CA1053669A - Intermediate cyclopentane derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Cyclopentane derivatives useful as intermediates in the preparation of 15-substituted-.omega.-pentanorprostaglandins and processes for the preparation thereof, the said cyclo-pentane derivatives having the formula:

...I
wherein A is cycloalkyl of from three to ten carbon atoms, 1-adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl), 2-indanyl or substituted 2-indanyl wherein the substitutent is halo, trifluoromethyl, lower alkyl or lower alkoxy;
Q is hydrogen, p-biphenylcarbonyl or 2-tetrahydro-pyranyl;
n is an integer from 0 to 5;
Y is =0, or ; Z is a single bond or a trans double bond, and X is =0 or

Description

105~6~9 _ ASE 5446-A_D2 This invention relates to the preparation of certain novel cyclopentane derivatives useful in the preparation of novel analogs of the naturally occurring prostaglandins. In particular, it relates to the preparation of various novel intermediates useful in the preparation of the novel 15-substituted-~J-pentanorprostaglandins described and claimed in Patent Application No. 185,366.
In accordance with the present invention there is provided a proces, for preparing a compound of the formula:
_<

Q o~ L--~(CH2)n-~ I
%

wherein A is cycloalkyl of from three to ten carbon atoms, l-adamantyl, 2-norbornyl, 2-tl,2,3,4-tetrahydronaphthyl), 2-indanyl or substituted 2-indanyl wherein the substituent is halo, trifluoromethyl, lower a~kyl or lower alkoxy;
Q is hydrogen, p-b;phenylcarbonyl or 2-tetrahydro-pyranyl;
n is an integer from O to 5;
H
Y is =0, or < ; Z is a single bond or OH ,R 0 a trans double bond, and X is =O or ~ , wherein Q' is Q' hydrogen or 2-tetrahydropyranyl and R is hydrogen or lower alkyl, with the proviso that when Q' is 2-tetrahydropyranyl Q is also 2-tetrahydropyranyl and when Q is p-biphenylcarbonyl and X and Y are =0, Z is a trans douhle bond; which comprises (a) reacting a compound of the formula:
o-~

~ O~" C~lo wherein Q" is p-biphenylcarbonyl, with a compound of the formula: o A - (CH2)n - C - CH2 - P(OCH3)2 to form a product of the formula:
o~
.. . .

~ (CH2~n~~

wherein A, Q" and n are as defined above;
(b) reducing a compound of the formula IlIa:
' o~
Q30~ L~(c~2) n~A . ~ ~ IIIa wherein A, n and Z are as defined above, and Q3 is hydrogen or p-biphenylcarbonyl, to form a compound of the formula:
0~

Q~O ~ tCH2)n-A . .. I~t H R
wherein A, n, Q3 and Z are as defined above and R is hydrogen, and, if des;red, separating the 8d~- and 8 B-isomers;
, ~ -2A-~0536~;9 (c) reacting a compound of formula IA as defined above, with a suitable alkylating agent to afford a compound of formula IV wherein A, n, Q and Z are as defined above and R is lower alky';
(d) catalytically hydroyencting a compound of formula IV above, wherein A, n and R are as defined above, Q is hydrogen and Z is a trans double bond to afford a compound of formula IV wherein A, n and R are as defined above, Q3 is hydrogen and Z is a single bond; and, if desired, reacting a compound of formula IV above, wherein A, n, Z and R are as defined above and Q3 is biphenylcarbonyl with K2C03 to afford a compound of formula IV wherein Q3 is hydrogen; and, if desired, separating the 8 ~- and 8B -isomers;
(e) reacting a compound of the formula:
~y HO ~ / (CH 2 ) n-A
R~OH . . . IVa wherein A, n, R and Z are as defined above and Y is =0, with

2,3-dihydropyran in the presence of an acid catalyst to afford a compound of the formula:
Q- ~ ~

Q20~ ~ (CH2) n-A
R~'~oQ2 . . . v wherein A, n, R and Z are as defined above, Y is -0 and Q2 jS
2-tetrahydropyranyl, (f) reacting a compound of formula V, above, wherein ~ -2B-A, n, R and Z are as defined above and Y is =O with an appropriate reducing ~gent to afford a compound of formula V wherein A, n, R and Z are as defined above and Y is <
OH
(g) catalytically hydrogenating a compound of formula V above, wherein A, n and R are as defined above, Z is a trans double bond and Y is =O, to afford a compound of formula V wherein A, n and R are as defined above, Y is =O and Z is a single bond.
Examples of novel intermediates prepared by the 0 process of this invention are of the formulae below:
a compound of the formula:

