~

- . ~ . .

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

~5~9 In o o ~ ~r U~ o . ~ ~D
o ~r ~ o w Q ~i ~ O O

~7 . ., In a ~ o ~r ~1 ~ ~ CQ
C~ ~ O CO O O O O ~ CO O O ~ ~ ~ ~ I`
O O ~1 0 ~ O O ~ /~ O O A V ¦ ~ O O O O
td ,~ ,p ,p ,~ p ,~ p ~ ~ W~ w~

t.

~ ~ w w ~ w w ~ w ~

'' ' ' ' 9~

o o o o o o~1 ~i ,- , o o o ~ ~ o a~ o o 1~ A A~ o O O ~O O CD ~D
~ ~ o~ ~ , V
f~ ~O OO~~OOO~OOO
r~ ~31 . o o ~1 o ~ ~ o o o . ~1 ~1 ~1 ~ ~1 _I A ~ O ~1 ~ I r-l O

~./~"
P~ ~) ~i ~ $~

$

m ~ ~ ~ m ~ m H~ 3 H ~ ,~

m m , . .

. . . . .
.. .. . --.. .
~ ~ .

~1 ..

o o o o A A

O ~ O ~ O
o ~ ,i d ", u~

~1 #
~ ~ o ~ ~ U

u~
~ ~ ~ ,~
~N ~ N

~5 $ ~ $ $ ~ $ ~

mU' ~9~ 8 ~ m ~ ~i m m m ~'1 m m m m m m m m m c~ ~

m m ~1~ 8 8 ~ ~ 8 8 5~

., ~
.. . - . . . .

~9~

~44a-Their antihyperkensive utility is determined by their abllity to lower the bloocl pressure o~ conscious hypertensive rats and dogs a statistically significant degree when administered orally to said hosts at the above-mentioned dosages.
Their tranqullizer activity is demonstrated by oral administration to rats 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.
The use of these compounds ~or the treatment of glaucoma is beliaved to be due to their ability to reduce intraocular pressure. Their effects on intraocular pressure are determined by tests on dogs. The test drug is instilled into the eye of a dog in the form of a solution or is administered systemically at various periods of time after which the eye is anesthetized by instillation of tetracaine hydrochloxide, 1/2~, 2 dropsO
A few minutes after this local anesthesia, intraocular pressure readings are taken with a Schiotz mechanical tonometer and, after fluorescein dye is administered, with a Holberg hand application tonometer. ~he test drug is conveniently used in a solution such as the following: test drug (1 mg.), ethanol tO 05 ml.), Tween 80 (polyoxyalkylene derivative of sorbitan mono-oleate, available from Atlas Powder Co., Wilmington, Delaware 19899) (50 mg.) and saline (to make 1 ml ), or in a more concentrated solution wherein the ingredients are present in proportions of 10 mg., 0.1~ ml~, 100 mg. and 1 mlO, respectively. For human use, concentrations of drug from 0.01 mg./kg. to 10 mgl/kg. are useful.
Their activity as diuretic agents is determined by the procedure of Lipschitz et al., J, Pharmacol., 79, 97 ~1943) which utilizes rats as the test animals. The dosage range for this use is the same as that noted above with respect to ~he use of the herein described compounds as analgesic agents.

~ . . . ..

~4b-This invention also provides pharmaceutical compositions, including unit dosage forms, valuable for the use of the herein described compounds a~ analgesics and other utilities disclosed herein. ThP dosage form may be given in single or multiple doses, as previously noted, to achieve the daily dosage effective for a particular utility.
The compounds (drugs) described herein can be formulated for administration in solid or liquid form for oral or parenteral administration. Capsules con-taining drugs of this invention~ i.e.; compound o Formulae I or II are prepared by mixiny one part by weight of drug with nine parts of excipient such as starch or milk sugar and then loading the mixture into telescoping gelatin capsules such that each capsule con-tains 100 parts of the mixture. Tablets containing com-pounds of Formulae I or II are prepared by compounding suitable mixtures of drug and standard ingredients used in preparing tablets, such as starch, binders and lubricants, such that each tablet contains from OoOl to 100 mg. of drug per tablet.
Suspensions and solutions of these drugs, particularly those wherein Rl (Formulae I and II) is hydroxy, are generally prepared just prior to use in order to avoid problems of stability of the drug (eOg, oxidation) or of suspensions or solution (e.g pre-cipitation) of the drug up on storage. Compositions suitable for such are generally dry solid compositions which are reconstituted for injectable administration Ethyl dl-3-(3,5-Dimethoxyanilino)butyrate A mixture of 3,5-dimethoxyaniline (95.7 g , 0.624 mole), ethyl acetoacetate (87.2 ml., 0 670 mole), benzene (535 ml.) and glacial acetic acid (3.3 ml.) is refluxed for 15 hours under an atmosphere of nitrogen and water collected by means of a Dean-Stark trap. The reaction mixture is cooled to room temperature, decolorized 5~9 -44c-~ith activated charcoal, filtered, and then concentrated under reduced pressure to give the product, ethyl 3-[3,4-dimethoxy)anilino]-2-butenoate, as an oil ~168.7 g.).
A mixture of ethyl 3-~3,5-dimethoxvanilino)-2-butenoate (5.0 g., 18.7 mmole) in glacial acetic acid ~42 ml.) and platinum oxide (250 mg,) is hydrogenated in a Parr shaker at 50 p.s.i. for 1.5 hours. The re-action mixture is filtered through filter-aid, ben~ene t50 ml.) added and the solution concentrated under re-duced pressure to an oil. The ~il is taken up in chloroform, the solution washed successively with saturated sodium bicarbonate solution (2 x 50 ml.) and saturated sodium chloride solution. It is then dried (MgSO4), filtered and concentrated under reduced pres-sure to give the product as an oil ~5.1 gl).
Repetition of the above procedure but using 168.7 g. of ethyl 3-(3,5-dimethoxyanilino)-2-butenoate, glacial acetic acid ~320 ml.) and pla~inum oxide ~2.15 g.) gives 169.8 g. of product.

. ~

~59~

EX~MPLE 2 Ethyl dl-3-(3,5-Dimethoxyanilin~ y~
To a solution of 3,5-dimethoxyaniline hydrochloride (370 g., 1.45 mole) reagent grade methanol ~4 5 1.) and ethyl acetoacetate (286.3 g., 2.64 mole) in a 12 liter round bottom, 3 neck flask fitted with methaniaal stirrer and reflux condenser is added sodium cyanoborohydride (54 g., 0.73 mole) in one portion. After the refluxing subsides tlO minutes) the mixture is heated on a steam bath for an additional 20 minutes. To the cooled reaction mixture is added additional sodium cyanoborohydride (5.4 g., 0.07 mole) and ethyl acetoacetate (28.6 g., 0.26 mole) and the mixture re1uxed for 30 minutes. This latter process is repeated once more.
The reaction mixture is isolated in portions by pouring ca. 500 ml. onto 1 liter of ice-water/500 ml.
methylene chloride, separating the layers and backwashing the aqueous phase with additional methylene chloride (100 ml.) (This process is repeated using 500 ml. portions until the entire reaction mixture is worked up.) The methylene chloride layers are combined and dried (MgSO4), decolorized with charcoal, filtered and evaporated to yield a yellow colored oil.
The excess ethyl acetoacetate iq distilled ~at 130C. oil bath temperature and 1-5 mm pressure) leaving the crude ethyl 3-(3,5-dimethoxyanilino)butyrate (an amber colored viscous oil): 376 g. (72% yield) which is used without further purification.
It has the following spectral characteristics:
1H NMR (60 MHx) ~CDCl (ppm): 5-82-6-0 (m~3H~

aromatic), 4.20(q,2H,ester methylene), 3.80-4.00(m,2H,-NH
and -N-CH-CH3), 3.78 (s, 6H, -OCH3), 2.40-2.55 (m,2H~-CH2 COOEt), 1.78 (d,3H,methyl) and 1.29 (t,3H,methyl).

~1~9~9~1 ~ XAMPLE 3 dl-Eth~1 3-(3,5-Dimethoxyanilino)hexanoate Following the procedure of Example 2, condensation of 3,5-dimethoxyaniline hydrochloride and ethyl butyryl-acetate gives ethyl d,1-3-(3,5-dimethoxyanilino)hexanoate.
It is converted to the hydrochloride salt by addition of hydrogen chloride to a methylene chloride solution thereof;
m.p. 127-129.5C. Recrystallization from cyclohexane/
benzene (5:1) gives the analytLcal sample, m.p. 126-128.5C.
Analysis: Calc'd for C16H25O4N-HCl: C, 57.91;
H, 7.90; N, 4.22 ~
Found: C, 57.89;
H, 7.74; N, 4.40 %
m/e - 295 (m+) H NMR (60 MHz) ~CDCl (ppm): 10~76-11.48 (b~
variable, 2H, NH2~), 6 77 (d, J=2Hz, 2H, meta H's), 6049, 6.45 (d of d, J=2Hz, lH, meta H), 4.08 (q, 2H, OCH2), 3.77 (s, 6H, [OCH3]2), ca. 3.5-4.8 (m, lH, CH~N), 2.90 (t, 2H, CH2-C=O), ca. 1.4-2.2 (m, 4H, [CH2]2), 102. (t, 3H, O-C-CH3), 0.84 (t, 3H, -C-CH3).

d,l-Ethyl 3-[(3,5-Dimethoxy-N-ethoxycarbo~l)anilino3b~xrate Method A -Ethyl chloroformate (71.4 ml. 0.75 mole) is added dropwise over a 45 minute period to a mixture of ethyl

3-t3,5-dimethoxyanilino)butyrate (159.8 g., 0.598 mole), methylene chloride (100 ml.), and pyridine (100 ml., 1.24 moles) at ~C. under a nitrogen atmosphere. The mixtuxe is stirred for 40 minutes following addition of the ethyl chloroformate and i~ then poured into a mixture o chloroform (750 ml.) and ice-water (500 ml.). The chloroform layer is separated, washed sucaessively with 10% hydrochloric acid (3 x 500 ml,), saturated aqtl~ous sodium bicarbonate (1 x 3~0 ml ) and saturated aqueous sodium chloride (1 x 400 ml.) and then dried (M~SO4). It is then decolorized with acti-vated charcoal and concentrated under reduced pressure to .

5~
-~7-an oil ~215 g.). The product is use~ ~s is.
Me thod B -_ _ _ Under a positive nitrogen atmosphere a mixtureof ethyl 3-(3,5-dimethoxyanilino)butyrate ~376 g., 1.4 mole), methylene chloride (1.4 liters) and anhydrous potassium carbonate (388.8 g., 2.81 mole) is stirred and cooled in an ice bath to 0-~ 5C. Ethyl chloroformate tl53 g., 1.41 mole) is added in one portion, The mixture is allowed to warm to room temperature over a period of one hour, ethyl chloroformate (153 g., 1.41 mole) is added once more and the mixture is refluxed on a steam bath Eor one hour.
It is then allowed to cool to room temperature and the potassium carbonate removed by filtration. The red colored filtrate is washed succ.essively with water (2 x 1000 ml.)~
brine (1 x 500 ml.), dried (MgSO43, and then decolorized~
and evaporated under reduced pressure to afford 439 g. of crude product which is used without further purification.

aromatic), 4.65 sextet, lH, ~N-CH-, CH3), 4.10-4.15 (2 quartets, 4H, ester methylenes), 3.70 (s, 6H, -OCH3), 2,30-2.60 ~m, 2H, -CH2COOEt), 1.00-1.40 (m, 9H, 3 methyl).

d,l-3-[(3,5-Dimethoxy-N-ethoxyc~ xl)anilinolbut~ric Acld Method A -Ethyl 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyrate (202 g., 0.595 mole), aqueous sodium hydroxide (595 ml. of lN) and ethanol (595 ml.) are combined and stirred at room temperature overnight. The reaction mixture is concentrat-ed to about 600 ml. volume under reduced pressure, theconcentrate diluted with water to 1200 ml. volume and ex-tracted with ethyl acetate ~3 x 750 ml.). The aqueous layer is then acidified with 10% hydrochloric acid to pH
2 and extracted again with ethyl acetate (3 x 750 ml.).
These latter extracts are combined, washed with brine~
dried (MgS04), filtered and concentratedln vacuo to yield the title product as an oil (163.5 g., 8802%).

.

Method B --A 5 liter 3 neck, round bottom flask equipped with mechanical stirrer and reflux condensor is charged with a solution of ethyl 3-[(3,5-dimethoxy-N-ethoxycarbonyl) anilino]-butyrate (439 g., 1.41 moles) in ethanol (2 liters), Sodium hydroxide (2 liters of lN) is added and khe mixture refluxed on a steam bath for 3 hours. The reaction mixture is poured onto 5 liters of ice-water and extracted in one liter portions with diethyl et:her (500 ml./portion). The aqueous layer i5 cooled by adcling ca. one liter of ice and ~hen acidified with concentrat:ed hydrochloric acid (1.75 ml., 2.1 moles). It is extracted in portions of one liter with methylene chloride (250 ml./portion)~ The methylene chloride layers are combined and dried over magnesium sul-fate, decolorized with charcoal and evaporated to drynes~
to yield a viscous yellow oil. Crystalllzation from ether/
cyclohexane (1:2) affords 224 g. (55.3%) of crystalline product, m.p. 78-80C. This material is used without further purifications in the following stepO

aromatic), 4~65 (sextet, lH, -N(COOC2H5)CH(CH3)CH2COOC2H5),

4.10 (quartet, 2H, ester methylene), 3.78 (s, 6H, -OCH3), 2~40-2.60 (m, 2H, -CH2COOHl, 1.18 (t), 1.28 (d, 6H,methyl), 10.8 (bs, variable, lH, CoO~).
MS (mol.ion) m/e - 311.
An analytical sample, obtained by recrystalliza-tion from ethyl ac~tate/hexane (1:5), melted at 89-91C.
Analysis: Calc'd for C15H21O6N: C, 57~86; H, 6.80; N, 4.50%
Found: C, 58.08; H, 6.65; N, 4.46%

d and 1-3[(3,5-Dimethoxy-4-N-ethoxycarbonyl)-anilinoJbutyric Acids ~
A mixture of dl-3-[(3,5-dimethoxy-N-ethoxycarbonyl) anilino]butyric acid (136.6 g., 0.44 mole) and l-ephedrine (72.5 g., 0.44 mole) is dissolved in methylene chloride 9~9 ~.9 (500 ml.). The methylene chloride is then removed i vacuo to yield the 1-ephedrine salt of dl-3-~(3,5-dimethoxy-N-ethoxycarbonyl)-anilino]butyric acid as an oil [~]25=
-20 0 (c=l.O,CHC13). Addition of ether (1500 ml.) causes crystallization of a white solid which is separated by filtration and dried (102 y.), m.p. 114-116C. Recrystal-lization from ethyl acetate/hexane ~ affords 71.1 g.
(34%) of the l-ephedrine salt of 1-3-~(3,5-dimethoxy-N-ethoxycarbonyllanilino]butyric acid; m.p. 126-127C.
Analysis: Calc'd for C25H36O7N2: C, 63.00;
H, 7.61; N, 5.88%
Found: C, 62.87;
H, 7.64; N, 5.88%
[~]D = ~43 5 (c=l.0, CHC13).
The l-ephedrine salt of the l-isomer is stirred in a mixture of ethyl acetate (1000 ml~) and 10% hydrochloric acid (400 ml.) for ten minutes. The organic phase is separat-ed, washed with 10% hydrochloric acid (2 x 400 ml.), dried and concentrated under reduced pressure to an oil. Crystal-lization of the oil from ethyl acetate/hexane (400 ml. of 1:1) affords 34.6 g. of 1-3-[(3,5-dimethoxy-N~ethoxycarbonyl) anilino]butyric acid, m.p. 96-97C.
Analysis: Calc'd for C15H21O6N: C, 57.86; H, 6.80; N, 4.50%
Found: C, 57.90; H, 6.66; N, 4.45%
[~]D = -25.4 (c=l.0, CHC13).

~. ~

~095~9 -49a-The mother liquor remaining from recrystallization of the l-ephedrine salt of the l-isomer is treated with hydrochloric acid as described above to give crude d-3-~3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid.
Treatment of the crude acid with d-ephedrine af~ords, after crystallization from ether, the d-ephedrine salt of the d-isomer, m.p. 124-125C.
Analysis: Calc'd for C25H36O7N2 H, 7.61; N, 5.88%
- Found: C, 62.82;
H, 7.47; N, 5.97%
[~]D = +44-0 (c=l.0, CHC13).
The d-ephedrine salt is converted ~o d-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid in the same manner as described above for conversion of the l-ephedrine salt to the free acid. M.p. 96-97C~ after recrystallization from ethyl acetate/hexane (3:5).
Analysis: Calc'd for C15H2106N: C, 57.86;
H, 6.80; N, 4.50%
Found: C, 57.~5;
H, 6.57; N, 4.35%
[~]D = +25.3 (c=l.0, CHC13~.

Me~hyl 3-(3,5-Dimethoxyanilino~propionate A mixture of 3,5-dimethoxyaniline ~114.9 g., 0.75 mole), methyl acrylate (69.73 g., 0.81 mole) and gla-cial acetic acid ~2 ml.) is refluxed for 20 hours. Reflux is discontinued and the reaction mixture is concentrated and then distilled in vacuo, to yield 106.8 g. (73.9%) 30 of the title product, b.p. 174-179C. (0.7 mm.).
H NMR (60 MHz) ~CDCl (ppm); 5.62-5.95 (m, 3H, aromatic), 4.1 (variable, bs, lH, -NH), 3.74 (s, 6H, -OCH3), 3.6~ (s, 3H, COOCH3), 3.41 and 2.59 (two 2H triplets, -NCH2 CH2CO2).
EXAMPI,E 8 d~l Methyl 3-{[3-hydroxy-5-(5-phenyl-2~pentyl)]anilino}
proE~onate A mixture of 3-hydroxy-5-(5-phenyl-2-pentyl)-aniline (1.0 g.), methyl acrylate (345 mg.), and acetic acid ~0.1 ml.) is heated at 106-1].0~C. overnight~ The cooled residue is dissolved in 100 m:L ethyl acetate and washed twice with 100 ml. of saturated sodium bicarbonate solu-tion. The organic phase is then dried (MgSO4) and evapor-ated to a crude residue which is chromatographed on 130 g.
of silioa gel using benzene-ether (2:1) as the eluant.
After elUtiOn of less polar impurities, 540 mg. (40%), d,l-methyl 3-{[3-hydroxy-5-(5-phenyl-2-pentyl)]anilino}
propionate is collectedA It has the following spectral characteristics:
CDCl (ppm): 7.14 (s, 5H aromat

5 83-6.13 ~m, 3H, aro~atic), 3.66 (s, 3H, -COOCH3), 3.37 (t, 2H, -NCH2), 2.16-2,78 (m, 5H, -CH2COO and benzylic), 1.28-1.69 (m, 4K, -(CH2)2-), 1.11 ~d, 3H, ~ CH3), 4.4-5.2 and 1.28-2.78 (variable, lH, NH, OH).
m/e - 341 (m+) Methyl 3-[t3l5-Dimethoxy-N-ethoxycarbonyl)anilino]
_eropionate Ethyl chloroformate (2.0 g., 8.4 mmole) is added dropwise over a 10 minute period to a mixture of methyl 3-(3,5-dimethoxyanilino)propionate (1.0 ml~, 10.5 mmole), methylene chloride (S ml.) and pyridine (5 ml.~ at 0C.
under a nitrogen atmosphere,- The mixture is stirred at 0C. for 20 minutes following addition of the ethyl chloroformate and then at room temperature for an additional 20 minutes, and is then poured into a mixture of methylçne chloride (75 ml.) and ice-water (50 ml.~. The methylene chloride layer is separated, washed successively with 10%

:::

~3ts~ 9 hydrochloric acid t2 x 50 ml.), saturated aqueous sodium bicarbonate (1 x 30 ml.) and saturated aqueous sodium chloride (1 x 40 ml.) and dried (MgSO4). It is then decolor-ized with activated charcoal and concentrated under reduced pressure to an oil (2.72 g.). The product is used as is.

