CA1069520A - PROCESS FOR THE PRODUCTION OF BICYCLIC 3.alpha.-HYDROXY LACTONE INTERMEDIATES USEFUL IN THE PREPARATION OF PROSTAGIANDIN_TYPE COMPOUNDS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention comprises an improved process whereby bicyclic lactones useful in the preparation of prostaglandin-type (PG-type) compounds are produced. In particular the process provides a method whereby the poten-tial 15.alpha.-hydroxy of a PG-type compound is introduced with high stereo-selectivity into the lactone side chain by reduction of a side chain oxo moiety.

Description

BACKGROUND OF THE INVENTION
The prostaglandins are a family of pharmacologically useful 20 carbon atom cyclopentane derivatives. They in-clude, for example PGF3a, PGF2a, PGFlaJ and corresponding PGE, PGA, PGB, and PGF~ compounds. Each of these prcsta-glandins may be considered as a derivative of prostanoic acid, which has the following structure and carbon atom numbering - ~ H

See for reference~ Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and the references cited therein.
Heavy solid lines in the above formula and the for-mulas hereinafter represent attachment of substituents above the plane of the cyclopentane ring (i.e., the beta configuration). Broken line attachments indicates attach-ment of substituents below the plane of the cyclopentane ring (i.e., the alpha configuration). When wavy lines are employed in connection with the formulas herein, attach-ment of substituents is in either the alpha or beta con-figuration, or as a mixture of a and ~ isomers.
Thus, for example PGF2 a, which is represented as ~5 follows:

HO
~ - " ==~" "--"-`COOH II

HO

has a hydroxy substituent at each of positions C-9, C-ll, and C-15 which is in the alpha configuration. Expressions such as C-9, C-ll, and C-15 refer to the carbon atom of the prostaglandin or prostaglandin analog which is in the posi-tion corresponding to the position of the same number inprostanoic acid~
The C-15 alcohol function of PGF2a above is in the S
configuration. See, Nature, 212, 38 (1966), for a discuss-ion of this and other stereochemical features of the prosta-glandins.
Likewise there are known in the art analogs of theseprostaglandins which are known to be useful for the same pharmacological purposes as the prostaglandins~ In parti-cular, many of these analogs, while maintaining the same cyclopentane ring structure of one of the various prosta-glandins, exhibit variation in the C-7 alpha side chain or C-13 beta side chainj or both.
Further, 3aJ5a-dihydroxy-2~-(3-oxo-trans-l-octenyl)-la cyclopentaneacetic acid y lactone, 3-acetate or 3-phenyl-benzoate (E. J. Corey, et al., J. Am. Chem. Soc. 92 ~97(1970) and E. J. Corey, et al., 93, 1491 (1971)) is known to be a useful 3-oxo bicyclic lactone intermediate in pre-paring optically active PGF2a and PGE~. This bicyclic lac-tone is represented by the formula ,0~

1~6~zo wherein Rl1 is acetyl or p-phenylbenzoyl. When prosta-glandin analogs, exhibiting variation in the C-1~ beta side chain as is known in the art, are to be prepared, corresponding bicyclic lactones useful in the preparation of these analogs are known according to the following for-mula:

~ I V
H
~C=C ~
R12d H `ICl-fi-R7 wherein L1 is / `
R3 R4, ,'~ .R3 R4, 20or a mixture of /"

and , \
R3 R4, wherein R3 and R4 are hydrogen, methyl or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro, only when the other is hydrogen or fluoro;
wherein R7 is (1) -(CH2)k-CH3, wherein k is 2 to 6, ~249 ~0~9~

inclusive,

(2) o ~--(T)s whe.rein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl, the various T's being the same or different,