~- ... IV

~ ~XR

a compound of the formula:
~y ~"'' ~
THPO' _ :~(C~2) nA
THP
a compound of the formula:

~-~
Ho~f CH2 ) nA
H

,.~

l(~S3~69 and a compound of ~he structure:
~, ~ ,~ (C112~A

wherein A is cycloalkyl of from three to ten carbon atoms, 1-adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl) wherein said group is racemic or optically act;ve, 2-indanyl or substituted 2-indanyl wherein the substituent is halo, tri-fluoromethyl, 'ower alkyl or lower alkoxy;
R is hydrogen or lower alkyl;
n is an inte(Jer from O to 5;
~ is hydrogen or p-biphenylcarbonyl;
THP is tetrahydropyranyl, Z is a single bond or trans double bond; and 'OH ~H
Y is =O, ' or \ H ~ OH
The process according to the invention may be illustrated by the reaction schemes which follow.

.

__, ., ~053669 Scheme A

~_~ ~CH2) n A
~ I

(~L~ 13 2)n A
~9 +

~J32)n~

~, (~,~Q{2)~

1~53~69 As shown in Scheme A, in 2--3 the oxophosphonate 2 is reacted with the known /Corey, et al., J. Am. Chem. Soc., 93, 1491 (1971~ aldehyde H to produce, after chromatography or crystallization, the enone 3. The compound in which the p-biphenyl carbonyl group is replaced with a p-biphenyl carbamoyl protecting group is also useful as a substitute for H and has the added benefit that in the reduction step (3~ 4) a higher percentage of the desired o~ isomer is produced.
The enone 3 can be converted to a mixture of tertiary alcohols 13 and 14 by reaction with the appropriate metallo alkyl and the isomeric 13 and 14 can be separated by column chromatography. The enone 3 can be reduced with zinc borohydride or with lithium trialkylborohydrides, such as lithium triethylborohydride, to a mixture of alcohols, _ and 5 which can be separated as above. In this reaction ethers such as tetrahydrofuran or l,2-dimethoxyethane are usually employed as solvents, although occasionally methanol is preferred to ensure specificity of reduction. Further trans-formations 4 are shown on Scheme B.
4 -~6 is a base catalyzed transesterification in whlch the p-biphenyl-carbonyl protecting group is removed.
This is most conveniently conducted with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6~7 involves the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory; however, the most usual one is tetrahydro-pyranyl, which can be incorporated in the molecule by treat-ment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid.

Scheme B

/;~, \~,~(CH2)A

~' ", q~3po~ ~CH2)n~A ~,~CH2)n A

, Scheme D illustrates the synthesis of precursors to the 13,14-dihydro-15-substituted-~-pentanorprostaglandins.
In 3~19 + 19' the enone 3 is reduced to the tetra-hydro compound through the use of any of the complex metal hydride reducing agents, LiAlH4, NaBH4, KBH4, LiBH4 and Zn(BH4)2. Especially preferred is NaBH4. The products, 19 and 19', are separated from each other by column chroma-tography.
Furthermore, the compounds 4 and 5 of Scheme A can be reduced catalytically with hydrogen to 19 and 19' respec-tively. The stage at which the double bond is reduced is not critical and hydrogenation of 6 or 7 of Scheme B will also afford useful intermediates for the 13,14 dihydro prosta-glandin analogs of the present invention. This reduction may be achieved with either a homogenous catalyst such as tris-tri-phenylphosphinechlororhodium (I), or with a hetero-geneous catalyst such as platinum, palladium or rhodium. In a similar way the precursors to the 15-lower alkyl-15-sub-stituted-~-pentanorprostaglandins are synthesized by sub-stituting compounds 13 and 14 for 4 and 5 respectively, in the synthesis jUQt described.

,1 ~t ~ul ` =I~ u~

~X

10536~9 The following examples are merely illustrative and in no way limit the ~cope of the appended claims. In these examples it will be appreciated that all temperatures are expressed in Centigrade, all melting and boiling points are uncorrected.