3-[(3~5-Dimethoxy-N-ethoXycarbonyl)anilino]-propionic Acid , Methyl 3-~(3,5-dimethoxy-N-ethoxycarbonyl)anilino]
propionate (2.72 g.~ 8.36 mmoles), aque~us sodium hydroxide (8.4 ml. of lN) and ethanol (8.4 ml.) are combined and stirred overnight under nitrogen at room temperature. The reaction mixture is then concentrated under reduced pressure to half-volume, diluted with water (35 ml.) and then extracted with ethyl acetate. The aqueous phase is acid-ified to pH 2 with 10~ hydrochloric acid and extracted with methylene chl~ride (3 x 50 ml.), The combined extracts are washed with brine, dried (MgSO4) and concentrated to give the product as an oil (2.47 g.) which is used as is.

l-Caxbethoxy-5,7-dimethoxy-4~cxD-1,2c3~4~tetrahydroq_inoline A mixture of 3-[~3,5-dimethoxy-N-ethoxycarbonyl) anilino]propionic acid (1.10 g., 3.7 mmole) and poly-phosphoric acid (4 g.) is heated at 65C. for 45 minutes under an atmosphere of nitrogen and is then cooled to 0C~
It is then taken up in a mixture of methylene chloride-water (200 ml. of 1:1). The organic layer is separated and the aqueous phase extracted again with methylene chloride (2 x 100 ml.). The combined extracts are washed with saturated sodium bicarbonate (3 x 100 ml.), brine (1 x 100 mlO) and then dried (MgSO4). Concentration of the dried extract gives the product as an oil which crystallizes from benzene.
Yield = 645 mg., m.p. 109-111C.
Analysis: Calc'd for C14H17O5N: C, 60021; H,

6.14; M, 5.02%
Found: C, 60011; H, 6.14; N, 4.80%

9~

~XA~P~ 12 5,7-Dih~ oxy-4 oxo-1~2,3 A mixture of glacial acetic acid (60 ml ), 48~
hydrobromic acid ~60 ml.) and l-carbethoxy 5,7 dimethoxy 4-oxo-1,2,3,4-tetrahydroquinoline (4,0 g., 14 3 mmole) is refluxed overnight and is then concentrated ln vacuo to a dark oil. The oil is dissolved in water (S0 ml.) and the aqueous solution neutralized to pH 6-7 with lN
sodium hydroxide. A saturated solution o salt water (50 ml.) is added and the resulting mixture extracted with ethyl acetate (3 x 150 ml.). The extracts are combined, dried (MgSO4) and concentrated under reduced pressure to an oil. The oil is taken up in benzene-ethyl acetate (1:1) and the solution charged to a silica gel col~n. The column is eluted with a volume of benzene equ~l ts the volume of the column and then with benzene-ethyl acetate (250 ml, of 4:1) and benzene-ethyl aaetate (250 ml. of 1:1).
Fractions (75 ml.) are collected. Fractions 4-9 are com-bined and evaporated under reduced pressure~ The oily residue is crystallized from ethanol-hexane (1:10). Yield =
1.86 g., m.p. 166-169C.
Further recrystallization raises the melting point to 171-172C.
m/e - 179 (m~) Analysis: Calc'd for CgH903N C, 60.33; H, 5.06; N, 7.82~
Found: C, 60025; H, 4.94; N, 7.55%

d -1-Carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahvdroauinoline A solution of 3-[(3,5-dimethoxy-N-ethoxycarbonyl) anilino]butyric acid (4.0 g., 12.8 mmole) in chloroorm (2 ml.) is added dropwise with stirring to polyphosphoric acid (5.0 g.) heated to 60C. on a steam bath The reaction mixture is held at 60-65C. for two hours and is then poured into a mixture of ice (100 g.) and ethyl ~s~
~ 53-acetate (100 ml.). The aqueous layer is further extracted with ethyl acetate (2 x 100 ml.) and the combined organic extracts washed successively with saturated sodium bicarbona~
solution (3 x lOQ ml.), ~rine ~l x`lOO ~ and is then driea ~
S anhydrous magnesium sulfate. Concentration of the dried extract under reduced pressure gives 2.6 g. of crude pro-duct.
Purification is accomplished by column chromato-graphy of a benzene solution of the crude produat (2.5 g.) on silic~ gel (95 g.). The column is eluted with a volume of benzene equal to one-half the volume of the column, followed by benzene/ethyl acetate ~1;1)~ Fractions (40 ml.) are collected. Fractions 9-18 are combined and evaporated in vacuo to give 1.55 g. of product which is purified further by recrystallization from petroleum ether-1.33 g., m.p. 92.5-94C.
Recrystallization of this product from hot e~hyl acetate/hexane (1:1) affords an analytical sample; m.p 94-95Co Analysis: Calc'd for C15Hl~O5N: C, 61.42; H, 6.53; N, 4.78%
Found: C, 61.54; H, 6.55; N, 4.94%
m/e - 293 (m+) IR (XBr) - 5.85, 5.95 ~ ( ~ O) d,l-5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline Method A -A mixture of glacial acetic acid (240 ml.), 48%
hydrobromic acid (240 ml.~ and 1-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (16.0 g., 55 mmole) i5 refluxed overnight and is then concentrated in vacuo ~o a dark oil The oil is dissolved in water ~200 ml.) and the aqueous solution neutralized to pH 6-7 with lN sodium hydroxideD A saturated solution of salt water (200 ml.) i-; added and the resulting mixture extracted with ethyl acetal:e (3 x 500 ml~). The extracts are combined, dried (MgSO~ ) and concentrated under reduced pressure to a dark oil (12.8 g. ) . Hexane-ethyl acetate ~10:1) is add-ed to the oil and the resulting crystals recovered by fil-tration (3.8 g.); m.p. 158-165~C. Triturakion of the crystals in ethyl acetate gives 1.65 g. of ~roduct; m.p.
165-168C.
Additional material separates from the mother liquors on standing (2.9 g,); m.p. 168-170C.~Column chromatography of the filtrate on silica gel using bcnzene-ether ~1:1) as solvent gives an additional 4~6 g. of pro-duct, m.p. 167-169C.
Further purification is achieved by recrystal-lizing the product from ethyl acetate; m.p. 173-174C.
Analysis: Calc'd for CloHllO3N: C, 62.16; H, 15 5.74; N, 7.25%
Found: C, 62.00; H, 5.83; N, 7.14%
m/e - 193 (m+) Method B -, A mixture of d,l-3-[(3,5-dimethoxy-N-ethoxy-carbonyl)anilino]butyric acid (100 g., 0.32 mole) and 48 hydrobromic acid (500 ml.)/glacial acetic acid (300 ml.) is heated in an oil bath at 110C. for 2 hours. The oil-bath temperature is then increased to 145C. and heating is continued for an additional 2 hours. During this last heating period an azeotropic mixture distills (boiling point 42 ~ llO~C~, ~200-300 ml.) and the deep-red homo-geneous solution is allowed to cool to room temperature The mixture is poured onto ice-wa,er (3 liters) and ether (2 liters), the layers are separated and the aqueous solu-tion is washed with ether 12 x 1000 ml.). The ether layers are combined and washed successively with water (2 x 1000 ml.), brine (1 x 500 ml.), saturated NaHCO3 solution (4 x 250 ml.) ancl brine (1 x 500 ml.) and then dried (MgSO4)c Decolorizati.on with charcoal and evaporation of the ether affords a yellow foam which is crystallized from caO 300 ml methylene chloride to give 31.3 g. (50.4%) of pure L~
.~ , 59~1~

5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.
Additional product can be isolated from the m~ther liquor by silica gel chromatography.
lH NMR (60 MHz) ~ (100 mg. sample/0.3 ml.
CDC13/0.2 ml. CD3SOCD3) (ppm): 12.40 (s,lH,C5-OH), 5.72 (d,2H,meta H), 5.38-5.60(bs,lH,C7-OH), 3.50-4.00(m,1H,C2H), 2.38-2.60~m,2H,C3-H2), 1.12~d,3H,methyl).
m/e - 193 (m ) Analysis: Calc'd for CloHl1O3N: C, 6~.16; H, 5.74; N, 7.25~
Found: C, 62.31; H, 5.85; N, 7.02~
Similarly, methyl dl-3-{[3-hydroxy-5-(5-phenyl-2-pentyl)]anilino}-propionate is converted to dl-5~hydroxy-

7-(5-phenyl-2-pentyl)-4-oxo-1,2,3,4-tetrahydroquinoline which is purified by column chromatography using silica gel and benzene/ether (5:1) as eluant.
m/e - 309 (m+) ) CDC13 (ppm): 12 22 (s, lH 50H) 7~14 (s, 5H, C6H5), 6.04 (d, J=2.5Hz, lH meta H), 5.87 (d, J=2.5Hz, lH meta H), 4.19-4,60 (b, lH, NH), 3.48 (~, 2H,CH2N), 2 18-2.89 (m, 5H, ArCH, ArCH2, CH2-C-O), 1.38-1.86 (m, 4H, -[CH2]2-), 1.13 (d, 3H, CH3)~
and ethyl dl-3-(3,5 dimethoxyanilino)hexanoate hydrochloride is converted to dl-5,6-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline; m,p. 117-119C7 (from methylene chloride).
m/e - 221 (m ), 135 (base peak, m - propyl).
and 1-3-[(3,5-dimethoxy-(N-ethoxy carbonyl) anilino]butyric acid is converted to d-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 167-168C~
[~]D5= +167.8(c=l.O, CH3OH).
m/e - 193 (m ) Analysis: Calc'd for CloHllO3N: C, 62.16; H~
5.74; N, 7.25%
Found: C, 61.87; H, ., .

5 . 62; N, 6 . ~696 and d-3-[3,5-dimethoxy-N-ethoxycarbonyl)anilino]
butyric acid is converted to 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinolinle; m.p. 166-168C, ~ ]25= -168.5 ~c=1~0~ CH3 m/e - 193 (m ) Analysis: Calc'd for CloHllO3N: C, 62.16; ~, 5.74; N, 7.25~
Found: C, 61.82; H, 5.83; N, 7.22~

A mixture of 3,5-dimethoxyaniline (230 g., 1~5 moles), methyl crotonate (150 g., 1.5 m~les) and glacial acetic acid (90 g., l.S moles) is heated at reflux for 6 hours. Additional glacial acetic acid (90 g., 1.5 moles) is added and the mixture refluxed overnight. Hydrobromic acid (1000 ml. of 48% solution) and glacial acetic acid (850 ml.) are addad to the reaction mixture which is heated at reflux for 4.5 hours. The ~itle pr~duct is isolated and purified according to the procedure of ~xample 12.
Yield = 36 g., m.p. 166-170C.
EXAMP~E 16 dl-5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrah dro uinoline _. ~ q __ _ A mixture of 3,5-dimethoxyaniline (4.6 g., 0.03 mol~), crotonic acid (2.54 g., 0.03 mole) and pyridine hydrochloride (3.0 g., 1.26 moles) is heated at 185-200C, for 45 minutes. The cooled reacti~n mixture is suspend-ed in water (500 ml.) (pH ~3) and the pH adjusted to 7 and the resultant mixture stirred for 10 minutes. The organic layer is separated, dried (MgSO4) and concentrated ~o 3.2 g. of a yellow oil.
A mixture of glacial aoetic a~id (110 ml.), 4a~
hydrobromic acid (110 ml.) and the yellow oil is refluxed for one hour and is then concentrated in vacuo to a dark oil~ The oil is dissolved in water and the aqueous solution ~:
neutralized to pH 6-7 with lN sodium hydroxide. A saturated ~s~

solution of salt water is added and the resulting mixtura extracted with ethyl acetate, The extracts are combined, dried (MgSO~) and concentratad under reduced pxessure to a dark oil (2.8 g.). Column chromatography of the crude residu~. on silica gel using benzene-ether (4:1) as eluant gives an additional 51Q mg. of product, m.p. 168-170C.
Further puri~ication is achieved ~y recrystalliz-in~ the product from ethyl acetate, m.p. 173~17~C.
Analysis: Calc'd for CloHllO3N: C, 62.16; H, 5.74; N, 7.25~
Found: C, 62.00; H, 5.83; N, 7.14%
m/e - 193 (m ), 178 ~m - methyl, base peak).
In a similar manner, 3,3-dimethyl acrylic acid and 3,5-dimethoxyaniline gives after purif1cation by silica gel chromatography (benzene/ether 1:1 as eluant) 5,7-dihydroxy-2,2-dimethyl-4-oxo-1,2,3,4-t~trahydroquinoline as a yellow oil.
Analysis (MS) Parent peak (m ) Calc d for CllH133N 07 0 9 Found: 207.0895 ~ase peak (m - 15) Calc d for C10H103N
Found: 192.0655 Similarly, styryl acetic acid and 3,5-dimethoxy-aniline are condensed to yield dl-5,7-dihydroxy-2-benzyl-4-oxo-1,2,3,4-tetrahydroquinoline as an oil after purifica-tion using benzene/ether (3:1) as eluant.
m/e = 269 ~m ) and 178 (m -benzyl, base peak) NMR (CDC13) ~ (ppm): 8.76 (s, lH, 5-OH), 7~18-7.6 (m, 5H, C6H5),5.84 ~d, J=3Hz, lH) and 5.62 (d, J-3Hz, lH) for the meta coupled aromatics, and 2.14-4.82 ~4m, 7~), for the remaining protons 7-OH, CH-N, CH2-C=0, -CH2-C6H5 and N-H).
-9~39 ~58-d,l-5-Hydroxy-2-mebhyl-7-(2-hQptylox~) 4 oxo 1,2,3,4-tetra-hYdro~uinoline Potassium hydroxide pellets ~325 mg., 52 mmole) is added to a solution of d,l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (].0 g., 52 mmole) in N,N-dimethylformamide (10 ml.). The mixture is slswly heated to 100C~ and to the resulting solution ~_-2-bromoheptane (1.08 g., 60 mmole) is added all at once with good stirring.
After 10 minutes additional potassium hydroxide (160 mg.) is added followed by additional d,l-2-bromoheptane (5--mg.). The addition of potassium hydroxide and d,1-2-bromohe~tane was repeated two more times u~ing 80 mg.
potassium hydroxide and 250 mg. d,l-2-bromoheptane each ~ime. The reaction mixture is stirred an additional 10 minutes and is then cooled. Chloroform (50 ml.) and aqueous sodium hydroxide (25 ml. of lN) ~re added, the mixture stirred for 10 minutes and the layers s~parated. The chloroform extraction is repeated, the extracts combined, dried (MgSO4) and concentrated under reduced pressure to a dark oil. The oil is chromatographed on silica gel (120 g.) using benzene as solvent. Fractions of 30 ml. each are collected The 12th-18th fractions are combined and con-centrated under reduced pressure b~ a light yellow oil (850 mg.) which crystallizes upon standing. ~he desired pro-duct is separated by filtration and recrystallized from hot hexane, m.p. 76-77CC.
The above procedure is repeated on a 20-fold scale but using benzene-ethyl acetate ~9:1) as chromato-graphic solvent. Fractions of 750 ml~ each are collected~
Combination of the 2nd-6th fractions affords 32 g. of oil -which partially crystallizes from hexane upon standing and cooling to give 18,2 g. of product. An additional 3.2 g.
is obtained by concentrating the mother liquor and allowing it to crystallize by standing in tha cold. Total yield =
21.4 g.
Analysis: Calc'd for C17H25O3N: C, 70.07; H,

8.65; N, 4.81%
'~

~Q~5~9 Found: C, 69.82; H, 8.67; N, 4.93~
m/e - 291 (m+) IR (KBr): 6.01 ~ (=0) In like manner, 5,7--dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline converted to d,l-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrelhydroquinoline, an oil.
1H NMR (~0 MHZ) ~cDcl3 PP
phenolic~, 5.5 and 5.7 (d, 2H,, J = 2Hz, aromatic), 4.6 (bs, lH, -NH), 4.1-4.6 (m, lHt -O-CH-), 3.3 (t, 2H, J = 7Hz, -CH2-), 2.6 (t, 2H, J = 7Hz, -C~2 ), 2.0-0.7 (m, remaining protons).

d,l-Hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrah~roquinolin~
A mixture of 5-phenyl-2-(R,S)-pentanol ~16.4 g., 100 mmole), triethylamine (28 ml" 200 mmole) and dry tetrahydrofuran (80 ml.) under a nitrogen atmosphere i3 cooled in an ice/water bath. Methanesulfonyl chloride (8.5 ml., 110 mM) in dry tetrahydrofuran (20 ml.) is added dropwise at such a rate that the temperature holds essen-tially constant. The mixture is allowed to warm to room temperature and is then filtered to remove triethylamine hydrochloride. The filter cake is washed with dry tetra-hydrofuran and the combined wash and filtrate evaporated under reduc~d 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. ~89.7%) yield of the mesylate of d,l-S-phenyl-2-pentanol whiah is used in the next step without further purification.
A mixture of d,1-5-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.0 g., 5.2 mmole), potassium carbonate (14.35 g., 0,104 mole), N,N-dimethylformamide (60 ml.) and d,l-5-phenyl-2-pentanol mesylate (13,68 g., :. . :

, ~5~

57 mmole), under a nitrogen atmosphere, is heated to 80-82C. in an oil bath for 1.75 hours. The mixture is cool-ed to room temperature and then poured into ic~/water (300 ml.). The aqueous solution is extracted with ethyl acetate (2 x 50 ml.) and the combined extracts washed successively with water (3 x 50 ml.) and saturated brine (1 x 50 ml,).
The extract is then dried (MgS04), decolorized with char-coal and evaporated to gi~e the product.
m/e - 339 (m+) The above procedure is repeated but using 114.8 g. (0.5~4 mole) of d,1-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, 612 ml. of N,N-dimethylformamide, 174.8 g. (1.265 moles) of potassium carbonate and 165.5 g. (0.638 mole) o d,l-5-phenyl-2-pentanol mesylate. The reaction mixture is cooled and poured onto ice water (4 liters) and the aqueous solution extracted with ethyl acetate (2 x 4 liters). The combined extract is washed with watsr ~4 x 2 liters~, bri~e ~1 x 2 liters) and dri~d (MgSO4), Evaporation affords 196 g.
of the title product. It is used without furth~r purifi-cation.

7.22 (s, SH, aromatic), 5.80 (d, J=3 H3, lH, meta H), 5.58 (d, J=3 H3, lH, meta H), 1.25 (d, 6~, CH3-CH-N and CH3-CH-O-), 1.41-4.81 (m, llH, r~maining protons).

d,l-5-Hydroxy-7-(5-ph~nyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahvdrocfuinoline Repe~ition of the procedure of Example 18 but using 5,7-dihydroxy-4-oxQ-1,2,3,4-tetrahydroquinoline in place of ~he 5,7-d hydroxy-2-methyl-4-oxo-1,2,3,4-tetra-hydroquinoline affords d,l-5-hydroxy-7-(5-phenyl-2-penty;oxy)-4-oxo-1,2,3,4-tetrahydroquinQline as an oil 5 in 74% yield.
mJe - 325 (m+) Analysis: Calc'd for C20H23N03: C~73.70; H, ~95~9 7,12; N, 4.31~
Found: C, 73.69; H, 7,15; N, 4.08%
H NMR ( 6 H ) CD~l 3 ( PP
phenolic), 7.3 ~s, 5H, aromat:ic), 5.8 (d, lH, aromatic, J = 2Hz), 5.6 (d, lHI aromatic, J = 2Hz), 4.7-4.1 (m, 2H, NH and O-CH), 3.5 (t, 2H, CH2, J = 7Hz), 3.1-2.1 (m~ 4H, 2-CH2-), 2.1-1.5 ~m, 4H, 2-CH2), 1.3 (d, 3H, -CH-CH3, J =
6HZ ) .
Similarly~ d,l-5,7-dihydroxy-2~methyl-4-oxo-1, 2,3,4-tetrahydroquinoline (27 g., 0.14 mole) is alkylated with 4-phenylbutyl methanesul~onate (35.2 g., 0.154 mole) to yield 41.1 g. (90%) of the desired d,l-5-hydroxy-2-methyl-7-~4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquino-line, m.p. 88-90C. Recrystallization from ethyl acetate-hexane tl:2) gives the analytical sample, m.p. 90-91C.
Calc'd ~or C~oH23O3N C, 73.82; H, 7.12; N, 4.30%
Found: C, 73.60; H, 7.09; N, 4.26%
m/e - 325 (m+) H NMR (60 MHz) ~CDCl3 (PP ) ( ~
-OH), 7.21 (s, 5H, C6H5), 5.74 ~d, J = 2.5 Hz, lH, meta H), 5.5 (d, J - 2.5Hz, lH, meta H), 4.36 (bs, lH, NH), 3.33-4.08 (m, 3H, -O-CH2, -CH-N), 2.29-2.83 (m, 4H, -CH2-C=O, C6H5-CH2), 1.51-1.~2 (m, 4H, -[CH2]2]), 1.23 (d, 3H, CH3-).
In like manner, alkylation of d-5,7-dihydroxy-4-ox~-1,2,3,4-tetrahydro~uinoline with d-2-octylmethanesul-fonate gives d-S-hydroxy-2-methyl-7-(2-(R)-octyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, m.p. 64-68C.
~]D = ~110.2 (c-1.0, CHC13).
and akylation of ~ 5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline with d,l-5-phenyl-2-pentanol mesylate gives d,1-5-hydroxy-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline;

~3 m/e - 367 (m+).

d,l-l-Foxmyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1, 2~ 3r 4-tetrahy~ro~ulnoline A solution o d,l-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline (195 g., ca, 0.5~ mole) in ethyl formate (1140 g., 14.6 moles) is added dropwise to sodium hydride (72 g., 3 . 0 m~les, obtain-ed bywashing 144 g. of 50% sodium hydride with hexane, 3 x 500 ml.), with good stirring. After about 1.5 hours when 2/3 of the ethyl formate solution i9 added, the addi tion is di~continued to allow the vigDroUs foaming to subside. Diethyl ether (600 ml.) is added and the mixture stirred for 15 minutes befora adding the remainder of the ethyl ormate soluti~n. When addition is complete diethyl ether (600 ml.) is added, the reaction mixture stirred for an additional 10 minutes and then poured onto ice water (2 liters). It is acidified to pH 1 with 10~ HCl and the phase separated and extracted with ethyl acetate (2 x 2 liters). The combined organic solutions are washed success-ively with water (2 x 2 lit~rs), brine (1 x one liter) and dried (MgS04). Concentration gives 231 g. of red-brown oil which is used without further purification.
Rf = 0~1-o5 ~stretched) of thin layer chromato-graphy, silica gel plates, benzene/ether (1:1).
Similarly, d,l-5-hydroxy-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,i,l,~ormyl-5-hydroxy-3-hydroxy-methylene-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline.
It i3 used in subsequent example~ as is.