(3) -CHe ~_(T)s , wherein T and s are as defined above, or (4) cis-CH=CH-CH2-CH3, with the proviso that R7 is (T)s only when R3 and R4 are hydrogen or methyl, being the same or different; and wherein R12 is hydrogen or carboxyacyl.
Each of the formulas herein which represents a prosta-glandin, a prostaglandin analog, or an intermediate there-for depicts the optically active form of the compound. ::
tn particular the optical isomer so represented is of the same relative stereochemical configuration as the corres-ponding prostaglandin obtained from mammalian tissues, or, if an intermediate,is of that stereochemical configuration which will yield the corresponding prostaglandin-type pro-~O~

duct which is of the same relative stereochemical configura-tion as the corresponding prostaglandin obtained from mammalian tissues.
Each of the above prostaglandins or prostaglandin analogs (i.e., prostaglandin-type compounds~ is named according to the system of nomenclature which designates each skeletal position and the particular substitution or structural variation from the corresponding parent prosta-glandin at that position. This system of nomenclature is described in N. A. Nelson, J. of Med. Chem. 17, 911 (1974) .
For the 3-oxo lactones of formula IV to be transformed to corresponding prostaglandin-type compounds (i.e., prosta-glandins or prostaglandin analogs) the 3-oxo moiety of the beta side chain of the formula III or formula IV compound must be reduced to form a corresponding 3-hydroxy lactone wherein the 3-hydroxy is the potential 15-hydroxy of an ultimate PG-type compound.
In many cases it is desirable to obtain the 3a-hydroxy epimer in preference to the 3~-hydroxy epimer since this stereochemical feature is preserved in subsequent transfor-mations to prostaglandin-type compounds by methods known in the art. Thus, there are prepared compounds with the same configuration at C-15 as PGF2a of formula II, and these com-pounds exhibit in many cases the more desired pharmacolo-gical properties. Accordingly, muth effort has been direc-ted at achieving stereochemical control of the reduction described above.
Methods disclosed in the prior art for effecting stereochemical control of the reduction have used various organic moieties in place of the Rll or Rl2 group in the 3~1~9 ~C~ 2 0 -formula-lll or formula-lV compound together with certain agents. For a discussion of the use of p-phenylbenzoyl/
andcarbamoyls such as p-phenylphenyl carbamoyl and phenyl-carbamoyl moieties in place of R11 or R12 in combination with reducing agents such as lithium limonene thexyl borohydride, i.e .J

H C(CH3 )2 -CH(CH3 )2 \B/

l ~
"-'f CH3 J

lithium thexyl-di-sec-butyl borohydride, and lithium tri-sec-butyl borohydride, see E. J. Corey, et al., J. Am.
Chem. Soc. 94, 8616 (1972).
FurtherJ a discussion of the preparation and use of lithium tri-sec-butyl borohydride is provided by H. C.
BrownJ et al.J J. Am. Chem. Soc. 94: 7159 (1972). Like-wiseJ a discussion of the preparation and use of potassium tri-sec-butyl borohydride is provided by C. A. erown, J. Am.
~hem. Soc. 9~. 4101 (1973).
SUMMARY OF THE INVENTION
A purpose of this invention is to provide a novel pro-cess suitable for large-scale production of bicyclic ~-hydroxy lactone intermediates useful in the preparation ofprostaglandin-type compounds.
A further purpose is to provide in the above-described process a method, which highly stereoselectively reduces the 3-oxo bicyclic lactone (e.g. formula lll or IV) to a corres-ponding 3~-hydroxy bicyclic lactone.

324y ~6~ S Z~

Accordingly, the present inv~ntion provides a novel process for preparing highly stereoselectively a 3a-hydroxy bicyclic lactone of the formula 10 4~

Rl30 ~ ~/C - C - R7 V
0.
wherein L1 and R7 are as defined above; and wherein Rl3 is a directing group as is defined below;
from a corresponding 3-oxo bicyclic lactone of the formula ~
,0 >