2- [3a~ Phenylbenzoyloxy-Sa-hydroxy-2~-(3-oxo-3-(2-indanyl)-trans-l-propen-l-yl)-cyclopent-la-yl]acetic acid, y-lactone:
To a solution, cooled in ice under nitrogen, of 17.2 ml. (32.6 mmoles) of a l.90M solution of n-butyllithium in hexane in lS0 ml. of dry 1,2-dimethoxyethane was added dropwise 9.2 g. (34.5 mmoles) of dimethyl-2-oxo-2-(2-indanyl)-ethylphosphonate. The solution was stirred in the cold for 10 minute~ then 11.9 g. (33.5 mmoles) of the known 2- [3a-lS ~phenylbenzoyloxy-Sa-hydroxy-23-formyl-cyclopent-la-yl]-acetic acid, y-lactone was added. The ice bath was removed;
the mixture was stirred for 1.0 hour then was quenched by the addition of glacial acetic acid (pH~S). The mixture was con-centrated and the resultant mixture was dissolved in methyl-ene chloride (300 ml.). The organic layer was washed with water (100 ml.), saturated sodium bicarbonate (S0 ml.),and saturated brine (50 ml.), was dried (anhydrous magnesium sulfate) and was concentrated to a semi-solid. Recrystal-lization of the crude product from isopropyl alcohol:methyl-ene chloride afforded the de~ired 2- [3a-~-phenylbenzoyloxy-Sa-hydroxy-2~-(3-oxo-3-(2-indanyl)-trans-1-propen-1-yl)cyclo-pent-la-yl~acetic acid, ~-lactone as white feathers melting at 170-172 and weighing 6.8S g. (42.896).
The ir spectrum (CHC13) of the product exhibited absorptions at 1775 cm~l for the lactone carbonyl, _g_ 1(~53ti69 at 1770 cm~l for the ester carbonyl, 1670 and 1625 cm~l for the ketone carbonyl and at 975 cm~l for the trans double bond.

.

u~ u~ In t` I` r~

o o o ,, _, _, _, o o o , o CO CO
F r~ ~ ~D
~) 1~ -- .
~ o o o t) `~ a _l _l , ,~
~ H Il~ O O
U~ ' ~ ~ I` I~
a~ ,~

1 ~
O o o O ~ . 00 0 I I I ;_ ~\
~¦ o 'I N

~rl In ~a ~
-- 11~ 1~

10536~9 2-(3a-~-Phenylbenzoyloxy-5-hydroxy-2~-(3-hydroxy-3-(2-indanyl)-trans-l-propen-l-yl)cyclopent-la-yl)acetic acid, y-lactone and 2-(3a-~-phenylbenzoyloxy-5a-hydroxy-3-(2-indanyl)-)-trans-l-propen-l-yl)cyclopent-la-yl)acetic acid, y-lactone.
To a solution of 6.73 g. (14.0 mmole) 2-(3a-p-phenylbenzoyloxy-5a-hydroxy-2~-(3-oxo-3-(2-indanyl)-trans-l-propen-l-yl)cyclopent-la-yl)acetic acid, y-lactone in 67 ml. dry tetrahydrofuran in a dry nitrogen atmosphere at ambient temperature was added dropwise 14.0 ml. of a 0.5M
zinc borohydride solution. After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise 14.0 ml. of a 0.5M zinc borohydride solution.
After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise, until hydrogen evolution ceased. The reaction m~Nre was allowed to stir for 5 minutes at which time 150 ml. dry methylene chloride was added. After drying (MgSO4~ and concentrating (water aspirator) the resultant semisolid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using mixtures of ethyl acetate:ether as eluents. After elution of less polar impurities a fraction containing 2.21 g. (32.8% yield) 2-(3a-phenylbenzoyloxy-5a-hydroxy-2~-~3a-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl) cyclopent-la-yl)acetic acid, y-lactone and a fraction contain-ing 1.79 g. (26.6% yield) of 2-(3a-~-phenylbenzoyloxy-5-hydroxy-23-(33-hydroxy-3-(2-indanyl)-trans-1-propen-yl)cyclo-pent-la-yl)acetic acid, lactone were collected.

~(~53S69 The ir spectrum (CHC13) both products had strong adsorption at 1770 cm~l (lactone carbonyl) and 1705 cm~
(ester carbonyl) and a medium adsorption at 970 cm 1 (trans olefln).