d,l-l-Formyl-5-hy~roxy-3-hydxoxymethylene-2-methyl-7-(2-heptyloxy)-4-oxo-l~2~3~4-tetrahydroquinoline To sodium hydride ~18.2 g., 0.38 mole) obtained by washing 50% sodium hydride in mineral oil dispersion with pentane i9 added dropwise, over a half-hour period, a solution o~ d,1-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-5 9~ ~

oxo-1,2,3,4-tetrahydroquinoline ~11.1 g., 0.038 mole) in ethyl formate ~110 g., 1,48 moles). Exothermic reaction occurs with vigorous evolution of hydrogen and formation of a yellow precipitate. The reaction mixture is cooled, ether ~750 ml.) added and the resulting mixture then heat-ed at reflux and stirred for 3 hours. It is then cooled to 0C. and nçutralized by addition of lN hy~rochloric acid ~400 ml.). The ether layer is separated and tha aqueous phase extracted with ether (2 x 150 ml.). The ether extracts are combined, washed succe~sively with sat-urated sodium bicarbonate solution (2 x 100 ml,) and brine(1 x 150 ml,) and then dried (MgSO~). Concentration of the dried extract affords an orange foam ~10.8 g.), An additional 2.3 g. iæ obtained by acidifying the sodium bicarbonate wash solutions with concentrated hydrochloric acid followed ~y extraction of the acid solution with ether ~2 x 100 ml.). Concentration of the combined ethereal extracts after drying gives 2.3 g. of product (Total =
13.1 g.). The product is usad as i9 .
~ H ) CDC13 ~PP ) ~ , ArOH), 8.8-11.9 ~m, lH, variable, =COH), 8.73 ~s, lH, N-CHO), 7 41 (s, lH, =CH), 6.32 ~s, 2H, aromatic), 5.52 (q, lH, -CH-N), 4.18-4.77 ~m, lH, -O-CH), 0 6-2.08 (m, 17H, CH3 C C5 11 an C 3 )-In like manner, d,l-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,l-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydro-quinoline.
1H NMR: (60 MHz) ~CDCl (60 MHz) ~CDCl (ppm):
12.22 (bs, lH, ArOH), 8.8-11.6 (variable, lH, =COH), 8.64 (s, lH, -CHO), 7.21 (bs, shoulder at 7.30, 6H, arom~tic and =CH), 6,23 and 6.17 (two lH doublets, J = 2Hz, meta), 5.42 (bq, lH, N-CH), 4.18-4.70 (m, lH, -OCH), 2.4-3.0 (m, 2H, Ar-CH2), 1.53-2.0 (m, 4H, -(CH2)2-), 1.29 (overlapping l~.r ~ss~s doublets, 6H, CH3-C-N and CH3-C-o).
d,1-5-Hydxoxy-7-(2-heptyloxv)-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,l-l-formyl-5-hydroxy-3-hydroxymethylene-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydro-quinoline, an oil.
H NMR (60 MHz) ~C~Cl (ppm): 1201 (bs, lH, phenolie), 8.8 ~9, lH, -N-CHO), 8.1 (s,lH), 703 (s, lH), 6.1(s, 2H, aromatic), 4.5 (bs, 2H, -CH2-), 4.2-4.8 (m, -O-CH2-), 2.0-0.7 (remaining protons).
d,l-5-hydroxy-7-(5-pentyl-2-pentyloxy3-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,l-l-formyl-5-hydroxy-3-hydr~xymethylene-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline.
H NMR (60 MHz) ~CDCl (ppm): 12.4 (bs, lH, phenolic), 8.5 (s, lH, CHO), 7.2 (m, 6H, aromatic and -CH~
6.2 (m, 2H, aromatic), 4.5 (s, 2H, -CH2-), 4.4 (m, lH, -CH-CH3), 2.6 (bt, 2H, -CH2-), 1.7 (m, 5H, remaining pro-tons), 1.3 (d, 3H, -CH-CH3, J = 6Hz).
and dl-5-hydroxy-2-methyl-7-~4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is converted to dl-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(4-phenyl-butyloxy)-4-oxo-1,2,3,4-tetrahydro~uinoline, m.pO 132-135C (from hexane). Recrystallization from hot methanol provides the analytical sample, m.p. 131-132C.
25Cal~d for C22H2305N: C, 69.27; H, 6.08; N, 3.67~
Found: C, 69.25; H, 5.88; N, 3.88~
m/e - 381 (m+) 30H NMR (60 MHæ) ~CDCl ~ppm): 12.4-1306 (m, H, =~OH), 12.26 (s, lH, 5-OH), 8062 (s, lH, -C(=O)-H), caO
7018-7.48 (m, lH, ,~H), 7.27 (s, 5H, C6H5), 6.26 (bs, 2H, meta H's), 5.46 (q, lH, CH-N), 3.82-4.23 (m, 3H, -CH2-0), 2.49-2.80 ~m, 3H, ArCH2), 1.67-2.02 (m, 4H, 5~¢19 - [CH2] 2-) ~ 1. 27 (d, 3H, CH3) .

dl-l-Formyl-5-hydroxy-2~methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydro~uinoline To a solution of dl-l-formyl-3-hydroxvmethylene-5-hydroxy-2~methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline (229 g , ca. 0.58 mole) in methanol (880 ml.) under a nitrogen atmosphere is added triethyl-amine (27.2 ml.) with stirring. Methyl vinyl ketone (97.0 ml.) is then added and the mixture stirred overnight at room temperature.
The reaction is complete at this point and com-prises a mixture of the title compound and dl-1,3-diformyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(oxo-butyl)-1,2,3,4-tetrahydroquinoline. The following steps are required to convert the diformyl compound to the de-sired title compound.
The reac~ion mixture is diluted with ether (6 liters) and then washed successively with 10~ aqueous sodium carbonate (4 x 1700 ml.), brine (1 x 2 liters) and then dried (MgSO4). Concentration of the solution af~ords 238 g. of a red-brown oilO The oil is dissolved in methanol (1920 ml ) and the solution cooled to 0C.
Potassium carbonate (21.2 g.) is added, the mixture stirred for 3 hours at 0C. and then treated with acetic acid (18.7 g.). The methanol is removed under reduced pressure and the resultant oil stirred with water (2 liter~) and ethyl acetate (2 liters) for 10 minutes. The aqueous phase is separated, extracted with ethyl acetate (1 x 2 liters) and the combined ethyl acetate solutions washed with water (2 x 2 liters), brine (1 x 2 liters) and dried (MgSO4). Concantration under reduced pressure and chroma-tography of the concentrate on silica gel (1.8 kg.) gives 159 g. of the title product.
35m/e - 437 (m~) lH NMR (60 MH~) ~CDC1 (ppm): 12.7 (s, lH, OH), '`: . : , ~ : ` :

~g~

8,78 (bs, lH, -CHO), 7~22 (s, 5H, aromatic), 6022 (bs, 2H, meta H's), 2.12 2,07 (s) 3~, -CH2-CO-) 1.31 ~d, 3H, -CH3-C-O-), and 1.57 5.23 ~m, 13H, remaining protons).
Similar treatment of 35 g. ~0.09 m~le) of dl-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-~4-phenyl-butyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline gives 22O7 g.
~60~) of dl-1-formyl-5-hydroxy-2-methyl-7-~4-phenylbutyl-oxy?--4-oxo-3-~3-oxobutyl)-1,2,3,4-tetrahydro~uinoline, m.p~ 101-103C. The analytical sample is obtained by -~
recrystallization from methanol, m.p. 104-105C.
Calc'd for C25H29O5N: C, 70.90; H, 6.90; N, 3.31%
Found: C, 70.77; H, 6.81; N, 3.46%
H NMR (60 ) CDC13 (PP ) ( ~
-OH), 9,08 (bs, lH, -CHO), 7.29 (s, 5H, C6H5), 6.25 (bs, 2H, meta H's), 4.88-5.43 (m, lH, -CHN), 3.86-4.21 ~m, 2H, -CH2-O-), ca. 2.49-3.02 [m, 7H, ArCH2, -(CH2)2-C~=O)-, -CH-C(=O)], 2.18 [s, 3H, CH3-C(=O)], 1.68-2~03 [m, 4H, -(CH2)2-], 1.13 ~d, 3H, CH3)~
m/e - 423 (m );
and d,l-l-formyl-5-hydroxy-3-hydroxymethylene-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydro-quinoline affords d,l-1-formyl-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline which is used as is, d,l-l-Formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline and d,l-1,3-Di-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-(3-oxo-butyi)-1~2,3,4-tetrahydroquinoline _ _ _ _ _ _ To a solution of d,l-5-hydroxy-3-hydroxymethyl-ene - 2-methyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydxoquino-line (13.1 g., 37.7 mmol~), in methanol (56 ml.) and methyl vinyl ketone (5.52 mg~, 68 mmol.) is added triethyl-amine (1.3 ml., 9.3 mmol.). The mixture is stirred for v 5~

18 hours under a nitrogen atmosphere at room t2mperature and is then diluted wikh ether (550 ml.). ~he solution is washed with 10% aqueous sodium bicarbonate solution (4 x 60 ml.), followed by brine (1 x 100 ml.) and dried (MgSO4). Removal of the ether by evaporation gives a dark oil ~16 g~). The oil is dissolved in a minimum volume of benzene and the solution chargled to a column of silica gel (500 gO). The column is then leluted with a volume of be~-ene P~ual to the volume of the column~ The eluting sol-vent is then changed to 15% ether-benzene and 100 ml.
fractions collected when the first color band beginR to elute off the column. Fractions 5~13 are combined and con-centrated under reduced pre sure to give d,l-1,3-diformyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-~3-oxobutyl)-1,2,3,4-tetrahydroquinoline as a yellow oil (8.7 g.).
The column is eluted further with 15% ether-bPnzene. Fractions 19-37 are combined and concentrated under reduced pressure to give d,l-l-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-3-)3-oxobutyl)-1,2,3,4-tetrahydro-quinoline as an oil (4.6 g.). Additional monoformyl pro-duct is obtained in the following manner:
1 g. of diformyl product is stirred with 200 mg, potassium carbonate in methanol (25 ml.) for two hours at 0C. The solvent is then evaporated in vacuo and the residue suspended in ether and filtered. The filtrate is concentrated and the rPsidue partitioned between ether and water. The organic layer is separated, the aqueous phase acidified with 10% hydrochloric acid and extracted with ether. The combined ether extracts are washed suo-cessively with satura~ed sodium bicarbonate and brine, andthen dried tMgso4)~ filtered and concentrated to yield additional monoformyl product.
The monoformyl derivative has the following NMR
spectrum:
1~l NMR (60 MH2) ~CDCl (ppm): 12-73 (S~ lH~
ArOH), 8.87 (S, lH, N-CHO), 6.12 (S, 2H, Aromatic), 4~78-5.50 (M, lH, N-CH), 4.11-4.72 (M,lH, -O-CH), 2.21 (S, 3H, .
., .

gc`~

CH3-C(=O)-), 0.63-3.12 (M,22H, remaining hydrogen~).
Similarly, the following compounds are prepared from ap-propriate reactants:
d,l-l-formyl-5-hydroxy-7-(2-heptyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4~tetrahyclroquinoline, an oil.
H NMR (60 MH2j ~cr)Cl (ppm): 12.8 (S, lH, phen-olic), 8.7 (S, lH, N-CHO), 6.1 (S, 2H, aromatic), 4 1-4.6 (m, lH, ~}{~), 4.1 (d, 2H, J35~ , 2.3-3.0 ~ 3~, CH2 and C~-C(=O)), 2.2 ~S, 3H, -C~=O)dC~3jl2.3-0.7 ~æmaining protons).
d,l-1-formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquino-line.
2) ~ CDCl 3 (ppm): 12.68 (S, lH, -OH) 3.82 (b, s, lH, -C(O)H), 7.20 (b, s, 5H, C6H5), 6.18 (b, s, 2H, aromatic), 4.78-5~34 (m, lH, -N-CH), 4.18-4.68 (m, lH, -O-CH), 2.17 (S, 3H, -C(O)CH3), 1.30 (d, 3H, -O-C-CH3), 1.12 (d, 3H, -N-C-CH3), 1.4-3.1 (m, llH, remain-ing H's).
d,l-l-formyl-5-hydroxy-7-(5-phenyl-2-pentyloxy)- 0 4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline.
m/e - 423 (m~) Also produced as by-product in each o these preparations is the corresponding 1,3-diformyl deri-vative.

~9S~

d,l-5,6,6a, 7-T e~rahydro-l-hydroxy-6~-m~thyl-3-~5-_phenyl-~E?entylo~benzo ~,~
A solution of d,l-l-formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl~-1,2,3,4-tetra-hydroquinoline (174 g., 0.398 mole) in methanolic 2N KOE
(5.9 liters) and methanol (5.9 liters) is stirred and heated at re~lux overnight under a nitrogen atmosphere. To the cooled solution is add~ ci~l (708 g.) dropwise with stirrin~ over a 15 min lte period. The resulting solution is concentrated by rotary evaportion (ln vacuo, water aspi-rator) to a semisolid which is filtered and washed first with water to remove potassium acetate and then with ethyl acetate until all the black tar is removed. Yield = 68 g, (44~6) yellow solids, m.p. 188-190C, Recrystallization from hot ethyl acetate affords the pure product, m.p. 194-lg5C
m/e - 391 ~m~) Analysis: Calc'd for C25H29O3N: C, 76 09; H, 7.47;
20 N, 3.58% Found: C, 76.43; H, 7.48; N, 3.58%
~TMS (100 mg. dissolved in 0.3 ml~
CD30D and 0.3 ml. CD3S(0)CD3) (ppm): 7 21 (s, 5H, aromatic), 5.80 (s, 2H, meta H's), 1.20 ~d, 6H, CH3-CHO and CH3-CH-N~.
From the mother liquors, a small amount ~ the 25 corresponding axial me~hyl derivative is obtained upon evaporation. It is purified by column chromatography on silica gel using benzene/ether ~1:1) as eluant~ Evaporatior, of the eluate and recrystallization of the residue from ether~hexane (1:1) affords analytically pure material, m.p.
225-228~C.
I ts Rf value upon thin layer chromatography on silica gel using 2.5% me~hanol in ether as eluant and visualization with fast blue is 0.34. The 6~-methyl deriv-ative axhibits Rf = 0.41.
m/e - 391 (mt) ~TMS (100 mg. dissolved in 0.3 ml-CD30D and 0.3 ml. CD35(0)CD31 (ppm): 7.19 ~s, 5H, aromatic), , j~ , ' ~' '~'~ , , .
~ .
:

.~. : ~

5.75 (s, 2H, meta H's), 1.21 ~d, 3H, CH3-CHO~ nd 0.95 ( d, 3H, CH 3-CH-N~ .
SimiLar treatment of 22 g. o~ dl-1-formyl-6-hydroxy-2~methyl-7-(4-phenylbutyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydro~uinolines ~ives 17.1 g. ~87~ of dl-5,6,6a,7-tetrahydro-1-hydroxy~6~-methyl-3-(4-phenylbutyl~
oxv)-benzo~c]quinolin-9(8H)-one, m.p. 222-224C. The analytical sample is obtained by recrystallization from methanol, m.p. 224-225C.
Calc'd for C24H27O3N: C, 76.36; H, 7 21; N, 3-71~
Found: C, 76.~3; ~, 7.08; ~, 3,68%
H NMR (60 MHz) [l:l mixture of (CD3~2SO and DC30D]: 1.24 (d, 3H, 6~-CH3) m/e - 377 (m+) Evaporation of the mother liquor gives 2 8 g (m.p. 185-195C.) of product shown by NMR tO be a mixture of the 6~-methyl d~rivative (ca. 40%) and dl-5,6,6a,7-tetrahydro-l-hydroxy-6a-methyl-3-(4-phenyl butyloxy)-benzo [c]-quinoline-9(8H)-one.
1H NMR (60 MHZ) [1:1 mixture of (CD3) 2SO and CD30D): 1.24 (d, 1.2H, 6~-CH3] and 0.95 ~d, 1,8H, 6~-CX3), XAMP~E 25 d,l-5,6,6a,7-Tetrahydro-l-hydroxy-6~-methyl-3-A solution of d,l-l-formyl-5-hydroxy-2-m2thyl-7-(2-heptyloxy~ -4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrah~dro-quinoline (4.5 g., 11.5 mmol.) in methanol (150 ml.) is treated with 2N methanolic potassium hydroxide solution (150 ml.). The mixture is stirred for one hour at room temperature and then heated at reflux under a nitrogen atmosphere for 20 hours. The dark red mixture is allowed to cool to room temperature, neutral$zed with acetic acid and concentrated under pressure to about 100 ml. The concentrate is diluted with water (400 ml) and the brown-red solid separated by filtration, washed with water anddried (~6 g.). It is triturated first in ether and then in methanol, filtered and dried (1.96 g.); m.p. 223-229C.

59C~

Recrystallization from hot methanol af~ords crystals meIt-ing at 235-237C.
AnalysiS: Calc'd for C21H2903N: C, 73.43; H, 8.51; N, 4.08 Found: C, 73.22; H, 8.30; N, 4.11~
Additional material is recovered by ~vaporation of all mother liquors and by chloroform extraction of the aqueous solution from which the brown-red crude pxoduct is obtained and subs~quent evaporation of the extract. The combined residues are purified by silica gel chromatography using ether as eluant.
In like manner, the following compounds are prepared from appropriate reactants:
d,l-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)benzo[c]-quinolin-9(8H)-on~ m.p. 170-173C.
(recrystallized from chloroform).
m/e - 377 (m+) Analysis: Calc'd for C2;4H2703N: C, 76.36; H, 7 21, N, 3.71%
Found: C, 76.38; H, 7.21; N, 3.85%
d,l-5,6,6a,7-tetrahydro-1-hydroxy-3-(2-heptyloxy) benzo[c]quinolin-9(8H)-one; m.p. 208-209C.
m~e - 329 (m+) Analysis: Calc'd for C20H2703N: C, 72.92; H, 8.26;
N, ~.25%
Found: C, 72.92; H, 8.31; N, 4.42%
d,l-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6~-propylbenæo[c]quinolin-9(8H)-one; m.p. 164-166C.
Analysis: Calc'd for C27H3303N: C, 77.29; H, 7~93;
N, 3.34%
Found: C, 76.97; H, 7.98; N, 3.41%
1-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6~-methyl-benzo[c]-quinolin-9(8H)-one; m.p. 176-178C. 2 [~]D = -416 0(c 0.33, CH30H) m/e - 391 (m ) ~. ' Analysis: Calc'd for c25H29O3N: C, 76.69; ~, 7.~7; N, 3OS8%
Found: c, 76.32; H, 7.36; N, 3.33%
d-5,6,6a,7-tetrahydrc)-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6~-mathyl-benzo~c]quinolin-9(8H)-one; m.p. 172~
174C.
[~]25 = ~412.9~ (c~I 0, CH30H) m~e - 391 (m~) Analysis: Calcld for C25H2903N: C, 76.69; H, 7.47;
N, 3.58%
Found: C, 76.40; H, 7.39; N, 3051%

d,l-5,6,6a,7,10,10a-He~ahydro-l-hydroxy-6~-methyl-3~:"~
A suspension of d,l-5,6,6a,7-tetrahydro l-hydroxy~
6~-methyl-3-(2 heptyloxy)benzo[c~quinolin-9(8H)-one (1.0 g., 2 91 mmole) in tetrahydrofuran (20 ml.) is added dropwise via an addition funnel to a rapidly stirred solution of lithi~m (0.1 g.) in liquid ammonia (75 ml., distilled through potassium hydroxide pellets). The addition funnel is rinsed with tetrahydrofuran (10 ml.). The mixture is stirred for 10 minut~s and then solid ammonium ahloride is added to discharge the blue color. The excess ammonia is allowed to evaporate and the residue taken up in water (100 ml.) and ethyl acetate (50 ml.). The ethyl acetate layer is separated and the aqueous phase extracted with ethyl acetate (2 x S0 mlO). The combined extracts are washed with brine, dried (MgSO4) and concentrated under reduced pressure to a brown semi-solid product (1.35 g.).
Trituration of the semi-solid in pentane/ether (1:1) gives a light brown solia (0.884 g.); m.p~ 130-138~C.
The above procedure is repeated but using 1.84 gO
(5.36 mmole) of the benzo[c]quinolin-9-one reactant, 0.18~ g, of lithium, :L40 ml. of liquid ammonia and 45 ml, of tetrahydrofuran. The residue (2.1 g.) remaining after evap-oration of the ammonia is dissolved in benzene and charged to a chromatography column ~3.8 x 61 cm) aontaining siLlca . , .:~:

gel ~250 g~) The column is eluted with a volume o~ de-gassed benzene equal to the volume of the column and then with 1700 ml. of degassed benzene-ether (9:1). Continued elution (1100 ml.) gives a brilliant red eluate which is concentrated to a light purple solid tS80 mg.) under reduced pressure and triturated in benzene-ethsr (1:11 to give 370 mg. of solid7 m.p. 154-156C. It is stored under nitrogen and in the darX. The isolated solids are mixtures of the cis- and trans- forms of the titla product.
m/e - 345 (m+) H NMR (100 MHz) ~CDCl (ppm): 6.85 and 7.49 (lH, broad variable, OH), 5.67, 5.71, 5.85, 5093 ~d, J = 2Hz, 2H
total, aromatic hydrogens for cis/trans mixture), 0.90 (t, 3H, terminal CH3), 1.12-4.43 ~m, remaining H).
EX~MPLE 27 Isomeric 5,6,6a,7,10,10a-Hexahydxo-l-acatoxy-6~-Pyridine (2.2 ml.) is added to a suspension of5,6,6a,7,10,10a-hexahydro-1-hydroxy-6~-methyl-3-(2-heptylox~) benzo[c]quinolin-9(8H)-one (222 mg., 0,642 mmole) in acetic anhydride (2.2 ml.) under a nitrogen atmosphere. The mixture is stirred for 1.5 hours at room tPmperature and is then poured onto ioe (50ml.)O The gum which saparat~s is extracted with ether ~3 x 50 ml.) and the combined extracts washed first with water (4 x 50 ml.) and then with brine ~1 x 60 ml~).
The extract is dried (MgSO4) and evaporated under reduced pressure to a red oil (250 mg.).
The oil is dissolved in a minimum of hot ether and charged to a silica gel (45 g.) column, packed and eluted with pentane-ether (3:1). The column is eluted with pentane-ether (3:1, 200 ml.). Elution is continued and fractions (10 ml.) collected. Fractions 22-32 are combined and con-centrated to a foam (113.5 mg.) which is crystallized from petroleum ether as white crys~als; m.p. 112~-114C.
Fraction 33-50 are combined and concentrated to a foam (89.7 mg.) which is recrystallized from petroleum ether as white crystals; m.p. 78-82C.