R ~ ~ C=C~ Vl Il 11 which comprises: .
highly stereoselectively reducing said bicyclic 3-oxo lactone with a potassium trialkyl borohydride of the formula 25K B~3H ( H (CH2)m-cH3 ~
(cH2)m+l-cH3J 9 wherein m is zero, one, 2, or 3.
The directing groups (R~3) which are useful for the ~49 ~0~9~20 purposes of the present invention are (1) -C-NH ~ R1 wherein R1 and R2 are hydrogen chloro, fluoro, bromo, alkyl of one to ~ carbon atoms, inclusive, or alkoxy of one to carbon atoms, inclusive, being the same or different; or (2) -C-N ~ - ~ Re ~1 wherein R1 and R2 are as defined above, being the same or different for each phenyl ring.
Especially preferred directing groups for the pur-poses of this invention are phenylcarbamoyl, i.e., -l-NH~

and p-tolylcarbamoyl, i..e., -C-NH ~ CH3 Other preferred directing groups include those wherein one of R1 and R2 is hydrogen and the other is methyl, methoxy, or chloro.
The reducing agents useful in this invention are a g g~rlus ol polussiulll Lriall<yl borolly(l~ s, i.e.

~ (CH2 )m-Cl l~
K~ B~ H ~ -CH
(CH2)m+l-CH3 J 3 '' ' /

wherein m i5 as defined above. For the purposes of this invention, it is especially preferred that the borohydride of the above formula wherein m = 0 be employed, that is, potassium tri sec-butyl borohydride.
Accordingly, the present invention, and particularly the preferred embodiments thereof, described above, provide surprising and unexpected advantages over procedures des-cribed in the prior art in the accomplishment of the pur-poses of the invention.
First, the present invention is surprisingly and un-expectedly more stereoselective than prior art procedures, and accordingly the ratio of alpha to beta hydroxy bicyclic lactone product produced is surprisingly and unexpectedly increased.
Second, the present invention is surprising and un-expectedly more useful for large scale or commercial produc-tion of its end-products in that:
(1) the direçting groups employed herein avoid the use of.groups (eOgO, p-phenylphenylcarbamoyl) known to pro-duce carcinogenic or suspected-carcinogenic by-products, .. ;~
(2) the reducing agent employed herein is simply, directly, and economically prepared, (3) the reaction conditions required to achieve opti-~0 mum stereoselectivity are less severe than those of the ~249 ~5~) prior art, and,

(4) the employment of this process permits crystalli-zation of an essentially pure 2J3,4,5,6-pentanor-PGF1a-type compound, to the exclusion of the 15P-hydroxy epimer, thereby obviating the need for a chromatographic separation of C-15 epimeric mixtures of PG-type products.
Reference to Chart A will make clear the operation of the novel process of this invention. L1, R7, and R13 are as defined above. M is potassium~ sodiumJ or lithium.
The formula Xl compound is known in the art or readily prepared by methods known in the art. The formula Xl com-pound is transformed into the formula Xll compound by replacement of the cyclopentane ring ~-hydroxy hydrogen with a directing group according to Rl3. When R13 is a phenyl or substituted phenylcarba~oyl directing group, the corresponding phenyl or substituted phenyl isocyanate of the formula 0=C-N ~ R1 wherein R1 and R2 are as defined above, is employed. The reaction is carried out preferably at zero to 25 C. The reaction is advantageously carried out in a pyridine dilu-ent or in a diluent such as tetrahydrofuran which containsa catalytic amount of pyridine. AlternativelyJ other pyridine-type bases may be employed such as the picolines and lutidines. Stronger tertiary amine bases (e.g. tri-ethylamine) are likewise useful. However, by the preferred ~0 method pyridine alone is used as a reaction diluent.

~ . .

CHART A

<~\ C~H XI

H 0 H~ \C - C - R7 ~I ;
' ' ' ~0~ ~

~ C-C-- ' R 13H/ ~ IC - ~ - R7 ,1, . ~ .

: lo ~

. Xlll ~H
~C=C ,;,~
R 1 30 ~ L

~ :

.

~ ' .

~l)69SZ~3 .

CHART A (conti nued) HO
,~ ~", CH2COO M+
<~ /H X I V

~r-C
13 H /C~ 5_ R7 - bH L-:
HO~
, CH2 -COO -M+
< I XV

HO' H~ ~C -C R7 H ~)H Ll .
-\ / ~ ' , HO
`~ , CH2 - C OOH
<~~[ XVI
? H
HOH . /C~--C R7 H OH L, - ~ .