.

~ o o U~ U~ o o ~ o~
_ o o U~
Id ~ I` I` I~ I`

1~ 1` ~ ~ 1` 1`
_, O

o o ~ ~

X ~ , , , , , ,., ~~ ~ N
I 'O I 0 'O 0 s 1~",~ o o \~ m m a~
~n o a o ,~ ~ ~ a ~ ~ ." o m O O I I N N ~I j 'I ~ O S
~ ~ S ~ ~
~ 0 O~

ES~ Cn N N ~

, 2-[3,5~-Dihydroxy-2~-(3~-hydroxy-3-(2-indanyl)-trans-1-proleen-l-yl)cyclopent-l~-yl]acetic acid, y-lactone:
A heterogeneous mixture of 2.21 g. (4.46 mmole) of 2-[3-p-phenylbenzoyloxy-5~-hydroxy-23-(3-hydroxy-3-(2-indanyl)-trans-l-propen-l-yl)cyclopent-la-yl]acetic acid, y-lactone, 40 ml. of dry tetrahydrofuran, 40 ml. of absolute methanol and 0.61 g. of finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour, then cooled to 0. To the cooled solution was added 4.46 ml. of l.ON aqueous hydrochloric acid. After stirring at 0 for an additional 10 minutes, 75 ml. of water was added with con-comitant formation of methyl p-phenylbenzoate which was collected by filtration. The filtrate was concentrated by rotary evaporation then was extracted with ethyl acetate (3x), the combined organic extracts were dried ~MgS04) and were concentrated to give 924 mg. (66%) of viscous, oily 2-[3,5-dihydroxy-2~-(3-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)-cyclopent-l-yl]acetic acid, y-lactone.
The ir spectrum ~CHC13) exhibited a strong adsorp-tion at 1770 cm~l for the lactone carbonyl and a medium adsorption at 970 cm~l for the trans double bond.

105~6~ii9 ~,, h O
P~ ~
_ ~¢ U . h ~: _ o o 1~
~ ~ I` --I 1` 1` ~ o. O
U d a o ,~ o h ~ r o H

P~

o ~0 U

O ;, ~ O~1 0 0 0 0 h O
1 ~q O
4~
~ O
U ~

O '~
.,~ O
~a u I O o d o O

J~

I

, .

2- [5a-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-tetrahydro-pyran-2-yloxy]-3-(2-1ndanyl)-trans-l-propen-l-yl)cyclopent-.
la-yl]acetic acid, y-lactone:
To a solution of 0.924 g. (2.94 m~ole)-2-[3,5c~dihydmxy-2~- (3a-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-lc~-yl]acetic acid, y-lactone in 49 ml. anhydrous methylene chloride and 0.86 ml. of 2,3-dihydropyran at 0 in a dry nitrogen atmosphere was added a few crystals of p-toluene-sulfonic acid, monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml. ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml.) then saturated brine (1 x 15 ml.), dried (MgS04) and concentrated to yield 1.38 g. (97.8%) crude 2- [5a-hydroxy-3c~-(tetrahydropyran-2-yloxy)-2~B- (3a- [tetrahydropyran-2-yloxy]-

3-(2-indanyl)trans-1-propen-1-yl)cyclopent-la-yl]acetic acid, y-lactone which was used without purification.
The ir spectrum ~CHC13) of the product exhibited a strong absorption at 1755 cm~l for the lactone carbonyl and a medium absorption at 965 cm~l for the trans double bond.

h bq /~ ~ o ".~ ~

O

~a ~ I o o ~

o " ~!

~
O
C

.. : .
.
: .. . - . : ' . .

2-[5-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydro-pyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetaldehyde, y-hemiacetal:
A solution of 1.39 g. (2.9 mmole) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetic acid, y-lactone in 20 ml. dry toluene was cooled to -78, in a dry nitrogen atmosphere. To this cooled solution was added

4.2 ml. of 20~ diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65 (15 minutes). After an additional 30 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and was concentrated by rotary evaporation. The resultant oil was slurried in methanol then was filtered to remove aluminum salts. Concen-tration of the filtrate afforded the crude product which was purified by silica gel (Baker "Analyzed" 60-200 mesh) column chromatography using mixtures of benzene:ethyl acetate as elements. After removal of less polar impuritie~ the desired 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydro-pyran-2-yloxy)-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetaldehyde, r-hemiacetal as a viscous oil weighing 1.17 g. (84.3%).
The ir spectrum (CHC13) of the purified product exhibited a medium absorption at 975 cm~l for the trans double bond and no carbonyl absorption.