~s~

The products are the isomer1c mono-acetylated compounds.
EXAMPI,E 28 d,l-5,6,6a,7,10,10a-E[exah~dro-l-acetoxy-6~-methyl-3-(2-hept~o~benzo~c]~Luinolin-3~8H~-one The procedure of Example 26 is repeated but u~ing double the quantities of reactants. The product (2.22 g.
is then directly acetylated according to the procedure of Example 34 to give 2.35 g. of acetylated product. This pro-duct is triturated in pentane-ether (3:1) to a tan solid (90S mg.) which whan recrystallized from ethanol gives 404 mg. of light tan crystals; m.p. 112-11305~C~
The mother liquors from which eaah of the above solids is separated are combined and concentrated. The residue is dissolved in a minimum of benzene-ether-methylen~
chloride (1:1:1) and charged to a silica gel (275 g~) column (packed and eluted with petroleum ether-ether [3 1]o The column is eluted first with 2 liters of petroleum ether-ether (3:1~ followed by 1.5 liters of petroleum ether-ather 20 (2 1) and 2 li~s of peb~le ~ ether-eth~r tl:l). Fractions 2-11 (50 ml. each) of eluate from the 1:1 solvent svsten æe oollacted and con-centrabed under reduced pressure ~o a foam t496 mg~), Crys~lization fix~
petroleum ether affords whitP crystals; m.p. 100~-113C.
t410 mg.). Recrystallization from ethanol-water ~1:11 gives d,l-trans-5,6,6a~,7,10,10a~-hexahydro-l~acetoxy-6~-me~
3-(2-heptyloxy1benzo[c]quinolin-9~8H~-one melting at 111-112C.
m/e - 387 (m~) Analysis: Calc'd for C23H33O4N: C, 71.29; ~, 8.58;
N, 3.61%
Found: C, 70.95; H, 8.64; N, 3.-58~
Fractions 12-18 and 19-27 (50 ml. each) are collected and concentrated to afford 273 mg. and 208 mg., respectively, of acetylated product. Crystallization of the residue from fractions 19-27 from petroleum ether gives white crystals tll9 mg.); m.p. 84-88C. Reorystallization from ethyl acetate-hexane (1:10) gives d,l-cis-5,6,6a~7, lO,lOa~-hexahydro-l-acetoxy-3-~2~h~ptyloxy)-6~-methyl-benzo [c]quinolin-9(8H)-one, m.p. 84-86C.
Analysis: Calc'a for C23H3304N: C, 71.29; H~
5~58; N, 3.61%
Found: C, 71.05; H, 8.48; N, 3.56~
Similarly, the following compounds are prepared from appropriate reactants: ;
d -trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(5-phqnyl-2-pentyloxy)benzo[c]quinolin-9(8H)-one, m.p. 80-82C, m/e - 435 (m+~
Analysis: Calc'd for C27H3304N: C, 74.45; H, 7.64; N, 3.22~
Found: C, 74.43; H, 7.73; N, 3,28%
~ -cis-5,6,6a~,7,10,10a~-hexahydro-1-acetox~-6~i-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9(8H)-one, m.p. 172-176C. as the hydrochloride salt from acetone-e~her (1:1).
Analysis: Calc'd for C27H3304N~HCl: C, 68,71;
H, 7,26; N, 2.97%
Found: C, 68.86; H, 7 16; N, 2.97%
d,l-trans-5,6,6a~,7,10,10aa-hexahydro-1-aceto~-3-(;-phenyl-2-pentyloxy)-6~-propylbenzo~a]quinolin-9(8H)-one;
m p 79-80C.
2S m/e - 463 (m+) d,l-cis-5,6,6a~,7,10,10a~-hexahydro-1-acatoxy-3-(5-phenyl-2-pentyloxy)-6~-propylbenzo[c]quinolin-9(8H)-one;
m.p. 144-146C~, as ~he HCl salt, m/e - 463 (m+) d-cis-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-(5-phenyl-2-pentyloxy)-6~-methylbenzo~c]quinolin-9(8H)-one;
m.p. 90-94C. (dec.) as the hydrochloride salt.
[a]25 ~ +22.8 (c=0.31, CH30H) m~e - 435 (m+) Anialysis: Calc'd for C27H3304N-HCl: C, 68.71; H, 7.26; N, 2097~
Found: C, 69.24; H, 7.30; N, 3.01%

d-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-t5-Phenyl-2-pentyloxy) 6~-methylbenzo[c]quinolin-9~8H~-one; m.p. 90-95~C. Sdec.) as the hydrochloride salt.
[~]D5= ~78.46 (c=0.13, CH30H).
m/e - 435 (m ) Analysis: Calc'd for C27H330~N HCl: C, 68.71;
H, 7.26; N, 2.97~
Found: C, 70.20;
H, 7~23; N, 3~07%
1-cis-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-(5-pkenyl-2-pentyloxy)-6~-methylbenzo[c~quinolin-9~8H)-one;
m.p. 90-92C. as the hydrochloride.
[a]25= -20.5 (c=0.19, CH30H) m~e - 435 ~m~) Analysis: Calc'd for C27H3304N~ECl: C, 68.71;
H, 7.26; N, 2.97%
Found: C, 68.92;
H, 7.23; N, 3.09%
l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-(5-phenyl-2-pentyloxy)-6~-methylbenzo[c]~uinolin-9~8H)-one;
m.p. 92-96C. as the hydrochloride.
[~]2 = _79.0 (c=0.10, CH30H) m/e - 435 (m ) Analysis: Calc'd for C27H3304N~HCl: C, 68.71;
H, 7.26; N, 2.97%
Found: C, 68.67;
H, 7.23; N, 3.02~
EXA~IPLE 29 d,l-5,6,6a,7,10,10a-Hexahydro-l-acetoxy-6~-methyl-0 3-(5-phenyl-2-pentyloxy)benzo~c]quinolin-9(8H)-one, trans-and cis- isomers . __ _ _ _ Ammonia (1150 ml.) is condensed directly into a ~5~9 flame-dried 3 liter~3 neck flask (under a nitrogen atmos-phere) equipped with mechanical stirrer, a 500 ml. dropping funnal and solid Co2/acetona cooling (~-75C.). Lithium ! wire t2.2 g., cut into l/4" pieces) is added and a charactex-istic blue color forms immediately. To the stirred blue solution at -78C. is added d,l-5,6,6a,7-tetrahydro-l-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-

9(8H)-one (21.5 g., 0.055 mole) dissolved in tetrahydrofuran (250 ml.) dropwise over a 10 minute period. A~ter an additional 5 minutes of stirring at -78C., the reaction mixture is quenched by ~he addition of dry ammonium chloride (20 g.). The cooling is then discontinued and the reaction mixture warmed slowly on a steam bath to evaporate the ammonia. When almost dry, ethyl acetate (2 liters) and wat~r (l liter) are added and the mixture stirred for 10 minutes. The layers are then separated and the a~ueous phase is extracted once more with ethyl acetate (500 ml ), The combined organic extracts are washed once with water (l liter), dried (MgSO4) and concentrated to a brown semi-solid (~28 g.) This residue is immediately dissolved inmethylene chloride (200 ml.), 4-dimethylaminopyridine (7.5 g., 0.061 mole) and triethylamine t6~1 g., 0.061 mole) added and the stirred solution cooled to 0C. (ice/water cooling) under a nitrogen atmosphere. Acetic anhydride (6~1 g., 0.061 mole) is then added dropwise over 5 minutes with good stirring. After an additional 30 minutes of stirring at 0C., the reaction mixture i8 diluted with ethyl acetate (2 liters) and water (l liter) and stirred ror 10 minutes. The aqueous is extracted once more with water and the combined organics washed successively with water (4 x 1 liter), saturated sodium bicarbonate ~l x 1 liter), brine (1 x 1 litex), dried (MgSO4) and concentrated to a light brown oil t~27 g.). The residue is chrom~to-graphed on 1.8 kg. of silica gel using benzene 15/ethyl acetate as t~e eluting solvent. One liter fractions are collected, Af~er elution of l~ss polar impurities, frac~ions 9~9 16-20 are combined and evaporated to a residue which i~
crystallized from ether/petroleum e~her to yield 5 6 g.
(23.4%) of the trans-isomer of the title product. Fractions 21-27 are combined to give 7.6 g. (3108~) of a mixture of the trans- and cis-isomers, and fractions 28-32 are com-bined to-give 7.6 g. (31~8%) of a mixture of the trans- and cis-isomers, and fractions 28-32 are combined to give 2.5 g. (10.4%) of the cis-isomer of the title product.
The ~rans-isomer exhibits the following character-istic~:
m/e - 435 (m+) 1H NMR (60 MHz)- ~cMsl (ppm): 7.24 (s, 5~, aromatic), 5.97 (s, 2H, meta H'~), 2.28 (s, 3H, CH3-C00), 1.23 (d, 3H, CH3-CH-0-), 1.20 (d, 3H, CH3-CH-N), 1.3-4.5 (m,17H, remaining protons).
M.P. - 81-83C.
Analysis: Calc'd for C27H3304N: Cl 74.45; H, 7.64;
N, 3,22%
Found: C, 74.15; H, 7~68; N, 3.18%
The cis-isomer has the following characteristics:
m/e - 435 (m+) M.P. of HC1 qalt - 172-176Co (dec.) (from acstone-ether).
Analysis: Calc'd for C27H3304N-HCl: C, 68071;
H, 7.26; N, 2,97~
Found: C, 68.86; H, 7.16; N, 2.97%
E XaMPLE 3 0 dl-5,6,6a,7,10,10a-Hexahydro-l-acetoxy-6~-methyl-3-~4-phenylbutyloxy)benzo[c]quinolin-9~8H)-one, trans- and - cis-is~mers Following the procedure of Example 28 dl-5,6,6a,7-tetrahydro-l-hydroxy-6~-methyl-3-(4-phenylbutyloxy)benzo[c~ -quinolin-9(8H)-one is first red~ced wit~ lithium and ammonia and then acylated to yield the desired hexahydro isomers.
Separation by ~olumn chromatography on silica gel using ether as eluant provides first dl-trans-5,6,6a~,7,10,10a~-hexa-hydro-l-acetoxy-6~-methyl-3-(4-phenylbutyloxy~benzo[c~

.. ~

i~S9G~

quinolin-9(8H)-one, m~p. 155-156C~ ~ter recrystallization from ethyl acetate/pentant (1:5).
Analysis: Calc'd for C26H3104N: C, 74.08; H, 7.41; N, 3.32%
Found: c, 74.00; H, 7 47; N, 3.22%
m/e - 421 (m~) Further purification of later fractions by addi-tional column chromatography on silica g~l using cyclohexane-ether ~1:1) as elu~nt yields the isomeric dl-cis-5,6,6a~,7, lO,lOa~-hexahydro-l-acetoxy-6~-methyl-3-(4~phenylbutyloxy) benzo[c]quinolin-9(8H)-one, m~p. 95-96C. after recrystaL~
lization from a~hyl ace~ate/haxane ~1:5).
m/e - 421 (m~) AnalysiR: Calc'd for C26H3104N: C, 74.08; H, 7041; N, 3,32%
Found: C, 73.95J H, 7,51; N, 3.31%

d,l-5,6,6a~,7,10,10a-hexahydro-1-acetoxy-3-~2-heEt~lo~y~-benzo[c]~uinolin-9~8H)-one A solution o~ d,l-5,6,6a,7-tetrah~dro-1-hydroxy-3-(2-heptyloxy)benzo[c]~uinolin-9(8H)-one (9~0 g.) in tetra-hydrofuran (100 ml) is added dropwise to a rapidly stirredsolution of lithium (0.1 g.) in liquid ammonia (750 ml.~.
An additional 0.1 gO of lithium is added portionwlse duriny the addition to insure a blue color. Tha mixture is stirred for 10 minutes and then the blue color discharged by addition of excess ammonium chloride. The excess ammonia is allowed to evaporate and the residue is taken up in a mixture of water and ethyl acetate. The organic layer is separated and the aqueous phase extracted twice more with ethyl acetat~
The combined extracts are washed with water, brine, dried (MgS04) and evaporated to give 8,45 g. of crude product as a brown solid.
The crude product (8.0 g.) is ~uspended in methyl-ene chloride (48 ml.) at 0C. and treated with N,N-dimethyl-4-aminopyridine ~3.24 g.) and triethylamine (3.72 ml.).
Acetic anhydride (2052 ml.~ is then added to the mixtu~e which is then stirred for 30 minutes at 0C. It is diluted with methylene chloride (300 ml.) and the methylene chloride ~959~i9 layer separated, washed wi~h water ~3 x 150 m~,), saturat~d sodium bicarbonate (1 x 100 ml,), ~rine (1 x 100 mLD~, and dried (MgS0~). Evaporation of the methylene chloride gives 13,7 g. of dark oil which is chromatographed on a silica gel (~50 gO) column, The column ~s eluted ~equentially with ether-hexane (1:1), ether-hexane (2:1) and etherO
Fractions of 18 ml, each are collected, Fractions 176-224 are combined and concentrated to an oil which is crystalliz-ed from hexane to give 3.24 g, (32~) yield of the trans-i~omer of the title compound a'3 light yellow crystals;
m,p. 65,5-68C, m/e - 373 (m+) IR (KBr): 5,82 (ketone C=0), 5,75 (ester C=0), 295 (NH) ~, Fractions 246-290 are combined and concentrated to give 0,55 g. (5%) of crude cis-isomer o~ the title com-pound as an oil. It is purified further by column chromatography as described above to give the pure cis-isomer as an oil.
m/e - 373 (m+) IR (CHC133: 5.82 (ketone C-0), 5,67 (ester C-0~, 2~92 (NH)~.
Analysis: Calc'd for C22H3104N: C, 70.75; X, 8037;
N, 3,75%
Found: C, 70,90; H, 8,54; N, 3,79%
Fractions 225-245 are combined and evaporat~d to give 2,69 g, (26%) of a mixtuxe of cls- and trans-isomers which are separated by the procedure described above, The following compounds are similarly prepared from d -5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyl-oxy)benzo[c]quinolin-9(8H)-one:
d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-aceto~-3-(5-phenyl-2-pentyloxy)benzo~c]quinolin-9(8HI-one, an oil, m/e - ~21 (m+) Analysis: Calc'd for C26H3104N: C, 74,08; H, 7.41;
N, 3,32~
Found: C, 74,16; H, 7,59; N, 3,20%

.

d,l-cis-5,6,6a~,7,10,10a~-hexahydro-`l-acetoxy-3~~5;phenyl-2-pentyloxy)benzo[c~qulnolin-9~8H~-one, an oil.
m/e - 421 (m~) Analysis: Calc'd for C26H3l04N: C, 74,08: H, 7.41;
N, 3 32 Found: C, 74.04; Hl 7.49; N, 3.54~
and d,l-5,6,6a,7-tetrahydro-l-hydroxy-6~-methyl-3-~5-phenyl-2-p~ntylaxy)benzo[c]~uinolin-9(8H~-one is convert-ed to:
d,l-trans-5,6,5a~,7,10,10aa hexahydro-l-acatoxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo~c]quinolin-9~8H)-one, and: d,l-cis-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(5-phenyl-2-pentyloXy)benzo[c]quinolin-9(8H)-one.
The isomeric products are transformed to their hydrochloride salts as described in the general procedure of salt formation. Characterizing data on the salts is provided below:
HCl Salt m/e R (a) Analysls ~b~
Isomer M.P. (C.) (m ) f _ trans 107-110 435 0~7468.92 7.17 2.86 cis 94-102 435 0.7268,74 6,93 3 12 (a)thin layer chromatography in benzene/ether (1:1 (b)Calc'd for C27H330~N~Cl: C, 68.71; H, 7-26;
. N, 2.96.
EX~MPLE 3 2 d,l-Trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9-h drox -6~-methvl-3-(2-he~tvloxv~benzolc]quinoline To a stirred suspension of 150 mg~ (0.39 mmole) d,1-trans-5,6,6a~,7,10,10aa-hexahydro-1-acetoxy-6~-methyl-3-(~-heptyloxy)-benzo[c~quinolin-9(8H)-one in ethanol (lO ml.) at 0C. is added 40 mg. of sodium borohydride. After 0.5 hr~, the reaction mixture is poured into a mixture of ice cold 5% acetic acid (50 ml~) and ether (75 ml.). After separation of ~he ether layer, the aqueous phase is extracted further with ether (2 x 50 ml.). The combined ether extracts are washed successlvely with water (2 x 50 ml.), saturated ~s~

sodium bicarbonate (1 x 50 ml.), brine (1 x 75 ml ), dried (MgS04), filtered and concentrated under reduced pressure to yield 156 mg. of a white foam containing a mixture of the axial (minor amount) and equatorial (major amount~
alcohols of d,l-trans-5,6,6a~,7,8,9,10,10a~-oatahydro-1-ace~oxy-9-hydroxy-~-methyl-3-(2-hep~ylo~y)benzo[c~quino-line m/e - 389 (m~) IR (CHC13) 5.72~ (ester carbonyl).
NMR (60 MHz, ~cMscl ) ~ showed a charact~ristic singlet at 2.28 ppm for the acetate methyl.
Th~ major and minor isomers are separated in the following manner: 180 mg. of the alcohols of d,l-trans-5,6, 6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9-hydroxy-6~-methyl-3-(2-heptyloxy)-benzo[c]quinoline are charged to a column containing 15 grams of silica gel and eluted with a solvent mixture of 3 parts benzene to 1 part ether. 15 ml. Frac-tions are collected. Fractions 6-8 are combined and con-centrated under reduced pressure to yield 13 mg. of d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-àcetoxy-9~-hydroxy-6~-methyl-3-(2-heptylox~)-benzo[c]quinollne.
Fractions 11-16 are ~ombined and concentrated to yield 83 mg. of d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-l-acetoxy-9~-hydroxy-6~-methyl-3-(2-heptyloxy)benzo[c]
quinoline.
Other compounds prepared from appropriate react-ants by the above procedure include the following:
d -trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9-hydroxy-6~-methyl-3-(S-phenyl-2-pentyloxy~benzo ~c]quinoline.
m/e - 437 (m+) IR (CHC13) - 5.70 ~ (ester carbonyl) Conversion to the hydrochloride yielded a solid (m.p. 188-190C.)~ Re~rystallization from acetone/methanol/
ether (25:1:100) affords an analytical sample of the 9~-alcohol, m.p. 193-194C.
Analysis: Calc'd for C27H35O4N HCl: C, 68.42; H, r ~s9~

7.66; N, 2~96%
Found: C, 68.48; ~, 7~70; N, 2.89%
Conversion to the methanesulfonate ~with methane-sulfonic acid in dichloromethane) giveR a solld which is recrystallized from ethyl acetate to yield white crystals, m.p. 110-114~C.
IR (CHC13): 2.9S, 3.70, 3.95, 5.60, 6.06, 6 19 and 6.27 Analysis: Calc'd for C27H35O4N CH403S: C, 63 0~;
H, 7 37; N, 2.63 Found: C, 62.90; }I, 7.31; N, 2,74 d,l- cis-5,6,6a~,7,8~9,10,10aB-oatahydro-l-acetoxy~
9-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy]benzo[c]quino-line.
m/e - 437 (m+) IR (CHC13) - 5.71 ~ (ester car~onyl) l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9~-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)'benzo[c]quino-line: m.p. 120-125C. (dec.) as the hydrochloride salt.
[a]D5 = -98.57 (c=0.351, CH30H) m/e - 437 (m+) Analysis: Calc'd for C27H35O4N HCl: C, 68.42; H, 7.66; N, 2.9 Found: C, 68024; H, 7~68; N, 3.00~
d-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetox~r-9~-hydroxy-6~-methyl-3-(5-phenyl-2-pentYloxy)benzo[c]qulno-line; m.p. 120-125C. ~dec.) as the hydrochloride salt ~]25 = +ggO33o (c=0.30, CH30H) m/e - 437 (m+) Analysis: Calc'd for C27H35O~N'HCl: C, 68.42; H, 7.66; N, 2.96%
Found: C, 68.41; H, 7.54; N, 2.95~
In like manner, the compounds tabulated below are prepared from appropriate reactants.