/1 .
0~ ~

~' XVI I
~ C=C / H
HO H~ /C~ C R7 H OH

-13- .
'~ .' -~ .

~ 2 ~

When the reaction is complete, by-products, such as N,N'-diphenylurea, or a corresponding substituted phenyl urea, are separated from the formula Xll product by cry-stallization thereof. However, by the preferred method purification by crystallization is omitted and the crude reaction product is used in the subsequent process steps of Chart A, as discussed above.
When R13 is a diphenyl carbamoyl directing group, the formula Xll compound is prepared from the formula Xl com-pound using the corresponding diphenyl carbamoyl chlorideor substituted diphenyl carbamoyl chloride of the formula R ~ \ N C ~
R1 / \ Cl wherein R~ and R2 are as defined above. The reaction pro- -`
ceeds by addition of one equivalent of sodium hydride to the above mixture. When the reaction is complete, any ex-cess sodium hydride is destroyed by the addition of an organic acid, e.g. acetic acid. Pure product is optionally recovered from the reaction mixture using conventional methods.
The formula XIII compound is obtained from the formula X!l compound by the novel highly stereoselective reduction of the present invention. This reduction proceeds at low temperatures, from -78 C. to -120 C., in order to achieve high selectivity. It is especially preferred that temper-~2 49 1Vf~9~20 atures of about -110 C. be employed. The reaction diluent for this reduction preferably comprises a mixture of diethyl ether and tetrahydrofuran in a ratio of ~ to 1.
While different ratios of this diluent mixture are useful in this invention, the freezing point of tetrahydrofuran (-65 C.) prohibits its exclusive use. However, the pre-sence of sufficient tetrahydrofuran to insure solution of reactants is desired.
A further requirement for this reduction, and the successive steps herein prior to the extraction of the borane (fro~ formula XIV), is that all reactants be made oxygen-free by bubbling nitrogen there through.
This procedure is required in order ~o avoid destruction of the trialkyl borane produced in the reduction of the formula XII compound.
The reduction is then accomplished by the addition of a potassium trialkyl borohydride of the formula ~ / (CH2)m-CH
K~3 B ( -CH
~ (CH2)m+1-C ~ 3 wherein m is as defined above. Preferably 1.2 to 1.4 molecular equivalents of potassium trialkyl borohydride per molecular equivalent of formula XII compound are employed.
The potassium trialkyl borohydrides of the above for-mula are prepared from the corresponding trialkyl boranes of the formula 3o 32~9 ~069~Z~3 ~ / (CH2)m-CH3 ~
B ~ -CH ) , (CH2)m~1-C ~ 3 wherein m is as defined above, by reaction of these boranes with potassium hydride. Procedures known in the art for potassium hydride reactions of trialkyl boranes are employed. See, for reference, C. A. Brown cited above.
These boranes are prepared by any of several methods known in the art. By a preferred method they are obtained from the reaction of diborane with an olefin of the formula CH3-(CH2)m-CH=CH-(CH2)~-CH3 wherein m is as defined above, by prior art procedures.
The formula XIV compound is then prepared by opening the lactone ring of the formula XIII compound. For this purpose sodium, potassium, or lithium hydroxide is advan-tageously employed in an aqueous solution as is known in the art.
The above solution containing the formula XIV com-pound further contains the trialkyl borane produced in the reduction of the formula XII compound to the formula XIII
compound. It is preferred that the trialkyl borane be separated from the formula XIV compound, for example, by extraction with diethyl ether, and that the trialkyl borane so obtained be reacted with potassium hydride, as discussed above, to regenerate the potassium trialkyl borohydride useful in the reduction step XII to XIII.
The formula XV compound i5 then prepared from the formu1a XIV compound by hydrolysis of the directing group.
This hydrolysis is accomplishéd by methods known in the art, for example, by addition of lithium, potassium, or preferably sodium hydroxide to the formula XIV compound with heating. The reaction is normally complete 7n about 24 hours at a reaction temperature of about 85 C., al-though higher temperatures are employed to shorten the reaction time.
The formula XVI compound is then prepared from the formula XV compound by separation of the formula XV com-pound from undesired organic by-products, followed by acidification and crystallization. The extraction of the undesired organic by-product proceeds by first adjusting the pH of the solution containing the formula XV compound to about 9.0 by addition of a mineral acid, e.g. phosphoric acid. Extraction of the resulting pH-adjusted mixture then proceeds by addition of an organic diluent, prefer-ably dichloromethane. The dichloromethane extract con-tains these undesired organic by-products, and such extract is accordingly discarded. Acidification thereafter pro-ceeds by careful cooling of the aqueous phase (0-5 C.) and acidifying to pH 4 by further addition of a mineral acid. Thereafter the desired formula XVI product may be recovered by extraction, for example, with ethyl acetate, and crystallization, which is achieved by conventional methods.
As obtained by the above procedure, the formula XVI
compound is obtained in crystalline form which substan-tially excludes the corresponding 15~-hydroxy epimer of the formula XVI compound. Accordingly, the above procedure -17~