lOS;~669 U C~ U

.C m ~ ~¦ U
O ~ H a~ n h O \~~ _ O
O

O

~1 ~
a O

_~ O
S

10S~669 2-[5-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-tetrahydro-pyran-2-yloxy)-8-(1-adamantyl)oct-1-yl)cyclopent-la]acetic ac$d, y-lactone (24e):
A heterogeneous mixture of 2.39 g. (4.2 mmoles) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-(tetrahydro-pyran-2-yloxy)-8-(1-adamantyl)-trans-1-octen-1-yl)cyclopent-la-yl]acetic acid, y-lactone and 239 mg. of 5% palladium in carbon in 25 ml. of absolute methanol is stirred under 1 atmosphere of hydrogen for 2 hours. The reaction mixture is filtered (Celite) and concentrated to provide 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-(tetrahydropyran-2-yloxy)-8-(1-adamantyl)oct-1-yl)cyclopent-la-yl]acetic acid, y-lactone.

2-[3a-~-Phenylbenzoyloxy-5a-hydroxy-2~-(3a-hydroxy-3~-methyl-

5-tl-adamantyl)-trans-1-penten-1-yl)cyclopent-la-yl]acetic acid, y-lactone and 2-[3-~-phenylbenzoyloxy-5-hydroxy-2~-(3~-hydroxy-3a-methyl-5-(1-adamantyl)-trans-1-penten-1-yl)-cyclopent-la-yl]acetic acid, y-lactone:
To a solution of 2.15 g. (4.0 mmoles) of 2-[3a-~-phenylbenzoyloxy-5a-hydroxy-2~-(3-oxo-5-(l~adamantyl)-trans-l-penten-l-yl)cyclopent-la-yl]acetic acid, y-lactone in 21 ml. of anhydrous ether and 20 ml. of tetrahydrofuran in a dry nitrogen atmosphere at -78 is added dropwise 4.0 ml. of a (l.OM) solution of methyllithium in ether (Alfa). After stir-ring at -78 for 15 minutes the reaction is quenched by the addition of glacial acetic acid until the pH of the mixture lOS~6~9 ie approximately 7. ~he mixture is then diluted with methyl-ene chlor~de and the diluted organic solution i9 washed with water and saturated brine, is dried (anhydrous magne~ium sulfate) and 19 concentrated to afford the epimeric alcohols.
The crude product is purified by column chroma-tography on silica gel to provide the 2-[3-~-phenylbenzoyl-oxy-Sa-hydroxy-2~-(3~-hydroxy-3~-methyl-5-(1-adamantyl~-trans-l-penten-l-yl)cyclopent-la-yl]acetic acid, y-lactone and the 2-13a-~-phenylbenzoyloxy-Sa-hydroxy-2~-(3~-hydroxy-3-methyl-5-(1-adamantyl)-trans-1-penten-1-yl)cyclopent-1~-yl]acetic acid, y-lactone.

N-Benzoyl 9-oxo-11~,15-bi~-(tetrahydropyran-2-yloxy)-15-(2-(5,6-dimethoxylndanyl))-5-ci~-13-tran~-~-pentanorpro~ta-dienamides To a olutlon, undor nltrogon, of 594 mg. (1.0 mmolo) of tho 9-oxo-11~,15~-bl~-~totrahydropyran-2-yloxy)-15-~5,6-dlmethoxylndanyl))-S-cl~-13-tran--~-pentanorprosta-dlenoic acld in 6 ml. of dry tetrahydrofuran i~ added 102 mg.
(1.0 mmole~) of trlethylamlne. The solution 1~ stlrred for 1 mlnute then 1.2 ml. of a l.OM ~olutlon of benzoyl i90-cyanate in tetrahydrofuran is added. The solutlon i5 stirred for an additional 10 minute~, then is quenched by the addi-tion of glacial acetic acid. The quenched solution is concen-10536~9 trated and the residue dissolved in ethyl acetate (20 ml.), is washed with water (lx), dried (anhydrous magnesium sulfate) and is concentrated to provide the desired N-benzoyl 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-(5~6-di-methoxyindanyl))-5-cls-13-trans-~-pentanorprostadienamide which is used without purification.