,, ~

CO ~ I` ~ ,~
~ a Z ~ ~ o 9 1` 1` 1` o ~ :~ t~
U~ ", oo o~ U~
o~
~D O
~ ~ o 1~ 1`
Z
U~ o ~ CO
~ ~ ~ CO ~ooco N
, O ~
$
~ æ~ ~ ~æ~ æ~

~) ~ i~ ~ ~ 5~ ~ N
~N N ~NN N

c~ >~ e~ ~ u~ D r ~< ~-~
O , ~ co O

~ ~ 'O ~ 0'0 'O ~,~
æ~ ~ f ~ ~
~D ~ m P~

1~ ~ ~ N 10 N ~! ~r N N ~ *

: :: :

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

~9~

E XAMPL:E 3 3 d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetox~-9~-hydroxy-6~-methyl-3-tS-phenyl-2-pentyloxy) benzo[c]quinoline Sodium borohydride (7.57 g., 0.20 mole) is added to methanol (205 ml.) undar a nitrogen atmosphere and cooled in an acet~ne/dry ice bath to about -75C. The mixture is stirred for about 20 minutes to dissolve most, if not all, the sodium borohydride, A solution of- dl-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-6B-methyl-3-~5-phenyl-2-pentyloxy)benzo[c~quinolin-9(8H~-one (8.71 g,, 0 02 mole) in tetrahydrofuran (88 ml.) is cooled to about -50C. and then added dropwise over a 5-10 minute period to the sodium borohydride solution. The reaction mixture is stirred at about -70C. for 30 minutes and is then poured onto a mix-ture of water (1000 mlO) containing ammonium chloride (45 g,, 0.80 mole), crushed ice (250 mlO) and ethyl acetate (250 ml.). The layers are separated and the aqueous extracted with ethyl acetate (3 x 200 ml.). The combined extracts are washed with water tl x 100 ml.) and dried (MgSO4). The dried extract is cooled to about 5C.
solution of ethyl acetate (15 ml.)/HCl, 1~5N (0.025 mole) is then added dropwise over a 15 minute period. Upon stirring the mixture at 0-5C~, the hydrochloride salt of the title product precipitates~ The mixture is stirred for a half-hour, filtered and the salt dried at 25C~/Q~055 mm. to give 6.378 g. (67 3~) of product, m~p 195-198C.
(dec.).
Alternatively, the title compound is prepared 0 by the following procedure.
d,l-trans-5,6,6a~,7,8,9,10,10~-octahydro-l-acetoxy-93-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy) benzo[c] quinoline A heterogeneous mixture of d,l-5,6,6a,7-tetra-hydro-1-acetoxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]
quinolin-9(8H)-one (3.0 g., 7 mmole) and palladium-on-carbon (5%, 3.0 g.) in methanol (30 ml.) is hydrogenated 59~

~86-at room temperature in a Parr apparatus under 50 p. .i.
hydrogen for three hour~. The catalyst is then ~lltered and the methanol filtrate evaporated under reduced pressure to ~ive the title product.
The product is taken up in ethyl acetate (300 ml and the resulting solution cooled to 0C. An excess of a saturated solution of hydrogen chloride in ethyl acetate is then added to precipitate the hydrochloride salt of the title product as a white solid. It is filtered, washed with ethyl acetate, and dried.
The d,l-5,6,6a,7-tetrahydro-1-acetoxy-6B-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]~uinolin-9(8H)-one is prepared as follows.
To a stirred ~olution of d,l-5,6,6a,7-tetrahydro-1-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo[C]~UinOli~
9(8H)-one (4.5 g., 0.0115 mole~ in pyrldine (45 ml,) at room temperature is added acetic anhydride (45 ml.). The resulting solution is stirred for 3,5 hours and is then poured onto ice-water (250 ml.) and the mixture extracted with diisopropyl ether (2 x 2S0 ml ). The combined extracts are washed with water (3 x 200 ml.), dried (MgSO4) and evaporated under reduced pressure to a yellow-brown oil which solidifies on scratching the walls of the flask con-taining it. Trituration of the solid wi~h n-heptane gives 2.0 g. of the l-aceto~r derivative (40~ yield). It i~
purified by recrystallizatlon from hot chloroform-n-hexane (1:4) to give the pure ester; m.p 136-140C.
m/e - 433 (m+) H NMR (60 MHz) ~CDC13 ~ppm): 7-21 tbs~ 5H~ aroma-tic), 6.62 (d, J=1,5 Hz, lH, C=C-H), 5O97 (d, J=3 Hz, lH, meta H), 5.86 (d, J=3Hz, lH, meta H), 2.27 [s, 3H, CH3-C
(=0)], 1.21 (d, J=7Hzr 6H, CH3-C-N, CH3-C-O), 1.49-4,51 (m, 14H, remaining protons).

d,L-cis-5,6,6aB,7,8,9,10,10aB-octahydro-l-acetoxy-9~-hydroxy-6B-methyl-3-(5-phenyl-2-pentyloxy)benzo _ _ [c] quinoline _ _ _ _ To a solution of d,l -cls-5,6,6a3,7,10,10aB-~o~s~r~

hexahydro-l-acetoxy 6~-methyl-8-(5-phenyl-2-pentyloxy) benzo[c]quinolin-9(8H)-one (1.0 g., 20296 mmole) ln dr~
tetrahydrofuran (100 ml.) at -18C. i9 added, with stirring, potassium tri-sec-butyl borohydride (4.6 ml. of 0.5M, 2.296 mmole) dropwise over a period vf five minutesO The reaction mixture is stirred an additional 30 minutes at -78C. and is then poured, with stirring, into a solution of 5~ acetic acid (250 ml.) and ether (500 ml.) pre-cooled to 0C. The layers are separated and the aqueous layer extracted with additional ether (250 ml.~O The com~ined ether extracts are washed successi~ely with water (2 x 250 ml~), saturated sodium bicarbonate soluton (1 x 250 ml.) and brine (1 x 250 ml.), dried (MgSO4) and concentrated in acuo to give a yellow oil (1.4 g.). The crude oil is chromatographed on silica gel (100 g.) using benzene~e~her (3:1) as eluant.
After elution of less polar impurities, the title ~ompound is isolated as a clear oil (700 mg.). The oil is dissolved in ether (35 ml.) and treated with ether saturated with HCl gas to gi~e the hydrochloride salt of the title compound (448 mg.), m.p. 115-124C. after recrystallization from ether/chloroform.
MS (mol. ion) = 437.
IR (KBr): 5.58 ~ (ester >C=O).
Analysis: Calc'd for C27H35O4N HCl: C, 68.41, ~, 7.66; N, 2.96 Found: C, 68.52; H, 7.91; N, 2.73~
The following compounds are prepared in like manner from appropriate reactants:
OH
-~ Z--W

~s~

M.P. MS
-z-w 4 R5 R6 R8 (C.) 5molOion) 5-phenyl- CH3 H HI ~ I ~H 168-170* 437 2-pentyloxy H CH 3 H~H oil S H CH3 H ~ I IH oil 437 *HCl salt. Analysis:
Calc~d for C27H35O4N^HCl: C, 68 41; H, 7.66;
Found: C, 68048; H, 7.57;
N, 2.93 E X~MPLE 35 d -trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9-diacetoxy-6~-methyl-3-~2-heptyloxy)benzo [c]

1.2 g. Of the unchromatographed reduction product of d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-6~-methyl- 3- ( 2-heptyloxy)benzo[c]-quinolin-9(8H)-one from Example 40 is stirred with excess acetic anhydrlde and pyridine overnight at room temperature. The mixture is poured into ice water, the aqueous mixture extracted with ether (3 x 100 ml.) and the combined extracts washed with water, brine, then dried ~MgSO4) and evaporated. The resi-due is su~jected to column chromatography (40 g. silica gel, benzene/ether [9:1~ as eluting solvent) to gi~e 680 mg. of the desired dl-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9-diacetoxy-6~-methyl-3-(2-heptyloxy)benzo[c]quinoline, which crystallizes on addition of hexane and ethyl a~etate, m.p 86-87C.
m/e - 431 (m+) IR (KBr) - 5.73 ~ (ester carbonyls).
1H NMR (60 MHz) ~CDC13 (ppm): 5.88 (bs, H2, H4 -2H), 2.28 and 2.05 [2 three-proton singlets, CH3-C(-O~-], and ca. 0.8-5.0 (multiplets, remaining protons).
Analysis: Calc'd for C25H3705N: C, 69.57; H, 8.64; N, 3.25~
Found: C, 69.51; H, 8.54; N, 3.14%
Similar tr~atment of 60 mg. dl-trans-5,6,6a~,7,8, ~3 . .

i3S9~

9,lO,lOa~-octahydro-l-acetoxy-g~-methyL-3-(4-phenylbutyloxy~
benzo~c]quinoline in p~ridine ll ml.~ and acetic anhydrlde (1 ml.) for 1 hour at room temperature yields ~he desired d,l-trans-5,6,6a~,7,8,9,10,10acl-octahydro-1,9~-diacetoxy-6~-methyl-3-(4-phen~lbutyloxy)benzo[c]quinoline, m.p. 146-147C. after r~ysta~ization irom ethyl acetate/hexane (1:1) .
m/e - 465 (m~) Analysis: Calc'd for C28H3505N: C, 72.23; H, 7.58; N, 3.01~
Found: C, 72.17; H, 7.61; N, 3.08%

d,l-trans-5~6,6a~,7,8,9,10,10a~-octahydro-1,9-dihydroxy-6~-methyl-3-(2-heptyloxy~-benzo[c~
quinoline A solution of 130 mg. d,l-trans-5,6,6a~,7,8,9, lO,lOa~-octahydro-l-acetoxy-9-hydroxy-6~-methyl-3-(2-heptyl-oxy)-benzo~c]quinoline and 46 mg. potassium car~onate in 35 ml. methanol is stirred at room temperature. After 30 minutes, the reaction mixture is neutralized with acetic acid and concentrated under reduced pressure, The resLdue is dissolved in ether (100 ml.), washed su~cessively with water (2 x 35 ml.), satur~ted sodium bicarbonate ~1 x 35 ml~, brine (1 x 40 ml.), dried (MgSO4) and conc~ntrated under reduced pressure to give 96 mg. d,l-trans-5,6,6a~,7,8~9,10, lOa~-octahydxorl,9-dihydroxy-6~-methyl-3-(2-heptyloxy~ benzo [c]quinoline as an amorphous solid, m.p. 80-100C. (dec.).
m~e - 347 (m~) The NMR (CDC13, 60 MHz) shows no absorption for the acetate methyl and the IR (C~3) had no absorption for an ester carbonyl.
In like manner, the following compound is prepared from the corresponding l-acetoxy derivative of Example 32.
d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9-5 dihydroxy-66-methyl-3-(5-phenyl-2-pentyloxy)be~zo[c]quinolineO
m~le - 395 (m~) Conversion to the hydrochloride gives a powder, ~ .

- 9o -m.p. 151-156C.
IR (Ksr): 3.00, 4.00 (~N=~,6.10 and 6.25 ~.
Similarly, d,l-trans-5,6,6a~,7,10,10a~-hexahydro-l-acetoxy-5-methyl-6~-methyl-3-(2-heptylox~)banzo[c~quinoli~
9(8H~-one is hydrolyzed to the corresponding 1-hydroxy com-pound; m.p. 157-160C.
m/e - 359 (m~) Analysis: Calc'd for C22H3303~: C, 73.50; H, 9.25;
N, 3.90%
Found: C, 73.16; H, 9.14; N, 3,85%

d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-(2-heptyloxy)-5-benzoyl-6~-methylbenzo[c]quinolin-9(RH)-one To a stirred solution of the product of Example 28, d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-aceto~-6~-methyl-3-(2-hep~yloxy)-benzo[c]quinolin-9t8H)-one ~812 mgO) in 2.5 ml. pyridine i~ added 421 mg. benzoyl chloride in 5 ml. chloroform. After two hours, the reaction mixture is poured onto ice and extracted twice with e~her. The com-bined ether extracts are washed with water, sodium bicarbon-ate, dried (MgS04) and filtered to yield, after concentra-tion and crystallization from ether/petrole~m ether, d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-~2-heptyloxy~-5-benzoyl-63-methylbenzo~c]quinolin-9¢8H~-one, m.p. 108-110C.
m/e - 491 (m+) Repetition of this procedure but using an equival- ;
ent amount of acetyl chloride in placa of benzoyl chloride and the appropriate benzo~o]quinoline affords the following compound:
d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acatoxy-3-(2-heptyloxy)-5-acetyl-6~-methylbenzo~c]quinolin-9t8H~-one.
m/e - 433 (m+) .~

d,l-trans-5,6,6A~,7,10,10ac~-hexahydro-1-acetoxy-5-methyl-6B-m~thyl-3-(2--heptyloxy)-b~nzo[c]quinolin-9(8H)-one S To a stirred solution of 387 mg. d,l-trans-5,6,6a~, 7,10,10aa-hexahydro-~-acetoxy-6~-methyl-3-(2-heptyloxy)-benzo~c]quinolin-9(8H)-one in 3 ml. acetonitrile coole~ to 15C~ is added 0~5 ml. 37~ aqueous formaldehyde followed by 100 mg. sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH until the reaction is complete as evidenced ~y no remaining starting material by thin layer chromatography. The product is isolated in the following manner.
Ice water and ether is added to the reac~ion mixtures, ~he ether layer separated and the aqueous extract-ed once more with ether. The combined ather layers are combined, dried and evaporated to yield the desired d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-5-methyl-6B,7, lO,lOa~-hexahydro-l-acetoxy-5-me~hyl-63-methyl-3-(2-heptyl-oxy)-benzo[c~quinolin-9(8H)-one as an oil.
1H NMR (60 MHZ, CDC13) shows a characteristic absorption at 2.85 ppm for ~ -CH3, In like manner, the following compounds are pre-pared from Appropriate reactants:
d,l_trans_5,6,6a~,7,10,10aa-hexahydro-1-acetoxy-5-methyl-3-(2-heptyloxy)benzo~c]quinolin-9~8H)-one, an oil.
d,l-trans-5,6,6a~,7,8,9,10,10ac~-octahydro-1,9-diacetoxy-5-mekhyl-6~-m~thyl-3-(2-hepkyloxy)benzo~c]
quinoline, an oil.
m/e - 445 (m~) In addition, the ~ollowing compounds are similarly prepared:
f~ R
0-~-CH3 0 ~
4 ~ Z-W

.:
.~

-Z-W R4 R5 Rfi R8 M.P . m/~
__ _ _ -O-CH-(CH2)3C6H5CH3 H CH3 ~ H 94-97C. 44g -O-CH-(CH2)3C6H5 CH3 H CH3 ~H oil 449 _~(CH2)4c6H5 CH3 H CH3 .I.,H 102-103C.3 ~35 lAs the HCl salt.
Analysis:
Calc~d for C28H35O4N~HCl: C, 69.19; H, 7.47; N, 2 88 Found: C, 68.72; H, 7.18; N, 2.74 Analysis:
Calc'd for C28H35O4N: C, 74.80; H, 7-857 N, 3-12 Found: C, 74.66; H, 8,05; N, 2 66 m.p. 69-75C. as the HCl salt.
3Analysis:
Calc'd for C27H33O4N: C, 74.45; H, 7,64; N~ 3,22~
Found: C, 73 8~; H, 7.51; N, 3.04%

d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9-dihydroxy-5-ethyl-6~-msthyl-3-(2-heptyloxy)benzo[c]
quinollne _ - -To a solution of 100 mg. lithium aluminum hydride in 5 ml. dry tetrahydrofuran (cooled in an icP/water bath~
is added dropwise a solution ~0 mg. d,l-tran~-5,6,6a~,7,8, 9,lO,lOaa-octahydro-l,9-dihydroxy-5-acetyl-6~-msthyl-3-(2-heptyloxy~benzo[c]quinoline in 3 ml. tetrahydrofuran.
After ~he addition is complete, the reaction mixture is heated at reflux for one hour and is then allowed to cool to room temperature. Equivalent amounts of water, followed by 3N potassium hydrox~de are added~ the resultant precipi-tate filtered and the filtrate concentrated in vacuo to yield the dasired N-ethyl derivative as an oil.
m/e - 375 (m~) `~;

,:

_ 93 - ~95~

d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9-hydroxy-5-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline Formaldehyde (1.1 ml. of 37% aqueous) is added to a solu-tion of d,l-trans-5,6,6a~,7,10,10ad-hexahydro-1-acetoxy-3-(5-phenyl-2-pentyloxy)benzolc]-quinolin-9(8H)-one in acetonitrile (15 ml.) at room temperature, followed by sodium cyanoborohydride (0.262 g.). The reaction mixture is stirred for one hour during which time the pH is maintained at neutral pH by addition of acetic acid as needed. Additional sodium cyanoborohydride (0.262 g.) and methanol (15 ml.) are added to the reaction mixture, which is then acidified to pH 3, stirred for two hours, and concentrated under reduced pressure to an oil. The oil is diluted with water (50 ml.), the pH then ad]usted to 9-10 by means of aqueous sodium hydroxide, and the alkaline mixture extracted with ether (3 x 200 ml.). The combined ether extracts are washed with brine, dried (Na2SO4) and concentrated under reduced pressure to a clear oil. The oil is then dissolved in 50% ether-hexane and charged to a silica gel column. The column is eluted first with 50% ether-hexane followed by 60%, 70% and 75% ether-hexane. The eluate is monitored by -thin layer chromatography (ether-10, hexane-l). The first product collected is d,l=trans-5,6,6a,7, lO,lOa-hexahydro-l-acetoxy-5-methyl-3-(5-phenyl-2-pentyloxy)-benzo[c] quinolin-9(8H)-one (0.125 g.) m/e - 435 (m+) Analysis: Calc'd for C27H3304N: C, 74.45; H, 7-64;
N, 3.22%
Found: C, 74.06; H, 7.77;
N, 3.31%
The second product is the 9~-hydroxy diastereomer of the title compound (25 mg.).
m/e -- 437 (m ) Analysis: Calc'd for C27H35O4N: C, 74.11; H, 8.06;
N, 3.20%
35Found: C, 73.96; H, 8.34;
N, 3.00%

S9~3 The third product is thQ 9B-hydroxy diastereomer of the title compound (0.7 g.).
m/e - 437 (m+) Analysis: Calc'd for C~7H3504N: C, 74.11; H, 8.06; N, 3.20%
Found: C, 73,56; ~, 7.86; N, 3.21~
Similarly, d,l-~rans-5,6,6a~,7,10,10aa-hexahydro-l-acetoxy-3-(2-heptyloxy~benzo[c]quinolin-9~8H)one is treat-ed with sodium cyanoborohydride to give:
d -trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-5-methyl-3-t2-heptyloxy)benzo[c]quinolin-9(8H)-one as an oil.
m/e - 387 (m+~
IR (CHC13): 5.80 (ketone C=o), 5.65 (ester C=o),~.
Analysis: Calc'd for C~3H3304N: C, 71.29; H, 8.58; N, 3.61%
Found: C, 70.78; H, 8.71; N, 3.27~
d,l-trans-5,6,6a~,7,8,9,10,10aa-octahydro~l-acetoxy-9~-hydroxy-5-methyl-3-(2-heptyloxy)benzo[c~quinolln~, 20 an oil.
m/e - 389 (m~) IR (CHC13): 2.80 (O-H); 5.70 (ester C=O), ~.
Analysis: Calc'd for C23H35O4N: C, 70.92; H, 9.06;
N, 3,60%
Found: C, 70.56;~H, 8.95; N, 3.56~
and d,l-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo~c]quinolin-9(8H)-one is converted to:
d,l-trans-5,6,6a~,7,10,10aa hexahydro~l-acetoxy-5-methyl-6~-methyl-3-(5-phenyl-2-pentyl~xy)benzo[c~quinolin-9(8H)-one;
d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-__ acetoxy-9~-hydroxy-5-methyl-6~-methyl-3-(S-phenyl-2-pentyl-oxy)benzo[c]quinoline, which is isolated as the hydrochlor-5 ide salt; m.p. 163-165C.
m/~e - 451 (m~) 9~

-94a-EXAMPLE ~1 dl-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-5-isobutyryl-3-(5-phen~1-2-pentyloxy)benzo[c]~uinolin-9(8H)-one A ~olution of isobu~yl chlorid (114 mg., I.7 mmole) in chlorofonm ~20 ml.) is slowly added with stirring b4 a ~olutlon of dl-trans-5,6,6a~,7,10,10a~-hexahydro-1-acetoxy-3-(5-phenyl-2-pentyloxy)benzo~c] quinolin-9 (8H)-one (450 mg., 1.07 mmole) in dry pyridine (1.5 ml.) at OCO and undar a nitrogen atmosphere. The r~action mixture is stlrred `
for five hours and is then poured into ice/water (50 ml.) The chloroform layer is separated and the aqueous layer extracted with chloroform (2 x 20 ml.). The chloroform extracts are combined and washed with 10% hydrochloric acid (2 x 10 ml.), followed by brine (1 x 10 ml.), and then dried (MgSO4). Concentration of the chloroform solution in vacuo give a yellow oil which solidifies upon standing. Trituration of the solid with hexane affords a white crystalline solid, which is recovered by filtration and dried ~400 mg.), m p. 128-129C.
Concentration of the hexane filtrate gives 121 mg. of oil.

d,l-trans-5,6,6a~,7,8,9,10,10~-octahydro-1-acetoxy-9~-hydroxy-5-isobutyryl-3-~5-phenyl-2-pentyl~xy)benzo[c~
~uinoline Sodium borohydride (38 mg., 1.0 mmole) is slowly added to a solution of d,l-trans-5,6,6aB,7,10,10a~-hexahydro-l-acetoxy-5-isobutyryl-3-(5-phenyl-2-pentyloxy?benzo~c]
quinolin-9(8H)-one (260 mg., 0.529 mmole) in absolute ethanol (20 ml.) 5-10C. under a nitrogen atmosphere, The reaction mixture is stirred for one hour and is then acidi-fied with 10% hydrochloric acid. The ethanol is removed by concentration under reduced pressure, Water ~10 ml.) is - added to the remainin~ solution which is then extracted with ethyl acetate (2 x 50 ml.). The extracts are combined, washed with brine and then dried (MgSO4). Concentration in vacuo affords the title compound as an amorphous solid (213 mg.) which is used without ~ur~her purification.

d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1,9~-diacetoxy-5-isobutyryl-3-(5-phenyl-2-pentyloxy)ben~o~c]
_ ~Luinoline . Under a nitrogen atmosphere, a solution of d,l-trans-5,6,6a~,7,8,9,10,10aa-octahydro-1-acetoxy-9~-hydroxy-5-isobutyryl-3-(5-phenyl-2-pentyloxy)-benzo[c~quinoline (213 mg., 0.432 mmole) in tetrahydrofuran (5 ml.) is added to a slurry of l~thium aluminum hydride ~100 m.g, 2~6 mmole) in tetrahydrofuran (5 ml.) at room temperature. The mixture is stirred overnight and then water (0.1 ml.), 15~ sodium hydroxide solution (0.1 ml.) and water (0.3 ml.) are added~
It is then filtered under nitrogen and the filter cake washed with tetrahydrofuran (2 x 5 ml.). The combined filtrate and wash solution are concentrated to a reddish oil (0.174 g.).
Ihe oil is dissolved under nitrogen in pyridine (1 ml.) and the solution cooled to 0C. Acetic anhydride (1 ml.) is added, with stirring, to the pyridine solution and the reaction mixture stirred for 30 minutes at 0C. It ,~

. . .