~249 10~

eliminates the need for chromatographic separation of the 15a- and 15~-hydroxy epimers produced by the reduction described for the preparation of the formula XIII compound from the formula XII compound.
The formula XVII compound is known to be a highly use-ful intermediate for preparing various PGFJ PGE, PGA, and PGB-type compounds. For example, the formula XVI compound is converted to the corresponding formula XVII lactone by methods known in the art, and the formula XVII lactone is known to be a highly useful intermediate in the prepara-tion of the above-mentioned prostaglandin-type compounds.
DESCRIPTION OF THE PREFERRED EMBOD!MENTS
The invention can be more fully understood by the following examples and preparation:
All temperatures are in degrees centigrade.
IR (infrared) absorption spectra are recorded on a Perkin-Elmer Model 421 infrared spectrophotometer. Except when specified otherwise, undiluted (neat) samples are used.
UV (ultraviolet) spectra are recorded on a Cary Model 15 spectrophotometer.
NMR (Nuc!ear Magnetic Resonance) spectra are recorded on a Varian A-60, a-60D, or T-60 spectrophotometer on a deuterochloroform solutions with tetramethylsilane as an interna1 standard.
Mass spectra are recorded on an CEG model 1108 Double Focusing High Resolution Mass Spectrometer or an LKB Model 9000 Gas-Chromatograph-Mass Spectrometer. Trimethylsilyl derivatives are used, except where otherwise specified.
"Brine", herein, refers to an aqueous saturated sodium chloride solution.

5~
.
The A-IX solvent system used in thin layer chromato-graphy is made up from ethyl acetate-acetic acid-2,2,4-tri-methylpentane-water (90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966).
"Skellysolve-B (SSB) refers to mixed isomeric hexanes.
Silica gel chromato~raphy, as used herein, is under-stood to include elution, collection of fractions, and co~bination of those ~ractions shown by TLC (thin layer chromatography) to contain the desired product free of starting material and impurities.
Melting points (MP) are determined on a Fisher-Johns melting point apparatus.
THF refers to tetrahydrofuran.
Specific Rotations, [a], are determined for solutions f a compound in the specified solvent at ambient tempera-ture with a Perkin-Elmer Model 141 Automatic Polarimeter.
Example 1 2,~,4,5,6-Pentanor-PGF1a prepared from 3a, 5a-dihydroxy 2~-(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid y lactone using a phenylca~ ~oyl directing group (Formula XVI:

is n-pentyl).
A. 3a,5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid y lactone (3.97 9.) ;s dissolved in

6 ml. of dry pyridine. To the resulting solution under a nitrogen atmosphere is added a solution of phenylisocyanate (2.14 9.) and dry pyridine (6 ml.) cooled to ~ C. The addition proceeds dropwise over a perTod of 3~ min. The .~ ,, .