2-[3a,5a-Dihydroxy-2~-(3a-hydroxy-3-(2-indanyl)-trans-1-_ ProPen-l-Yl)cYclopent-l-yl]acetaldehyde, y-hemiacetal:
To a solution, cooled to -78, of 750 mg. (1.5 mmole) of the 2-[3a-~-phenylbenzoyloxy-5a-hydroxy-2~-(3a-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]-acetic acid, y-lactone in 15 ml. of toluene is added 7.5 ml.
of a 20% solution of diisobutylaluminum hydride in hexane (Alfa). The reaction mixture is stirred in the cold for 1.0 hour, then is quenched by the addition of methanol until gas evolution ceases. The quenched mixture is let warm to room temperature then is concentrated. The residue is stirred with methanol (3x) and is concentrated. Purification of the crude product by silica gel chromatography affords the desir-ed 2-[3a,5a-dihydroxy-2~-(3a-hydroxy-3-(2-indanyl)-trans-1-propen-l-yl)cyclopent-la-yl]acetaldehyde, y-hemiacetal.

Claims (3)

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

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

...I

wherein A is cycloalkyl of from three to ten carbon atoms, 1-adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl), 2-indanyl or substituted 2-indanyl wherein the substituent is halo, trifluoromethyl, lower alkyl or lower alkoxy;
Q is hydrogen, p-biphenylcarbonyl or 2-tetrahydro-pyranyl;
n is an integer from 0 to 5;
Y is =0, or ; Z is a single bond or a trans double bond, and X is =0 or wherein Q' is hydrogen or 2-tetrahydropyranyl and R is hydrogen or lower alkyl, with the proviso that when Q' is 2-tetrahydropyranyl Q is also 2-tetrahydro-pyranyl and when Q is p-biphenylcarbonyl and X and Y are =0, Z is a trans double bond; which comprises (a) reacting a compound of the formula:

wherein Q" is p-biphenylcarbonyl, with a compound of the formula:

to form a product of the formula:

... IA

wherein A, Q" and n are as defined above;
(b) reducing a compound of the formula IIIa:

...IIIa wherein A, n and Z are as defined above, and Q3 is hydrogen or p-biphenylcarbonyl, to form a compound of the formula:

... IV
wherein A, n, Q3 and Z are as defined above and R is hydrogen, and, if desired, separating the 8 .alpha.- and 8 .beta.-isomers;
(c) reacting a compound of formula IA as defined above, with a suitable alkylating agent to afford a compound of formula IV wherein A, n, Q3 and Z are as defined above and R is lower alkyl;
(d) catalytically hydrogenating a compound of formula IV
above,wherein A, n and R are as defined above, Q3 is hydrogen and Z is a trans double bond to afford a compound of formula IV
wherein A, n and R are as defined above, Q3 is hydrogen and Z is a single bond; and if desired, reacting a compound of formula IV
above, wherein A, n, Z and R are as defined above and Q3 is biphenylcarbonyl with K2CO3 to afford a compound of formula IV

wherein Q3 is hydrogen; and, if desired, separating the 8?-and 8 .beta. -isomers;
(e) reacting a compound of the formula:

...IVa wherein A, n, R and Z are as defined above and Y is =0, with 2,3-dihydropyran in the presence of an acid catalyst to afford a compound of the formula:

...V

wherein A, n, R and Z are as defined above, Y is =0 and Q2 is 2-tetrahydropyranyl;
(f) reacting a compound of formula V, above, wherein A, n, R and Z are as defined above and Y is =0 with an appropriate reducing agent to afford a compound of formula V wherein A, n, R and Z are as defined above and Y is ;
(g) catalytically hydrogenating a compound of formula V
above, wherein A, n and R are as defined above, Z is a trans double bond and Y is =0, to afford a compound of formula V
wherein A, n and R are as defined above, Y is =0 and Z is a single bond.

2. A compound of the formula:

... IA

wherein A and Q" are as defined in claim 1, when prepared by a process according to claim 1(a) or an obvious chemical equivalent thereof.

3. A compound of the formula:

...IV
wherein n, A, R, Z and Q3 are as defined in claim 1, when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.