~0~ 9 is then poured into water (25 ml.~ and extracted with ethyl acetate (3 x 25 ml.). The extracts are com~ined, washed with brine, dried (MgSO4) and concentrated to a brown oil tl84 mg ). The oil i5 flushed with nitrogen and chromato-graphed on silica gel (40 g.) using benzene~ether ~9:1) as eluent. Fractions of 10 ml. each are collected. F.ractio~
2-10 are combined and concentrated to an oil (109 mg.).
m/e - 521 (m~) Analysis: Calc'd for C32H4305N: C, 73 67; H, 8 31;
N, 2.68~
Found: C, 74.33; H, 8.89; N, 2.23%
1H NMR (60 MHZ)~CDcl (ppm): 7,22 ~s, 5H, aromatic 6 05 (d, lH, aromatic), 5.90 (d, 1H, aromatic), 4.90 (bs,, lH), 4.30 (bs, lH), 3.10 (d, 2H, N-CH23, 2 90 ~d, 2H, N-C~2), 2.70 (bs, 2H), 2.40 and 2.15 (s, 6H, 2-CH3-Coo-), 185 (bs, 2H, H7 and H8), 1.5 (m), 1.05 (d, 6H ~ ~3) 1.0-3.0 (variable, remaining protons).

d,l-trans-5,6,6a~,7,10,10aa-Hexahydro-l-hydroxy-5-acetyl-6~-methyl-9-methylene-3-t2-heptyloxy)benzo~c]
quinoline Triphenylmethyl phosphonium bromide (742 mg., 2.12 mmole) is added to a solution of sodium hydride (0.95 g., 2.0 mmole) in dimethyl sulfoxide (50 ml.) at 50C. The reaction mixture is then heated at 70C. for three hours after which ~O-trans-5,6,6a~,7,10,10a~-hexahydro~ cetoxy-5-acetyl-6~-methyl-3(2-heptyloxy)ben2O[c]quinolin-9~8H~-one (0.858 g., 2,0 mmole) in dimethyl sulfoxide (50 ml.) is added. The reaction mixture is heated at 70C. overnight, and then cooled and poured into a mixture of ice and water containing sodium bicarbonate (12.5 g.). The aqueous mixture is extracted with benzena, dried (Na2SO~) and evaporated under reduced pressure to give the crude product. It is purified by column chromatography over silica gel in h~xane-benzene (1~

~l39~

EX~MPLE 45 d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-hydroxy-5-ethvl-9-hydroxymethyl-6~-methyl-3-~2-heptylox~
benzo[c]auinollne To a solution of d,l-trans-5,6,6a~,7,10,10a~-hexahydro-l-hydroxy-5-acetyl-6~-methyl-9-m~thylene-3-(2-heptyloxy)benzo[c]quinoline (0.855 g., 2 mmole~ in tetra-hydrofuran ~30 ml.) at 0-5C., is added dropwise a lM
- solution of diborane in tetrahydrofuran ~borane-tetrahydro-furan complex) (6 ml.). After the addition the reaction mixture is held at room temperature for 30 minutes and then treated with water to decompose exc~ss hydride.
The reaction mixture is then warmed to 50C. on a water bath and 3N sodium hydroxide (3 ml.) added followed by dropwise addition of 30% hydrogen peroxide (3 ml.).
After addition, the mixture is held at room temperature for one hour, potassium carbonate (1.5 g.) added and the tetrahydrofuran layer separated. The aqueous phase is extracted with tetrahydrofuran (3 x 10 ml,), the extracts combined, dried (MgS04) and concentrated to give the product Purification is achieved by column chromatography on silica gel using ether-hexane.

d,l-7,10-dihydro-1-hydroxy-3-(2-heptyLoxy)kenzo [c]-quinolin-g~8H)-one e~hylene ketal and d,l-5,6,6a,7,10,10a-hexahydro-1-hydroxy-3-(2-heptyl-o~-benzo~c]quinolin-9(8H)-one ethylene ketal A suspension of d,l-trans-5,6,6a~,7-tetrahydro-1-hydroxy-3-(2-heptyloxy)benzo[c]quinolin-9~8H)-one (0~50 g , 30 1.52 mmoles), ethylene glycol ~0.43 ml 7.70 mmoles~ and p-toluenesulfonic acid monohydrate ~0,28 gO, 1.46 mmoles~
in benzene ~25 ml.) is heated at reflux for 45 minutes The by-product water is azeotropically removed. The dark suspension thus produced is taken up in a mixture of ether and saturated sodium bicarbonate solution. me organic layer is separated, washed with saturated agueous sodium bicarbon-ate solution, dried (MgS04), and concentrated to an oil which ls th~n chromatographed on silica gel ~50 g.) using ether as eluant. Fraction of 10 ml. eaah are collected Fractions 12-18 are combined and evaporated to give 203 mg of the ethylene ketal of the hexahydro deriva~
tive.
m/e - 375 (m+) IR (CHC13): 2.98 ~ (superposition of N-H and O-H
stretch).
lH NMR (60 MHz) ~cMDcl (ppm) 5.7 (s, 2H, aromatic), 4.0 (s, 4H, ketal ethylene) and3absorption for remaining protons.
Fractions 42-65 are combined and concentrated to afford 146 mg. of a yellow solid. Trituration of the solid in ether-pentane (1:1) gives 85 mg. of 7,10-dihydro-1-hydroxy-3(2-heptyloxy)benzo[c]quinolin-9(8H)-one ~thylene ketal, m.p. 171-173C.
m/e - 371 ~m ) IR (KBr): 2.98~ (o-H1~
lH NMR (60 M~Iz) ~CDCl (ppm): 8,6 (s, lH, C-6 aromatic) t 6.6 and 7.0 (bd, 2H, aromatic), 4;1 (bs, 4H, ethylene ketal), 3.9 (bs, 2H, C-10 methylene), 3.1 (t, 2H, C-7 ethylene), 2 0 (bt, 2H, C-8 methylsne) and other absorp~
tions for remaining protonsO
Analysis: Calc'd for C22H29O4N: C, 71.13; H, 7.87;
N, 3.77%
Found: C, 71.19; H, 7.67; N, 3.61%
In like manner, d,l-5,6,6a,7,10,10a-hexahydro-1-hydroxy-3-(2-heptyloxy)-6-methylbenzo[c]quinolin-9(8H)-one ethylene ketal is converted to d,l-7,10-dihydro-1-hydroxy-3-(2-heptyloxy)-6-methylbenzo[c]quinolin-9(8H)-one ethylene ketal.
mfe - 385 (m~) lH NMR (60 MHz) ~CDCl (ppm3: 6,8 and 6 4 ~two lH
doublets, aromatic), 5.7 (bs, 1~, phenolic), 4.0 (bs, 4H, ethylene ketal), 3.9 (bs, 2H, C-10 -CH2-), 3.1 (bt, 2H, C-8 -CH2-), 2,5 ~s, 3H, 6-CH3), 2.0 (bt, 2H, C-7 -CH2-), and other absorpt:ions for remaining protons.

;
. ~
.

9591~

E~MPL~ 47 d,l-5,6, 6A~, 7, 1 0, lOa~-~exahydro-l-hydroxy-6~-methyl-3-~2- ~ ~ ~ne Equimolar amounts of m-chloroperbenzoic acid and d,l-$,6,6a~, 7, 1 0, 1 0 a~-hexahydro-1-hydroxy-6~-methyl-3-(2-heptylthio)benzo~c]quinolin-9(8H)-one are added to a mixture of chloroform and acetic acid (2:1) and the reactlon mixture stirred for one hour at room t~emperature. The organic phase is then separated, washed with water, dried (MgS04) and evaporated to drynoss to give the title product.

d,l-trans-5,6,6a,7,10,10a-Hexahydro-l-hydroxy-6~-methyl-3-(2-heptylsulfonyl)benzo~c~quinolin-9 (8H-~-one `
~ . _ _ , .
The procedure of Example 47 is repeated but using two equivalents of m-chloroperbenzoic acid or oxidizing agent per mole of thio ether reactant to give the title compound.
E XAMPL Er 4-9 d,l-5,6,6a,7-Tetrahydro-1-(4-morpholinobUtyryl-oxy)-6~-methyl-3-(2-heptyloxy)benzo[c~quinolin-9(8H~-one To a solution of d,l-5,6,6a,7-tetrahydro-1-hydroxy-6~-methyl-3t2-heptyloxy)benzo~c]quin~ n 9(8H) one (O.Sl g~, 1.5 mmole) in dry methylene chlorid~ (25 ml.) is added 4-morpholinobutyric acid hydrochlorida (O.315 g., 1.5 mmole~
and the mixture stirred at room temperature under a nitrog~n atmosphere. A O.lM solution of dicyclohexylcarbodiimide in methylene chloride (12.5 ml~, 1.5 mmole) is added dropwise and the mixture stirrad for 24 hours, It is then filtered and evaporated to give the title product which is purified by column chromatography on silica gel.

d,:L-trans-5,6,6a~,7,8,9,10,10ac~-Octahydro-1-(4-N-___ piperidylbutyryloxy)-9-hydroxy-6~-methyl-3-(5-phenyl-2-pentyLox~ benzo~c]~uinoline hydrochloride ;
To a 25C. solution of d,l-trans-5,6,6a~,7,8,9,10, lOa~-octahydro-l,9-dihydroxy 6~-methyl-3-(5-phenyl-2-pentyl-. ~ ~

oxy)benzo~clquinoline (1.0 g., 2.53 mmoLes~ in methylene chloride ~20 ml.) is added 4-N--piperidylbutyric acid hydro-chloride (0.524 g., 2.53 mm~les) qnd clicvclohexylcarbodllmi~
~0.573 g., 2.78 mmoles). Thb reaktion mixture is stirred at 25C. for 6 hours and then cooled for 12 hours and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 1 3 g, of sol~d of the mono-hydrochloride salt.
IR (KBr): 2.95, 3,70, 5~65 (ester CaO) r 6.13 and 6.27 ~.
Preparative layer c ~omatography of a portion of this solid on 0.5 mm. thick silica gel and elution with 10%
methanol-methylene dichloride affords the free base, d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro 1-(4-N-piperidyl-butyryloxy)-9-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)ben7o [c]quinoline.
lH NMR (60 MHz) ~cTMcl (ppm): 1.12 (d, J=7 Hz, C-3 side-chain me~hyl), 1.25 (d, J=~ Hz, C-6 methyl), 5.84 (s, two ArH) and 7.16 (s, 5H).
Treatment of this free base with excess hydrogen chloride in ethar yields the dihydrochloride salt as a hygroscopic powder.

; c~ 5,6,6a,7 Tetrahydro-1-(4-N-piperidvlbutyryloxy~-6~-methyl-methyl-3-(5-phenyl-2-pantyloxy)ben~o[c~quinolin-9(8H)-one hy~ ochloride To a 25C. solution of d,l-5,6,6a,7-tetrahydro-1-hydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo~c]quinolina-9(8H)-one (550 mg., 1.41 mmol~) in methylene chloride ~26 ml.) is added 4-N-piperidylbutyric acid hydrochloride (291 mg., 1~41 mmole) and dicyclohexylcarbodiimide (319 mgO, 1.55 mmole). The reaction mixture is stirred for 18 hours and is then cooled to 0C. and filtered, Evaporation of the filtrate and trituration of the residue with ether gives 800 mg. of d,l-5,6,6a,7-tetrahydro-1-(4-N-piperidylbutyryl-oxy)-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo[c~quinoline 9 (8H)-one hydrochloride as a hygroscopic yellow powder~

, ~

~s~

IR ~CHC13~: 2.92, 4.14 (HN=~, 5~69 (ester), 6O00 6.20 and 6 40 ~.
In like manner, d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-(4-N-morpho1inobutyryloxy)-9-hydro~y-6B-methyl-3-(5-phenyl-2-pentyloxy)benzo[~]quinollne hydrochlorlde is prepared from 4-N-morpholinobutyric acid and d,l-trans-5,6, 6a3,7,8,9,10,10aa-octahydro-1,9-dihydroxy-6~-methyl-3-(5-phenyl-2-pentyloxy)benzo~c3quinoline:
IR (KBr): 3.00, 3.75, 5067 (ester C~O), 6.15 and 6.30 ~.

d,l-7,10-Dihydro-l-hydroxy-3-(2-heptyloxy)-6-methyl-A solution of d,l-7,10-dihydro-1-hydroxy-3-t~
heptyloxy)benzo~c]-quinolin-~(8H)-one ethylene ketal ~371 mg., 1.0 mmole) in ether (50 ml.) is slowly addad to an ice-cold solution of methyl-lithium (44 mg., 2 0 mmole) in ether (25 ml.). The 5-lithio-6-methyl derivative thus ob-tained is dissolved in dry ether and treatad with dry oxygen to give, after filtration and evaporation of the solvent, the title compound.

General Hydrochloride Salt Formation Excess hydrogen chloride ls passed into a solution of the appropriate benzo[c]quinoline of formulae I or II
and the resulting precipitate s~parated and recrystallized from an appropriate solvent, e.g., methanol-ether ~l lO)o In this manner the following salt is preparedo d,l-trans-5,6,6a~,7,8,9,10,10a~-octahydro-1-acetoxy-9~-hydroxy-6~-mPthyl-3-(5-phenyl-2-pentyloxy~benzo [c]quinoline, m p 191-193C.
m/e - 437 (m+) Analysis: Calcld for C27H36O4NCl: C, 68.48; H, 7.70; N, 2.89 Found: C, 68 42; H, 7.66; N, 2 96 P REPARAT I ON A
2 -B romo-5-~henyi1~
To phosphorous pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride ~10 ml.) to phosphorous tribromide (15.0 ~.) in methylene chloride (15 ml.~ at 0C., is added 5-phenyl-2 pentanol (812 g.~ in methylene chloride at 0C. The mixture is ~tirred for 2.5 hours at 0C. and is then allowed to warm to room tQmpera-ture. Water (50 ml.) is added, the mixture sti~red for on~
hour and the methylene chloricle layer separat~d. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magne~ium sulfate. Concentration of the dried extracts gives 12.4 g. of title produck as a light yellow oil.
NMR: ~cMsl 1.6 (D,3,methyl,J = 7Hz), 1.6-2.0 (M,4,ethylene), 2.3-~.0 (bd,T,2,benzylic-methylene), 3.7-4.2 (M,l,methine), 6.9-7.4 (M,5,aromatic).
PREPARATION B
2-(3 ! 5-Dimethoxyphenyl)-5-phenylpentane A solution of l-bromopropylben~ene (51.7 g.-~ in ether (234 ml.) is adde~ dropwise over a 2-hour period to a refluxing mixture of magnesium (7~32 g.) in ether (78 ml.~.
The reaction mixture i8 refluxed for 30 minutes longer and then a solution o 3,5-dimethoxy-acetophenone ~50 g.) in ether (78 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenchod by addition of saturated ammonium chloride (23~ ml.), the ether layer i~
separated and the aqueous phase extracted with ether (3 x 200 ml.). The combined ether extracts are dried over magnesium sulfate and concentrated undsr vacuum to yield 81 g. of an oil. Forty grams of the oil is hydrogenated in a mixture containing ethanol (300 ml.), concentrated hydro-chloric acid (2 ml.) and 5% palladium-on-carbon (5 g.).
The catalyst is filtered off and the ethanol removed under vacuum. The residue is distilled under vacuum yielding 28 g. of 2-(3,5-dimethoxyphenyl)-5-phenylpentane (b.p. 0.125 ,~, ;

mm., 154-159C ) ~CDC13 1.25 (d,3,~-C~3), 1~3-2.1 (M,4,ethylene~
2.2-2.9 (M,3,benzyllc-methylene,mathinyl), 3.45 (S,6, methoxyl), 6.2-6.7 (M,3,aromatic), 7.2 ~S,5,aromatic) PREPARATION C
2-(3,5-Dihydroxyphen~1)-5-~heny~entane A mixture of 2-(3,5-dimethoxyphanyl)-5-phenyl~
pentane (22 g.) and pyridine hydroGhloride (94 g.~ under nitrogen is heated to 190C. for 2 hour~ with vigorous stirring. The reaction mixture i~ cooled, di~solved ln 6N hydrochloric acid ~200 ml.) and diluted with watar to 600 ml. The aqueous solution is extracted with ethyl acetate (4 x 100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield 24 g. of crude product. The product is purified by silica gel chromatography to yield 19.2 g, of 2-(3,5-dihydroxyphenyl)-5-phenylpentane as an oil.
NMR: ~cTMDcl 1.1 (d,3,~-methyl), 1.35-1.65 ~M,4, ethylene), 2.2-2.8 (~,3,benzylic-methylene,methinyl), 6~1-6.5 (M,3,aromatic), 6.65 (bd.S, 2, hydroxyl), 7-7.4 ~M,5, aromatic).
Following the procedures o~ Preparations B and C, the compounds listed below are prepared by substituting the appropriate l-bromoalkylbenzene ~or l~bromopropylbenzene:
2~(3,5-dihydroxyphenyl)-6-phenylhexane--NMR: ~TMS 1.1 (D,3,a-methyl, J-7 cps), loQ~
1.9 [M,6,~H2(CH2)3-C~(CH3)-Ar], 2.2-2.8 (M,3,benzylic methylene,methinyl), 6.0 (bd.S, 2,phenolic OH)~ 6.2-6,4 (M,3,aromatic), 7~1-7.4 (M,5,aromatic).
1-(3,5-dihydroxyphenyl)-2-phenylethane-m.p.: 76-77C.
2-(3,5-dihydroxyphenyl-4-phenylbutane (an oil)--NMR: ~cMscl 1.1, 1.25 (d,2,methyl), 1.45-2,0 (M,2,methylene), 2~15-2O7 (M,3,benzylic-methylene,methinyl), 6.3 (S,3,aromatic), 6.85 (S,2,hydroxyl-D2O overlay), 7.1 (S,5,aromatic) .
. .
:` :

5~

PREPARATION D
1-(3,5-Dihydroxyphen~1)-2-methy~ ~4~ ylbutane A solution of n-butyL lithium (29 mlO of 2.2 M) is added dropwise to 3,5-dimethoxybenzyl kriphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude l-(3,5-dimethoxyphenyl)-2-methyl~4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel (400 g.) and elution with benzena. Yield: lO g. as an oil.
NMR: &CTMDSl 1.95 (S,3), 2.3-3.1 (M,4), 3 8 (S,6~, 6.15-6,6 (M,3), 7.1-7.5 ~(M,6).
The l-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene (9.4`g.) thus prepared is dissolved in ethanol (250 ml.) and catalytically hydrogenated at 45 p.s.i. in the presence of palladium-on-charcoal (l g, of 10%) and concen-trated hydrochloric acid (1 ml.). Yield: 9.4 g. of l-(3,5-dimethoxyphenyl~-2-methyl-4-phenylbutans as an oil.
NMR: ~TDMcl 0 g (d,3), 1.35-1.95 (M,3), 2.2-2 9 (M,4), 3.75 (S,6), 6.~5 (S,3), 7.25 ~(S,5).
It is d~meth~lated according to the procedure of Preparation C to give 1-(3,5-dihydroxyphenyl)-2-methyl-4-phenylbutane.
The 3,5-dimethoxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 3,5-dimethoxy-benzyl bromide (12 g.) and triphenylphosphine ~14.2 g.) in acetonitrile (200 ml.) for one hour. The reaction mixture is then cooled and the crystalline product recovere3d ~y filtration, washed with ~th~r and dried (20 g.); m.p. 269-270C.
PREPAR~TION E
2-Methyl-2-(3,5-dihydroxyphenyl)-5-phenylpentane To a solution of the Grignard reagent prepared .~
~ii r from 2-phenylbromoethane (5.5 g.), maynesi~ (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 ona hour~ The mixture i~
then extractad with ether, the extract dried tMgS04) and concentrated to an oil. Distillation of the oil ln vacuo affords 2-methyl-2-(3~s-dimethoxyphenyl)-5-phenyl-3-pen~ne;
b.p. 168C./0.2 mm. (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 with 6N hydrochloric acid. The ethanol is removed under reduced pressure a~d the residue extracted with ether. The extract is dried (MgSO4) and concentrated to give 2-methyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-penkanol as an oil (52 g., 88~ yield).
The pentanol (16 g.) is taken up in ether (100 ml.) and reacted with powder potassiurn (2,5 g.) in ether (200 ml~.
Carbon disulfide (equimolar to the potassiurn) is added and the mixture stirred for a half-hour. Methyl iodide t9.0 g.
is then added and the reaction mixture stirred for 6 hour~O
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 g.) and the mixture refluxed for 18 hours. Evaporation of the alcohol and distillation of the residue gives 2-mekhyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentene.
The~ pentene derivative is catalytically hydrogen-ated according to the procedure of Preparation D and the resulting 2-rnethyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentane d~methylated via the procedure of Preparation C togive the product.

~5~

PREPARATION F
3,5-Dibenzyloxyacetophenone Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3,5-dibenzyl-oxybenzoic acid (175 g., 0.532 M) in ether (250 ml.)-tetrahydrofuran (1400 ml.) maintained at 15-20C. After stirring an additional 0~75 hour at 10-15C., water (600 ml.) is slowly added keeping the reaction temperature below 20C. The aqueous layer is separated and extracted with ether(3 x 250 ml.). Th2 organic phases are combined, washed with saturated sodium chloride solution (4 x 300 ml.), dried over sodium sulfate, and concentrated under vacuum to give an oil which slowly crystallized from isopropyl ether.
The crude product i9 recrystallized from ~ther-hexane to yield 104.7 g. ~59%) of product; m.p. 59-61C.
PREPARATION G

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 170C. for 4 hours. The clear melt is cooled to room temperature, triturated with ether and the precipitate of triphenyl phosphine oxide removed by filtration. The filtrate is concentrated under vacuum to an oily residue which is chromatographed over silica gel (1500 g.~ and eluted with banzene:hexane solutions of incraasing benzene concentration beginning with 40:60 and ending with 100~
benzene. Concentration of appropriate fractions gives an oily residue which is crystallized f~om hexane. Yield:
40.2 g. (77~); m.p. 73-75C.
Analysis: Calc'd for C26H26O4: C, 77.58; H, 6.51 Found: C, 77.72; H, 6.60%
In like manner, ethyl 3-(3,5-dimethoxyphenyl) crotonate is prepared from 3,5-dimethoxyacetophenone (51.7 g.) and carbethoxymethylene triphenylphosphorane (200 g.).
Yield = 61.8 g , 86%, b.p. 146-162C. at 0.3 mm.