~ s~
above reaction mixture is then stirred at 0 C. for an additional ~0 min. then allowed to warm to room temperature with stirring until the reaction is shown to be complete by thin layer chromatography (ethyl acetate in Skellysolve~
B; 1 lJ . The reaction proceeds to completion in about 18 hours, thereby yieIding the phenylurethane deiivative of the lactone starting material.
The pure product above is optionally recovered by adding 10 to 15 volumes of water to the reaction mixture and thereafter extracting with 45 ml. of ethyl acetate. The combined ethyl acetate layers are washed once with water and -twice with a one molar aqueous solution of phosphoric acid.
Finally, the organic phase is then washed with water, dried over sodium sulfateJ and evaporated under reduced pressure at 35 C. to yield an oil. This oil is then dissolved in benzene and cooled to about 5 C., maintaining that tem- ~
perature for one hour. A diphenylurea precipitate forms and this precipitate is filtered and washed with cold benzene.
The organic phase is then evaporated under vacuum yielding 6.05 9. of the pnenylurethane derivative of the lactone starting material. On recrystallization from methanol this product exhibits a melting point at 92-94 C. NMR absorp-tions in deuterochloroform at 5.1, 6.15, 6.7, and 7.3 ~.
Also characteristic infrared absorptions are observed at 1695, 1730, and 1770 cm. 1.
B. With exclusion of moisture 6.0 9. of the reaction product of part A above is dissolved in 25 ml. of dry tetrahydrofuran and the resulting mixture is thereafter diluted wlth 120 ml. of dry diethyl ether. Oxygen is then excluded from this solution by bubbling nitrogen through the 3 i i~
. ~, ~, ~, , .

~2~'3 ~N~9 ~ Z ~ ' solution for several minutesO This solution under nitrogen atmosphete is then cooled to -110 C. in a 95 percent ethanol-bath cooled first with dry ice to -78 C. and thereafter further cooled to -110 C. with intermi~ent addition of liquid nitrogen so as to maintain the reaction temperature. To this cooled solution is then ad~ed 54.8 ml. of 0.5 M potassium tri-sec-butyl borohydride in tetra-hydrofuran diluted to a 100 ml. volume by addition of dry diethyl ether. The addition proceeds dropwise over a per-iod of 2-3 hours. Reaction progress is monitored by thin layer chromatography (ethyl acetate and,Skellysolve B;

7:3). The addition of the potassium tri-sec-butyl boro-hydride solution is terminated when the starting material is consumed. The reaction is then quenched by addition of 10 ml. of oxygen-free methanol and 25 ml. of oxygen-free water. The reaction mixture is then allowed to warm to 10-20 C. The formula Xlll lactone thereby,formed is used in the steps below without further purification or charac-terization.
C. To the reaction product of part B above is added with stirring 9 ml. of oxygen-free 10 percent aqueous sod-ium hydroxide. The reaction mixture is allowed to warm to room temperature and the progress of the reaction is mon-itored by thin layer cl-r~r~Lography to completion.
2~ ri-sec-butyl borane is then extracted from the reaction product of part C above by adding 25 ml. of oxygen^free water to the reaction mixture, shaking~ and thereafter separating the lower aqueous phas,e. The organic phase is then,washed once with a partially saturated sodium chloride solution which is then added to the aqueous ex- ' ~6~

tract. The combined aqueous layers are then extracted with diethyl ether. There results from this extraction three layers: an aqueous layer, a tetrahydrofuran-containing layer, and the ethereal layer. The ethereal layer is com- ~-bined with the organic phase obtained above and this com-bined organic phase is dried over magnesium sulfate and evaporated to an oil under oxygen-free conditions. This oil consists essentially of tri-sec-butyl borane, with some contamination comprising diphenylurea.
E. The organic and tetrahydrofuran layers obtained by the extraction of part D above are added to 4.2 9. of sodium hydroxide. This mixture is then heated to 85 C.
for about 16-18 hours to achieve hydrolysis of the 11-phenylurethane directing group. Progress of this reaction is monitored conveniently by silica gel TLC.
The resulting mixture is then cooled to room temperature and the pH adjusted to 9.0 by addition of 2 M phosphoric acid. This mixture is then extracted twice with dichloro-methane, thereafter discarding these dichloromethane ex-tracts. The aqueous phase is then cooled to 0-5 C. and carefully acidified to a pH of 4. The resulting acidic solution is then saturated by addition of solid sodium chloride. Thereafter this saturated aqueous solution is extracted with 400 ml. of ethyl acetate and the organic extracts so formed are washed twice with brine to remove undesired by-products. The resulting organic phase is then cooled and benzene is added to the mixture until the mixture becomes turbid. This organic mixture is then dried over sodium sulfate and the solvent evaporated at 30 C. under vacuum. Crystallization of the formula XIV product occurs 3~4 ~ 9SZ~ ' during this evaporation. Ethyl acetate is then added so as to yield a volume of 20-30 ml. and the ethyl acetate mixture is then cooled a~ 0 C. for 2 hours to complete crystalliza^
tion. The ethyl acetate is ~hen removed by filtration and the filtrate is rlnsed with cold ethyl acetate. The re-sulting crystals are then dried to constant weight, yield-ing 3.13 9. o~ pure formula XVI product.
PreParation 1 Recycle of tri-sec-butyl borane to pOt-assium tri-sec-butyl borohydride.
Tri-sec-butyl borane (as obtained from Example 1, part D) is dissolved in 100 ml. of oxygen-free Skellysolve~
B (7so~ric hexanes). The diphenylurea present in this mixture, being Insoluble in Skellysolve B, is separated~
The solvent is then evaporated under nitrogen atmosphere and vacuum to yield tri-sec-butyl borane.
One and one-half grams of 57 percent potassium hydride suspension in mineral oil is dissolved in 25 ml. of dry oxygen-free tetrahydrofuran. The resulting slurry is cooled ~o 0 C. under nitrogen atmosphere. Trl-sec-butyl borane (1.575 g.~, as obtalned above, in 5 ml. of tetrahydr~furan Is added drapwlse over 10 min, The resul~lng mixture is allowed to warm to room tem-pera~re and thereafter stirred for 1 ho~r. The stirrtng ts stopped and fine solids are allowed to settle ~vernlght.
Z5 ~h~ resul~ing mlxture Is then flltered under nltrogen at-mo~phere through a ftne slntared glass funnel yleldlng a clear ltgh~ yellow solu~lon of the tltle compound.
P)~ ~ 2,3,4,5,6~Pentanor-PG~2~ prepared from 3a,-~-dlhydroxy-2~(3-oxo trans-1-octenyl)-1~-~0 cyclopentaneacet~c acld y laetone uslng a , ~E3 ' ' ~ ~9 ~ 2V

diphenylcarbamate directing group.
A. At room temperature under nitrogen atmosphere the formula Xl lactone starting material (5.0 9.) in 70 ml. of tetrahydrofuran and ~.4 g. of diphenylcarbamoyl chloride are mixed with stirring. Thereafter sodium hydride (~00 mg., as a 57 percent suspension in mineral oil) is slowly added. Progress of the reaction is monitored by thin layer chromatography, and when shown to be complete, about 3 hr., the reaction is quenched by slow dropwise addition of acetic acid.
Thereafter the diphenylcarbamoyl derivative is puri-fied by evaporation of the solvent, addition of ice water, extraction with dichloromethane, and subjection of the dichloromethane extract to washing, drying, and evapora-tion of solvent. The melting point is 80-82 C. The ultraviolet spectrum shows ~max. (ethanol) at 230 ~
(~ 22,528). Characteristic NMR absorptions are observed at 4.0, 6.0, 6.6, and 7.25 ~. Characteristic infrared absorptions are observed 1666, 1686, 1700, and 1775 ~.
B. The title product is obtained by subjecting the reaction product of part A above successively to the pro-cedures described in Example 1, parts B-E.
ExamPle 3 2,3,4,5,6-Pentanor-PGF1a prepared from 3a,-5~-dihydroxy-2~ -oxo-trans-l-octenyl)-la cyclopentaneacetic acid y lactone using a p-tolylcarbamoyl directing group.
A. The formula Xl lactone, p-tolylisocyanate, and triethylamine are stirred in freshly distilled tetrahydro-furan at room temperature. When the resulting reaction is ~ shown to be complete by thin layer chromatography, the Z~