PREPARATION H

A solution of athyl 3-(3,5-dibenzyloxyphenyl) crotonate (24.1 g., 60 mM) in ether (250 mlO~ is added to a mixture of lithi~ aluminum hydride ~3.42 g., 90 mM) and ether (250 ml.). Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture refluxed for 12 hours and then cooled.
Water (3.4 ml.), sodium hydroxide (3.4 ml. of 6N) and water (10 ml.) are then added successively to the reaction mixture.
The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil - 2.4 g, (98~).
Rf = 0,25 [silica gel:benæene~l8~:ethyl acetate~l)].
m/e - 362 (m+) Analysis: Calc'd for C24H26O3: C, 79.53; H, 7,23%
Foùnd: C, 79.37; H, 7.11 %
In like manner, ethyl 3-(3,5-dimethoxyphenyl~
crotonate ~60.4 g.) is reduced to 3-(3,5-dimethoxyphenyl) butanol t48,0 g,, 90~).
PREPARATION I
;
3-~3,5-Dibenzyloxyphenyl)butyl Tosylate Tosyl chloride (11~1 g,, 58,1 mM) is added to a solution of 3-~3,5-dibenzyloxyph~nyl)-1-butanol ~20.7 g., 57 mM) in pyridine (90 ml.) at -45C, Ths reaction mixture is held at -35C. for 18 hours and is then diluted with'cold 2N hydrochloric acid (1500 ml.) and extracted with ether (5 x 250 ml.), The combined extracts are washed with saturat-ed sodiùm chloride'solu~ion ~4 x 250 ml.) and then dried (Na2S04~.
Concentration of the drisd extra~t affords the product as an oil. It is crystallized by treatment with ether-h~xane.
Yield: 24.63 g. (84~).
Analysis: Calc'd for C31H32O5S: C, 72.06; H, 6.24 Found: C, 72.05; H, 6.29%
PREPARATION J
., 3-(3,5-Dibenzyloxyphenyl)~l-phenox~butane A solution of phenol (4.56 g., 48,6 mM) in dimethylformamide (40 ml.) is added under a nitrogen atmos-phere to a suspension of sodium hydride ~2,32 g,, 48.6mM of 50% previously washed with pentane) in dimPthylEormamide (70 ml.) at 60C. The r~action mixture is stirred for one hour at 60-70C., after which a solution of 3-(3,5-dib2nzyloxyphenyl)butyl tosylate (23.93 g., 46,3 mM~ in dimethylformamide (80 ml.) is added, Th~ reac~ion mixture is stirred at 80C. for a half-hour and~is then cooled to room temperature, diluted 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 300 ml,) and s~turated sodium chloride solution (3 x 300 ml,) and then dried (Na2S04), Removal of the solvent under reduced pressure affords the product as an oil.
The oily residue is dissolved in benæene and filtered through silica gel (100 g,), Concentration of the filtrate under reduced pressure gives the product as an oil. Yield: 14.86 g. (73%).
Rf = 0,7 (silica gel, benzene).
m/e - 438 (m ) Analysis: Calc'd for C30H30O3: C, 82.16; H, 6,89%
Found: C, 82.07; H, 6,84%
PREPARATION K
3-(3,5-Dih~drox~phenyl)-l-phenoxybutane A solution of 3-(3,5-dibenzyloxyphenyl)-1-phenoxybutane (14.7 g,, 133.5 mM) in a mixtura of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s,i. hydrogen in the presence of 10~ palladium-on-carbon (1,5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an,oil. The oil is puri~ied by~chromatography on silica gel (100 g,) and eluting with benzene ethyl acetate consisting of 0-10~ ethyl acetate.
The middle fractions are combined and concentrated to give the title product: 7,8 g. (80~), as an oil.
Rf ~ 0,25 [~ilica gel, benzene (4J, methanol ~12], m/el - 258 (m~) An~lysis: Calc'd for Cl~H18O3: C, 74,39; H, 7,02%

~S9~

~109- .
Foundo C, 74.13; }I, 7.00~
PREPA~rrION L
l-Bromo-3-t3,5-dimethoxyphenyl~butane A solution of phosphorous tribromide (5.7 ml,, 0006 mole) in ether ~30 ml.) i!: added to a solution of 3-(3,5-dim~thoxyphenyl)-1-butanoL (30.0 g., 0.143 mole) in ~ther (20 ml.) at -5C. to -10'~C. and the reaction mixture stirred at -5C. to -10C. fQr 2.5 hours, It is then warmed to room temperakure and stirred for an additional 30 minutes. The mixture is poured over ice t200 g.) and the resulting mixturs extracted with ether (3 x 50 ml.). The combined extracts are washed with 5% sodium hydroxide solu-tion (3 x 50 ml.), saturated sodium chloride solutdon (1 x 50 ml.) and dried (Na2SO4). Removal o the ether and vacuum distillation of tha residue affords the title product; 25 g~
(55% yield); b.p. 125-132C, at 0.4 mm, PREPARATION_M
4 - t 3! 5-Dihydro~rphenyl ) -1- ( 4_ py 'rrldyl ) pentane A mixture of 3-(3,5-dimethoxyphenyl)butyl tri-phenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethyl-sulfoxide (50 ml.) is added to 4-pyridinecar~oxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran ~40 ml.). The resulting mixture is then added dropwise to a slurry of 50~ ~odium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0-5C. Following completion of addition, the mixture is stirred for one hour at 0-5C. and then concentrated under reduced pressuræ
The concentrate is diluted with water (200 ml.) and then acidified with 6N HCl. The aqueous acid solution is ex-tracted with ~enzene (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 (MgS04)affords 4-(3, 5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene (7.1 g., 70%) as an oil.
Catalvtic hydrogenation of the thus-produced pentene derivative according to the procedure given in Preparation D gives 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl) , ' pentane in quantitative yield; m.p. 131-133C~
The pentane derivative thus obtained i8 demethyl-ated by heati~g a mixture of the compound (7.15 g., 25 mmoles) and pyridin~ hydrochloride (35 g.) under a nitrogen atmosphere at 210C, ~or 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 ~y distillation in vacuo. Ethanol (S0 ml.) is added to the residue and the inorganic salts which precipitate are filtered off. Tha filtra~e is concentrated in vacuo and the residue chromatographed on silica gel (150 g.) using as eluting agents 5% ethanol/benzene (4 liters), 10~ ethano~
benzene (1 liter), 13% ethanol/benzene (1 liter) and 16%
ethanol/benzene (5 liters), The product is isolated as a glassy solid by concentration of appropriate fractions of the eluate. Yield = 5.0 g (78%).
The 3-(3,5-dimethoxyphenyl)butyltriphenylphos-phonium bromide is prepared by refluxing a mixture of 1~
bromo-3-(3,5-dimethoxyphPnyl)butane (21,5 g., 78.5 mmoles) and triphenyl phosphine (20~5 g, 78,5 mmoles~ in xylene (60 ml.) for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The filter cake is wash~d with ether and dried in a vacuum desicator to give 36.4 g.
(86%) yield of product; m.p. 190-200C.
PREPARATION N
~ ~_~
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 mM).
The reaction mixture is stirred for one hour at 25C,, for one-half hour at 50C. and is then cooled, The mixture is diluted with water (50 ml.) and added tc a mixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleum --ether (25 ml,,). The organic ex~ract is washed twice with water (250 m'L.), dried (MgSO~) and evaporatad to an oil, Fractional dLstillatior of the oil yields 8.0 g~ (75%) of 3,5-dimethoxy-~-methylstyrene oxide, bop. 93-97C., 0.2 mm, ~, ~lal9S~

IR (CC14): 2780, 1595, 1196, 1151, 1058 cm 1 W (95~ ethanol): ~max ~ 279 nm (~ = 2068)o m/e - 19~ (m+) PMR (CDC13) (60 MHz~ 70 (S~ CH3-), 2.76 ~d,J =
6 Hz, &, 2~95 (d,J = 6HZ,~C~L~), 3.81 (S,CH30-), 6.41 ~t,J = 2Hz, ArH) and 6,58 (d,J = 2Hz, ArH).
Analysis: Calc'd for Cl1H14O3: C, 68-02; H, 7.27 Found: C, 67.96; H, 7.28%
PREPARATION O

10 _ ___ _ ~ _ A mixture of dry 2-phenylethanol (30 ml., 251 mM~
and sodium metal (690 mg., 30 mM) is heated at 110C for 30 minutes. The resulting lM solution of sodium 2-phenyl-~thoxide is cooled to 60C., 3,5-dimethoxy-~-methylstyrene oxide (2 g,, 10.3 mM) added and the reaction heated 15 hour~
at 60C. The reaction mixture is cooled and added to a mixture of ether and water. The ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenylethanol is removed by vaauum distillation (b.p. ~65C., 0.1 mm.) leaving a 3.5 g. residue~ The residue i8 purified via column chromatography on Merck silica gel 60 (300 g.) and eluted in 15 ml. fractions with 60% ether-pentane. Fractions 52-88 yielded2 9 g. (89~) of 2-(3,5-dimethox~phenyl)-2-hydroxypropyl 2-phenylethyl ether.
IR (CC14): 353~, 1595, 1202, 1153 cm 1 W (95% ethanol): ~max = 278 (E = 1830), 273 (~ -1860).
m/e - 316 (m~) PMR (CDC13, 60 MXz): ~01.46 (S,CH3-), 2.86 ~S,OH)~
2.86 (t,J = 7Hz, -CH2-Ph), 3.53 (S,-CH20), 3.71 (t,J - 7Hz, -CH2O), 3.80 (S,OCH3), 6,38 (t,J = 2Hz, ~rH), 6.61 (d,J
2Hz, ArH) and 7.23 (S,PhH).
Analysis: Calc'd for ClgH24O4: C, 72.12; H, 7.65%
Yound: C, 71.92; H, 7.63 PPEPARATION P
2-(3,5-Dimethoxyphenyl)propyl 2-Phenylethyl Ether ,, _ ., . ,_ _ To a 0C. ~olution of 2-(3,5-dimethoxyph~nyl)-2-.`~
. ,~

. ~ :

5~

-112~
hydroxypropyl 2-phenylethyl ether (550 mg., 1.74 mM) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 ml., 5.22 mM). The reaction is allowed to warm to 20C.
over a 1.5 hour periodO It is then stirred for 1.5 hours at 20C. and then added to ether (150 ml.) and 15~ sodium carbonate (100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3 x 50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml ), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake ceases (26.5 ml., 20 min.), the r~action ig filtered through diatomaceous earth and the filtrate evap~rated to an oil.
The oil is purified via preparative layer chromatography on silica gel plates, eluted twice with 6:1 pentane:ether to yield 211 mg. (40~) of 2-~3,5-dimethoxyphenyl)propyl 2-phenylethyl ether~
IR (CCl~): 1600, 1205, 1155, 1109 cm 1 m/e - 300 (m+) PMR (CDC13, 60 MHz) ~ 1.22 (d,J - 7Hz, CH3-), 2.82 (t,J - 7Hz, CH2Ph),~2.8 (H-C-Me), 3.6 (-CH2-O-CH2-), 3.75 (S, OCH3), 6.35 (m,Ar~) and 7.18 (S,Ph~).
PREPARATION Q
2-(3,5-Dihydroxyphenyl)propyl_ 2-Phenylethyl Ether A mixture of 2-(3,5-dimathoxyphenyl)propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine ~0~4 ml., 4.96 mM) and dry pyridine hydrochlorids (4 g., 34,6 mM) is heated at 190C. for 6 hours. The reac~ion mixture is cooled and added to a mixture of water (100 ml~) and ether (150 ml.).
The ether extract is washad once with water ~50 ml.~ and, along with ~ second ether extraot (50 ml.) of the aqueous phase, is dried over magnesium sulfate and evaporated to an oil. The oil is purified via preparative layer chromato-graphy on silica gel platas, eluted six times with 30~
ether-pentane to yield 65.8 mg. (37~) of 2-(3,5-dihydroxy-phenyl)propyl 2-phenylethyl ether.
IR (CHC13): 3559, 3279, 1605, 1147, 1105 cm m/e - 272 (m+) PMR (CDC13, 60 MHz) ~ 1.18 (d,J ~ 7Hz, CH3-), 2.80 (t,J = 7Hz, CH2Ph), 2.80 (H-~-Me), 3.4-3.8 (-C~2OCH~-), 6.08 (t,J = 2HZ, ArH), 6021 (d,J = 2Hz, ArH) and 7.16 (S,Ph~).
PREPARATION R
4-(3,5-Dihydro~ hen ~
Under a nitrogen atmosphere a mixture of 3, 5-dibenzyloxyacetophenone (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phenoxypropyltriphenylphosphonium bromide (7.18 g., o.a5 M) in dimethylsulfoxide (450 ml.) is added dropwise over 1.75 hours to a suspension of 50~ sodium hydride (7.89 g., 0.165 M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0-5C. After stirrang for 4 hours at 0-5C. the reaction is allowed to warm to room temperature and is then carefully stirred into ice watar (2000 ml.), acidified with concentrated hydro-chloric acid, and extracted with ethyl ~cetate (5 x ~00 ml.).
The combined organic phases are washed with saturated aodium chloride solution ~3 x 300 ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphlne oxide. Filtration, followed by concentration of the filt-rate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane conslsting of 30% ~o 100% benzene. From the middle fractions 51 g.
(75%) of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene is isolated as an oil; R~ = 0.8 (siliaa gel, 2-benzene:l-hexane); m/e - 450 tm ).
Analysis: Calc'd for C31H30O3: C, 82.63; H, 6.71%
Found: C, 8~90; H~ 6.69~
A solution of 4-~3,5-dibenzyloxyphenyl~-1-phenoxy-pent-3-ene ~51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), e~hyl acetate (160 ml.) and concentrated hydro-chloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10~ Pd/C. Removal of the catalyst by filtration and concentration of the flltrate under vacuum yields 30.8 g. (100%) of product as a visc~u3 oil.

.;

~9Sg!~9 Analysis: Calc'd for C17H~0O3: C, 74.97; H, 7.40 Found: C, 74.5~; H, 7.~5 PREPARATION S
3-Hydroxy-5-pentylaniline Olivetol (1.8 g., O.OlM), ammonium chloride ~2.65 g., 0.05M), sodium bisulfite (5.2 g,, 0.05M) and ammonium hydroxide (12.5 ml.) are combined and heated ~n a steel bom~
at 230C. for a half-hour. The bomb is then cooled, the contents dissolved e~hyl acetata (350 ml.). Hydrochloric acid ~300 ml. of 10%) is added, the mixture stirred and then the organic layer separated. The extraction is repeated two more times. The aqueous acid solution is neutralized with 6N sodium hydroxide and then extracted with chloroform (3 x 300 ml.). The aombined chloroform extracts are dried and concentrated. The residue is taken up in ethyl acetate, decolorized with charcoal and concentrated. The addition of hexane to the residue causes it to crystallize: 270 mg.: m.p.
88-91C. When recrystallized from hot ethyl acetate-hexane (1-1) it melts at 95-96C.
Analysis: Calc'd for CllH17ON: C, 73.70: H, 9.56; N, 7.81%
Found: C, 73.64; H, 9.62; N. 7.91%
PREPARATION T
d,l-N-Acetyl-3-h ~ xy~(5-phen~-2-pentyl)aniline A solution of 2.4 g. (9.5 mmole) d,1-3-hydroxy-5-(5-phenyl-2-pentyl)aniline in 24 ml. p~ridine and 24 ml~
acetic anhydride is stirred at room temperature for 45 minutes~ The reaction mixture is poured onto 200 ml. each of water and ethyl acetate. After stirring for 10 minute~, the organic layer is separated and washed suacessively with water (4 x 100 ml.), brine (1 x 100 ml.), dried (MgSO4), filtered and concentrated to yield 3.5 g. of crude d,l-N-acetyl-3-acetoxy-5-(5-phenyl-2-pentyl)aniline. A solution of d,l-N-acetyl-3-ac~toxy-5-~5-phenyl-2-pentyl)aniline and 1 g. potassil~m car~onate in 100 ml. methanol is stirred at room temperature for one hour, filtered, concentrated and dissolved in ethyl acetate. The organic solution is washed , .
. ..:

: .

~g5~

-115~
wi~h water, dried (MgSO~) and concentrated to an oil which is crystallized from hexane to yield 1.5 g. d, 1-N-acetyl-3-hydroxy-5-~5-phenyl-2-pentyl)aniline, m.p. 128-130C.
m/e - 297 (m+) lH NMR ~60 MHz) ~TMSl (ppm): 8.64 (bs, lH, -NH), 7.12, 6.58 and 6.45 (bs, ~H varia~le, ArOH), 2.19-2.78 (m, 3H~ Ar-CH and Ar-CH2), 2.05 (s, 3H, CH3-C(-O)-~, 1.3-1.78 (m, 4H, (CH2) 2)~ 1.12 (d, 3H, -C-CH3), PREPA~A'rION U
d,l-3-Benzyloxy-5-(5-ph ~
To a stirred solution of 1.2 g~ d,l_-N-acetyl-3-hydroxy-5-(5-phenyl-2-pentyl)aniline (4.03 mmole) in 50 ml.
tetrahydrofuran is added 193 mg. of 50~ sodium hydride (4.03 mmole). After 30 minutes of stirring, 1.38 g. (8.06 mmole) of a-bromotoluene is added and qtirring continued for 16 hours. The reaction mixture is then filtered, 1 ml. of acetic acid added to the filtrate which is then concentrated and chromatographed (silica gel, benzene/ether [2:1] as eluent) to yield 1.43 g. d,l-N-ace~yl-3-benzylox~-5-(5-phenyl-2-pentyl)-aniline as an oil, m/e - 387 (m+) CDC13 (ppm): 7-88 (b9, lH N H) 7.38, 7.20, 6.84, 6.59 (bs, 5H, 6H, lH, lH, arom~tic), 5.0 (s, 2H, -O-C~2Ar), 2.21-2.98 (m, 3H, Ar-CH and Ar-CH2), 2.07 (s, 3H, CH3-C(=O)-N), 1.30-1.69 (m, 4H, -(CH2)2), 1.15 (d, 3H, CH3-~-Ar).
A solution of 1.4 g. d,l-N-acetyl-3-benzyloxy-5-(5-phenyl-2-pentyl)-aniline, 14 ml. 20~ potassium hydroxide, 14 ml. methanol and 10 ml. 2-propanol is heated at raflux on a steam bath for 4 days. After cooling, water and ethyl acetate are added and the mixture stirred for 10 minutes.
The organic phase is separated and the aqueous phase extract-ed again wi~l ethyl acetate. The organic solutions ara combined, dried (MgS04), conc~ntrated in ~acuo and chromato-graphed (35 g. silica gel, benzsne/ether [3:1] as eluent) to yield d,l~-3-benzyloxy-5-(5-phenyl-2-pentyl)aniline as an oil, m/e - 345 (m+) CDC13 (PPm) ( S, - aromatic), 7.13 (bs, 5H, aromatic), 6.01-6.33 (m, 3H
aromatic), 4.95 (9~ 2H, ArCH2O;, 3.48 (bS, 2H variable, NH2~, 2.17-2.88 (m, 3H, Ar-CH and Ar-CH2), 1.32-1.76 (m, 4H, ~CH2~2~, 1,14 (d, 3H, -C-CH3).
PREPARATION V
d,l-5-Phenyl-2-Pentanol Mesylate To a stirred solutioll of 5-phenyl-2-pentanol t482 10 g ; 2.94 mol2s) in tetrahydrofuran (2250 ml.) at 0C. is added methanesulfonyl chloride (300 ml.) at such a rate that the internal temperature does not rise above 10C. (total addition time 4.5 hours). After addition is complete, the reaction mixture is allowed to warm to room temperature and stirring iq continu2d for an additional hour. The reaction mixture is filtered and the supernate concentrated to a light yellow oil (2800 g.) which is dissolved in chloro~orm ~2 1.) and washed with water (4 x 1 1.), brine (1 x 1 1.), charcoal treated (50 g.) dried (MgS04), filtered through diatomaceous earth and concentrated to a light orange oil (687 g., 95~ yield). This material is sùitable for use with-out further purification.
1H NMR(60 MHZ) ~TCMC1 (ppm): 7.23 (S, 5H aromatic), 4.53-5.13 (m, 1H, -CH-O-), 2.9~ ~S, 3H, O-SO2-CH3), 2.42-2.93 (m, 2H, -CH2C~H5), 1.50-1.92 (m, 4H, --(CH2) 2-), 1.23 ( S, 3H, O-CH -CH 3) Similarly, the following mesylakes are prepared from appropriatP alcohols:
4-phenybutanol mesylate, a yellow oil.
m/e - 228 (m+) 1H NMR (60 MHZ) ~CTMC13 (PPm): 7 22 (bS, 5H~
aromatic), 4.08-4.34 (m, 2H, -C}I2-O-), 3.93 (S, 3H, SO2CH3), 2.40-2.82 (m, 2H, -CH2C6H5), 1.51-1.93 (m, 4H, -(CH2)2-).
1-;2-octanol m~sylate, a colorless oil.
[~l 25= -9 695 (C - 2.6, CHC13) 1H NMR (60 MHZ) ~CTMDC1 (PPm): 4-79 Cbg, 1H, --CEI-O-), 2.97 (S,, 3H, S-CH3), 1.40 ~d, 3H, CH3-CH), 0.87 ~t, 3H, '~
! ~._ ', ;

, H~-CH2), 1.0-2.0 ~m, 10 H, -`~CH~) 5-) .
d-2-octanol mesylate.
~]D = +9.238 tC -- 2.8, CHC13) . H NMR, iden~ical to tha l-form.

jF

Claims (131)

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

1. A process for the preparation of a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein Q is or wherein R is hydrogen or an acyl group selected from alkanoyl groups having from one to five carbon atoms; R1 is hydrogen or an acyl group selected from benzoyl, 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 the same or different and is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitro-gen to which they are attached form a 5- or 6-membered heterocyclic ring, said ring being piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylpiperazino having from one to four carbon atoms in the alkyl group; R4 is hydro-gen, alkyl having from 1 to 6 carbon atoms or -(CH2)z-C6H5 wherein z is an integer from 1 to 4; R5 is hydrogen, methyl or ethyl; R6 is hydrogen, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; -(CH2)x-C6H5 wherein x is an integer from 1 to 4, or -CO(CH2)x-1-C6H5; z is alkylene having from one to nine carbon atoms, or -(alk1)m-X-(alk2)n- wherain each of (alk1) and (alk2) is the same or different and is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than nine, each of m and n is 0 or 1, and x is O, S, SO or SO2; and w is hydrogen, methyl, pyridyl, wherein W1 is hydrogen, fluoro or chloro; which comprises reduction of a compound of the formula:

wherein R1, R4, R5, R6, W and Z are as defined above, either by:
a) catalytic hydrogenation to produce a compound wherein Q is ; or b) by reduction with an alkali metal in liquid ammonia to produce a compound wherein Q is and if necessary subsequent reduction with a metal halide to produce a compound wherein Q is ;
and when necessary to produce a compound wherein one or more of R and R1 is other than hydrogen acylating a product of the reduction;
and when necessary to produce a compound wherein R6 is other than hydrogen reacting a product obtained as above wherein R6; is hydrogen with formaldehyde or an alkyl or acyl halide and then when necessary reacting the product obtained with an alkali metal complex hydride to produce a compound wherein R6 is alkyl or (CH2)n-C6H5.

2. A process according to claim 1, for the production of a compound wherein Q is wherein there is em-ployed as starting material a compound wherein R1 is as defined in claim 1, R5 is hydrogen or methyl and each of R4 and R6 is hydrogen or alkyl of 1 to 6 carbon atoms.

3. A process according to claim 2, wherein there is employed as starting material a compound wherein R1 is hydrogen or acetyl; Z is -(alk1)m-X-(alk2)n and W is hydro-gen or phenyl.

4. A process according to claim 3, wherein there is employed as starting material a compound wherein Z is -(alk1)m-O-(alk2)n.

5. A process according to claim 4, wherein there is employed as starting material a compound wherein Z is -O-(alk2)-, and R1 is hydrogen or acetyl.

6. A process according to claim 5, wherein there is employed as starting material a compound wherein Z is -OCH(CH3)-CH2-CH2-CH2- and W is phenyl.

7. A process according to claim 1, wherein a compound of the formula:
wherein R1, R4, R5, W and Z are as defined in claim 1, is reduced by reaction with an alkali metal in liquid ammonia and subsequent thereto and prior to reduction with a metal hydride the product is reacted with formaldehyde so that the product of the reduction with metal hydride is one wherein R6 is methyl.

8. A process according to claim 1, wherein a compound of the formula:

wherein R1, R4, R5, W and Z are as defined in claim 1, is reduced by reaction with an alkali metal in liquid ammonia and subsequent thereto and prior to reduction with a metal hydride, the product is reacted with acetyl chloride so that the product of the reaction with metal hydride is one where in R6 is ethyl.

9. A process according to claim 1, wherein a compound of the formula:

wherein R1, R4, R5, R6, Z and W are as defined in claim 1 is reduced by reaction with an alkali metal in liquid ammonia, the cis and trans isomers in the product are separated and the trans isomer is subsequently further reduced by reaction with a metal hydride.

10. A process according to claim 9, wherein there is employed as starting material a compound wherein R6 is hydrogen, subsequent to said reduction with alkali metal and to said separation of cis and trans isomers but prior to further reduction with a metal hydride the product is re-acted with formaldehyde so that the product resulting from the reduction with metal hydride is one wherein R6 is methyl.

11. A process according to claim 9, wherein there is employed as starting material a compound wherein R6 is hydro-gen subsequent to said reduction with alkali metal and to said separation of cis and trans isomers but prior to further reduction with a metal hydride, the product is reacted with acetyl chloride so that the product of the reduction with metal hydride is one wherein R6 is ethyl.

12. A process according to claim 9, wherein there is employed as starting material a compound wherein R1 is hydrogen and subsequent to said reduction with alkali metal in liquid ammonia but prior to said separation of isomers and further reduction with metal hydride the product is acetylated to give a compound wherein R1 is acetyl.

13. A process according to claim 10, wherein there is employed as starting material a compound wherein R1 is hydro-gen and subsequent to said reduction with alkali metal in liquid ammonia but prior to said separation of isomers the product is acetylated to give a compound wherein R1 is acetyl.

14. A process according to claim 9, wherein there is employed as starting material a compound wherein Z is -O-alk2 and W is hydrogen or phenyl.

15. A process according to claim 14, wherein in the starting material employed Z is OCH(CH3)(CH2)3 and W is phenyl.

16. A process according to claim 15, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl and R5 is hydrogen.

17. A process according to claim 16, wherein there is employed as starting material a compound wherein R6 is hydrogen.

18. A process according to claim 16, wherein there is employed as starting material a compound wherein R6 is methyl.

19. A process according to claim 16, wherein there is employed as starting material a compound wherein R6 is ethyl.

20. A process according to claim 15, wherein there is employed as starting material a compound wherein R4 and R5 are each methyl.

21. A process according to claim 20, wherein there is employed as starting material a compound wherein R6 is hydrogen.

22. A process according to claim 20, wherein there is employed as starting material a compound wherein R6 is methyl.

23. A process according to claim 20, wherein there is employed as starting material a compound wherein R6 is ethyl.

24. A process according to claim 9, wherein Z is OCH(CH3)(CH2)2 and W is phenyl.

25. A process according to claim 10, wherein Z is OCH(CH3)(CH2)3, W is phenyl, R4 is .beta.-methyl and R5 is hydrogen.

26. A process according to claim 10, wherein Z is OCH(CH3)(CH2)3, W is phenyl and R4 and R5 are each methyl.

27. A process according to alaim 11, wherein Z is OCH(CH3)(CH2)3, W is phenyL, R4 is .beta.-methyl and R5 is hydrogen,

28. A process according to claim 11, wherein Z is OCH(CH3)(CH2)3, W is phenyl and each of R4 and R5 is methyl.

29. A process according to claim 12, wherein Z is OCH(CH3)(CH2)3, W is phenyl, R4 is .beta.-methyl and R5 is hydrogen.

30. A process according to claim 12, wherein Z is OCH(CH3)(CH2)3, W is phenyl and each of R4 and R5 is methyl.

31. A process according to claim 13, wherein Z is OCH(CH3)(CH2)3, W is phenyl, R4 is .beta.-methyl and R5 is hydrogen.

32. A process according to claim 13, wherein Z is OCH(CH3)(CH2)3, W is phenyl and each of R4 and R5 is methyl.

33. A process according to claim 14, wherein there is employed as starting material a compound wherein Z is O-CH(CH3)(CH2)5 and W is hydrogen.

34. A process according to claim 33, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl and R5 is hydrogen,

35. A process acaording to claim 34, wherein there is employed as starting material a compound wherein R6 is hydrogen.

36. A process according to claim 34, wherein there is employed as starting material a compound wherein R6 is methyl.

37. A process aacording to claim 34, wherein there is employed as starting material a compound wherein R6 is ethyl.

38. A process according to claim 33, wherein there is employed as starting material a compound wherein each of R4 and R5 is methyl.

39. A process according to claim 38, wherein there is employed as starting material a compound wherein R6 is hydrogen.

40. A process according to claim 38, wherein there is used as starting material a compound wherein R6 is methyl.

41. A process according to claim 38, wherein there is employed as starting material a compound wherein R6 is ethyl.

42. A process according to claim 10, wherein Z is OCH(CH3)(CH2)5 and W is hydrogen, R4 is .beta.-methyl and R5 is hydrogen.

43. A process according to claim 10, wherein Z is OCH(CH3)(CH2)5, W is hydrogen and each of R4 and R5 is methyl.

44. A process according to claim 11, wherein Z is OCH(CH3)(CH2)5 and W is hydrogen, R4 is .beta.-methyl and R5 is hydrogen.

45. A process according to claim 11, wherein the starting material employed is one wherein Z is OCH(CH3)(CH2)5, W is hydrogen and each of R4 and R5 is methyl.

46. A process according to claim 12, wherein Z is OCH(CH3)(CH2)5, W is hydrogen, R4 is .beta.-methyl and R5 is hydrogen.

47. A process according to claim 12, wherein Z is OCH(CH3)(CH2)5, W is hydrogen and R4 and R5 are each mekhyl.

48. A process according to claim 13, wherein Z is OCH(CH3)(CH2)5, W is hydrogen, R4 is .beta.-methyl and R5 is hydrogen.

49. A process according to claim 13, wherein Z is OCH(CH3)(CH2)5, W is hydrogen and R4 and R5 are each methyl

50. A process according to claim 2, wherein there is employed as starting material a compound wherein Z is alkylene of from 1 to 9 carbon atoms and W is hydrogen or phenyl,

51. A process according to claim 50, wherein there is employed as starting material a compound wherein R1 is acetyl.

52. A process according to claim 50, wherein a compound of the formula:

wherein R4 and R5 are each hydrogen or methyl, R6 is hydro-gen, methyl or ethyl, Z is alkylene of 1 to 9 carbon atoms and W is hydrogen or phenyl is reacted with an alkali metal in liquid ammonia, the product thereof is acylated and then subjected to reduction with a metal hydride.

53. A process according to claim 51, wherein subse-quent to the reaction with alkali metal in liquid ammonia but prior to reduction with metal hydride the product is reacted with formaldehyde so that the product of the sub-sequent reduction with metal hydride is a compound whersin R6 is methyl.

54. A process according to claim 52, wherein subsequent to the reaction with alkali metal in liquid ammonia but prior to reduction with metal hydride the product is reacted with formaldehyde so that the product of the subsequent re-duction with metal hydride is a compound whexein R6 is methyl.

55. A process according to claim 51, wherein there is employed as starting material a compound wherein W is hydrogen.

56. A process according to claim 52, wherein there is employed as starting material a compound wherein W is hydrogen.

57. A process according to claim 53, wherein there is employed as starting material a compound wherein W is hydrogen.

58. A process according to claim 55, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl.

59. A process according to claim 56, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl.

60. A process according to claim 57, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl.

61. A process according to claim 58, wherein there is employed as starting material a compound wherein Z is C(CH3)(CH2)6-.

62. A process according to claim 59, wharein there is employed as starting material a compound wherein Z is C(CH3)(CH2)6-.

63. A process according to claim 60, wherein there is employed as starting material a compound wherein Z is -C(CH3)(CH2)6-.

64. A process according to claim 51, wherein the starting material employed is a compound wherein W is phenyl.

65. A process according to claim 52, wherein the starting material is a compound wherein W is phenyl.

66. A process according to claim 51, wherein the starting material employed is a compound wherein R4 and R5 are each methyl, R6 is hydrogen, Z is -CH(CH3)(CH2)3 and W
is phenyl.

67. A process according to claim 52, wherein the starting material employed is a compound wherein R4 and R5 are each methyl, R6 is hydrogen, Z is -CH(CH3)(CH2)3 and W
is phenyl.

68. A process according to claim 50, wherein subsequent to the reaction with alkali metal in liquid ammonia the cis and trans isomer products are separated prior to the sub-sequent reduction with metal hydride.

69. A process according to claim 68, wherein the starting material employed is one wherein R1 is acetyl, R4 is .alpha.-methyl, R5 and R6 are hydrogen, Z is CH(CH3)(CH2)3 and W is phenyl.

70. A process according to claim 68, wherein subsequent to said reaction with alkali metal in liquid ammonia the product is acetylated.

71. A process according to claim 70, wherein there is employed as starting material a compound wherein R1 is hydrogen, R4 is .alpha.-methyl, R5 and R6 are hydrogen, Z is CH(CH3)(CH2)3- and W is phenyl.

72. A process according to claim 1, for the production of a compound wherein Q is wherein there is employed as starting material a compound wherein R5 is hydrogen or methyl, each of R4 and R6 is hydrogen or alkyl, R1 is hydro-gen or alkanoyl, Z is -(alk1)m-O-(alk2)n and W is phenyl or hydrogen.

73. A process according to claim 72, wherein there is employed as starting material a compound wherein R1 is hydro gen and wherein subsequent to the reduction with alkali metal in liquid ammonia the product is acetylated to product a com-pound wherein R1 is acetyl.

74. A process according to claim 72, wherein there is employed as starting material a compound wherein Z is -O-(alk2)n and W is phenyl.

75. A process according to claim 73, wherein there is employed as starting material a compound wherein Z is -O-(alk2)n and W is phenyl.

76. A process according to claim 74, wherein R4 is .beta.-methyl and each of R5 and R6 is hydrogen.

77. A process according to claim 75, wherein R4 is .beta.-methyl and each of R5 and R6 is hydrogen.

78. A process according to claim 76, wherein Z is -O-CH(CH3)(CH2)3-.

79. A process according to claim 77, wherein Z is as -O-CH(CH3)(CH2)3-.

80. A process according to claim 72, wherein R1 is as defined in claim 72, R4 is .beta.-methyl, R5 is hydrogen or methyl, R6 is hydrogen, Z is -OCH(CH3)(CH2)5 and W is hydrogen.

81. A process according to claim 73, wherein R1 is acetyl, R4 is .beta.-methyl, R5 is hydrogen or methyl, R6 is hydrogen, Z is -OCH(CH3)(CH2)5 and W is hydrogen.

82. A process according to claim 5, wherein there is employed as starting material a compound wherein R4 is .beta.-methyl.

83. A process according to claim 5, wherein there is employed as starting material a compound wherein each of R4 and R5 is methyl.

84. A process according to claim 83, wherein there is employed as starting material a compound wherein R1 is acetyl.

85. A process according to claim 82, wherein there is employed as starting material a compound wherein Z is -OCH(CH3)(CH2)3, and W is phenyl.

86. A process according to claim 83, wherein there is employed as starting material a compound wherein Z is OCH(CH3)(CH2)3 and W is phenyl.

87. A process according to claim 82, wherein there is employed as starting material a compound wherein Z is OCH(CH3)(CH2)5 and W is phenyl.

88. A process according to claim 83, wherein there is employed as starting material a compound wherein Z is OCH(CH3)(CH2)5 and W is phenyl.

89. A compound of the formula:

wherein Q, R1, R4, R5, R6, W and Z are as defined in claim 1, whenever obtained by the process of claim 1 or an obvious equivalent thereof.

90. A compound of the formula:

wherein R is hydrogen or alkanoyl having from one to five car-bon atoms, R1 is hydrogen or an acyl group selected from ben-zoyl, 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 the same or different and 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, said ring being piperidino, pyrrolo, pyrrolidino, morpholino or N-alkyl-piperazino having from one to four carbon atoms in the alkyl group; R5 is hydrogen and each of R4 and R6 is hydrogen or alkyl of 1 to 6 carbon atoms, Z is alkylene of from one to nine carbon atoms or -(alk1)m-X-(alk2)n wherein each of alk1 and alk2 is the same or different and is alkylene of from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than nine, each of m and n is O or 1 and X is O, S, SO or SO2 and W is hydrogen, methyl, pyridyl or wherein W1 is hydrogen, fluoro or chloro, whenever obtained by the process of claim 2 or an obvious chemical equivalent thereof.

91. A compound according to claim 90, wherein R1 is hy-drogen or acetyl, Z is -(alk1)m-X-(alk2)n wherein alk1, alk2, m, n and X are as defined in claim 90 and W is hydrogen or phenyl whenever obtained by the process of claim 3 or an ob-vious chemical equivalent thereof.

92. A compound according to claim 90, wherein R1 is hy-drogen or acetyl, Z is -(alk1)m-O-(alk2)n wherein alk1, alk2, m and n are as defined in claim 90 and W is hydrogen or phenyl whenever obtained by the process of claim 4 or an obvious chemical equivalent thereof.

93. A compound according to claim 90, wherein R1 is hy-drogen or acetyl, Z is -O-(alk2)n wherein alk2 and n are as defined in claim 90, and W is hydrogen or phenyl whenever obtained by the process of claim 5 or an obvious chemical equivalent thereof.

94. A compound according to claim 90, wherein R1 is hydrogen or acetyl, Z is OCH(CH3)(CH2)3 and W is phenyl, whenever obtained by the pro-cess of claim 6 or an obvious chemical equivalent thereof.

95. A compound according to claim 90, wherein R1 is as defined in claim 90 and R6 is methyl, whenever obtained by the process of claim 7 or an obvious equivalent thereof.

96. A compound according to claim 90, wherein R1 is as defined in claim 90, and R6 is ethyl, whenever obtained by the process of claim 8 or an obvious equivalent thereof.

97. A trans isomer of a compound of the formula:

wherein R is hydrogen or an acyl group selected from alkan-oyl groups having from one to five carbon atoms; R1 is hydro-gen or an acyl group selected from benzoyl, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is O or an integer from 1 to 4; each of R2 and R3 when taken individually is the same or different and 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, said ring being piperidino, pyrrolo, pyrrolidino, morpholino or N-alkyl-piperazino having from one to four carbon atoms in the alkyl group; R4 is hydrogen, alkyl having from 1 to 6 carbon atoms or -(CH2)z-C6H5 wherein z is an integer from 1 to 4; R5 is hydrogen, methyl or ethyl, R6 is hydrogen, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms, -(CH2)x-C6H5 wherein x is an integer from 1 to 4, or -CO(CH2)x-1-C6H5; z is alkylene having from one to nine carbon atoms, or -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) is the same or different and is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than nine; each of m and n is 0 or 1; and X is O, S, SO or SO2; and W is hydrogen, methyl, pyridyl, wherein W1 is hydrogen, fluoro or chloro; whenever obtained by the process of claim 9 or an obvious equivalent thereof.

98. A trans isomer according to claim 97, wherein R6 is methyl, whenever obtained by the process of claim 10 or an obvious equivalent thereof.

99. A trans isomer according to claim 97, wherein R6 is ethyl, whenever obtained by the process of claim 11 or an obvious equivalent thereof.

100. A trans isomer according to claim 97, wherein R1 is acetyl, whenever obtained by the process of either of claims 12 and 13 or an obvious equivalent thereof.

101. A trans isomer according to claim 97, wherein Z is O-alk2 and W is hydrogen or phenyl, whenever obtained by the process of claim 14 or an obvious equivalent thereof.

102. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1 and R4 is .beta.-methyl, whenever obtained by the process of claim 17 or an obvious equivalent thereof.

103. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1 and R4 is .beta.-methyl, whenever obtained by the process of either of claims 18 and 25 or an obvious equivalent thereof.

104. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1 and R4 is .beta.-methyl, whenever obtained by the process of either of claims 16 and 27 or an obvious equivalent thereof.

105. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1, whenever obtained by the process of claim 21 or an obvious equivalent thereof.

106. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1, whenever obtained by the process of either of claims 22 and 26 or an obvious equivalent thereof.

107. A trans isomer of the formula:

wherein R and R1 are as defined in claim 1, whenever obtained by the process of either of claims 23 and 28.

108. A trans isomer of the formula:

wherein R is hydrogen or an acyl group selected from alkanoyl groups having from one to five carbon atoms and R6 is hydrogen, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; -(CH2)x-C6H5 wherein x is an integer from 1 to 4, or -CO(CH2)x-1C6H5; and R4 is methyl whenever obtained by the process of claim 29

109. A trans isomer of the formula:

wherein R is hydrogen or an acyl group selected from alkanoyl groups having from one to five carbon atoms and R6 is hydrogen, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; -(CH2)x-C6H5 wherein x is an integer from 1 to 4, or -CO(CH2)x-1C6H5; whenever obtained by the process of claim 30 or an obvious equivalent thereof.

110. A trans isomer according to claim 108, wherein R is as defined in claim 1 and R4 is .beta.-methyl, and R6 is methyl, whenever obtained by the process of claim 31 or an obvious equivalent thereof.

111. A trans isomer according to claim 109, wherein R6 is methyl, whenever obtained by the process of claim 32 or an obvious equivalent thereof.

112. A trans isomer of the formula:

wherein R, R1, R4, R5 and R6 are as defined in claim 1, whenever obtained by the process of claim 33 or an obvious equivalent thereof.

113. A trans former of the formula:

wherein each of R and R1 is hydrogen or alkanoyl of 1 to 5 carbon atoms and R6 is hydrogen or alkyl of 1 to 6 carbon atoms and R4 is .beta.-methyl whenever obtained by the process of claim 34 or an obvious equivalent thereof.

114. A trans isomer according to claim 113, wherein R6 is hydrogen, whenever obtained by the process of claim 33 or an obvious equivalent thereof.

115. A trans isomer according to claim 113, wherein R6 is methyl, whenever obtained by the process of either of claims 36 and 42 or an obvious equivalent thereof.

116. A trans isomer according to claim 113, wherein R6 is ethyl, whenever obtained by the process of either of claims 37 and 44 or an obvious equivalent thereof.

117. A trans isomer of the formula:

wherein each of R and R1 is hydrogen or alkanoyl of 1 to 5 carbon atoms and R6 is hydrogen or alkyl of 1 to 6 carbon atoms, whenever obtained by the process of claim 38 or an obvious equivalent thereof.

118. A trans isomer according to claim 117, wherein R6 is hydrogen whenever obtained by the process of claim 39 or an obvious equivalent thereof.

119. A trans isomer according to claim 117, wherein R6 is methyl, whenever obtained by the process of either of claims 40 and 43 or an obvious equivalent thereof.

120. A trans isomer according to claim 117, wherein R6 is ethyl, whenever obtained by the process of either of claims 41 and 45 or an obvious equivalent thereof.

121. A compound of the formula:

wherein R1, R4, R5, R6, W and Z are as defined in claim 72, whenever obtained by the process of claim 72 or an obvious equivalent thereof.

122. A compound according to claim 121, wherein R4, R5, R6, W and Z are as defined in claim 121 and R1 is acetyl, whenever obtained by the process of claim 73 or an obvious equivalent thereof.

123. A compound according to claim 121, wherein R1, R4, R5 and R6 are as defined in claim 121 and Z is -O-(alk2)n and W is phenyl, whenever obtained by the process of claim 74 or an obvious equivalent thereof.

124. A compound according to claim 121, wherein R1 is acetyl, R4, R5 and R6 are as defined in claim 121 and Z is -O-(alk2)n and W is phenyl, whenever obtained by the process of claim 75 or an obvious equivalent thereof.

125. A compound according to claim 121, wherein R1 is as defined in claim 121, R4 is .beta.-methyl, R5 and R6 are each hydrogen, Z is -O-(alk2)n and W is phenyl, whenever obtained by the process of claim 76 or an obvious equivalent thereof.

126. A compound according to claim 121, wherein R1 is acetyl, R4 is .beta.-methyl, R5 and R6 are each hydrogen, Z is O-(alk2)n and W is phenyl, whenever obtained by the process of claim 77 or an obvious equivalent thereof.

127. A compound according to claim 121, wherein R1 is as defined in claim 121, R4 is .beta.-methyl, each of R5 and R6 is hydrogen, Z is -O--CH(CH3)(CH2)3 and W is phenyl, when-ever obtained by the process of claim 78 or an obvious equivalent thereof.

128. A compound according to claim 121, wherein R1 is acetyl, R4 is .beta.-methyl, each of R5 and R6 is hydrogen, Z is -O-CH(CH3)(CH2)3 and W is phenyl, whenever obtained by the process of claim 79 or an obvious equivalent thereof.

129. A compound according to claim 121, wherein R1 is as defined in claim 121, R4 is .beta.-methyl, R5 is methyl or hydrogen, R6 is hydrogen, Z is -OCH(CH3)(CH2)5 and W is hydrogen, whenever obtained by the process of claim 80 or an obvious equivalent thereof.

130. A compound according to claim 121, wherein R1 is acetyl, R4 is .beta.-methyl, R5 is methyl or hydrogen, R6 is hydrogen, Z is -OCH(CH3)(CH2)5 and W is hydrogen, whenever obtained by the process of claim 81 or an obvious equivalent thereof.

131. A process according to claim 1, wherein said com-pound of the formula:

wherein R1, R4, R5, R6, Z and W are as defined in claim 1, has been obtained by reacting a compound of the formula:

wherein R1 is hydrogen, benzyl, methyl or ethyl and R7 is hydrogen or formyl with a base.