tetrahydrofuran is removed by evaporation, and the result-ing mixture combined with cold water and thereafter ex-tracted with dichloromethane. The pure formula Xll p-tolyl-urethane derivative is recovered by subjection to silica gel chromatography and subsequent crystallization from ethyl acetate and Skellysolve B (isomeric hexanes), The melting point 80.5-82.5 C. The ultraviolet spectrum ) shows ~max. at 234 ~ (~ = 26,933). The NMR spec trum shows characteristic absorptions at 5.05, 6.17, 6.8, and 7.0-7.4 ~.
B. Using the reaction product of part A above, and following the procedures described in Example 1, parts B-E, the title compound is prepared.
ExamPle 4 2,3,4,5,6-Pentanor-PGF1a prepared from 3a,-5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid y lactone using a (2~5-dichlorophenyl)carbamoyldirectin9 group.
A. The formula Xl lactone starting material and 2,5-dichlorophenylisocyanate are stirred together in dry pyri-dine at room temperature. When the reaction is shown to be complete by thin layer chromatography, isolation of the product proceeds by addition of cold water and extraction with ethyl acetate. The ethyl acetate extract is subjected to silica gel chromatography and crystallization from ethyl acetate and Skellysolve B to yield pure product. The pro-duct shows thin layer chromatographic Rf of 0.11 (ethyl acetate and Skellysolve B; 1:1) .
B. Using the reaction product of part A above and following the procedure of Example 1, parts B-E, there is ~249 iO~g5~0 prepared the title compound.
Example ~ 2,3,4,5,6-Pentanor-PGF1a prepared from 3~J-5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-la-cyclopentaneacetic acid y lactone using a 3-(p-bromophenyl)carbamoyl directing group.
A. Following the procedure of Example 4, part A, but using in piace of 2,5-dichlorophenylisocyanate, p-bromo-phenylisocyanate, there is prepared the corresponding 3-(p-bromophenyl)urethane product.
B. Using the reaction product of part A above, and following the procedure of Example 1J parts B-E, there is prepared the title compound.
Example 6 2,3,4,5,6-Pentanor-PGFia prepared from 3a,-5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid y lac~one using a 3-(p-ethoxyphenyl)carbamoyl directing group.
A. Following the procedure of Example 4, part A, but using p-ethoxyphenylisocyanate in place of 2,5-dichloro-phenylisocyanate there is prepared the corresponding 3-(p-ethoxyphenyl)urethane derivative of the lactone starting material. The melting point is 91-93 C.
B. Using the reaction product of part A above, and following the procedure of Example 1J parts B-E, there is prepared the title compound.
Following the procedure of any of Examples 1-6, but using in place of potassium-tri-sec-butyl borohydride one of the following potassium borohydrides:
tri-(3-hexyl), tri-(4-octyl), or tri-(5-dqcy~) ~LO~i95~) :

there is obtained the formula XVI product.
Further, following the procedure of any of Examples 1-6, or following the procedure described in the preceding paragraph, but replacing the lactone starting material therein ~ith a 3~,5a-dihydroxy-1a-cyclopentaneacetic acid y lactone which i5 substituted at the 2~-position with one of the following substituents:
3-oxo-4-methyl-trans-1-octenyl;
3-oxo-4,4-dimethyl-trans-1-octenyl;
3-oxo-4-fluoro-trans-1-octenyl;
3-oxo-4,4-difluoro-trans-1-octenyl;
3-oxo-4-phenoxy-trans-1-butenyl;
3-oxo-4-(m-chlorophenoxy)-trans-1-butenyl;
3-oxo-4-(m-trifluoromethylphenoxy)-trans-1-butenyl;
3-oxo-4-(p-fluorophenoxy)-trans-1-butenyl;
3-oxo-4-phenoxy-trans-1-pentenyl;
3-oxo-4-(m-chlorophenoxy)-trans-1-pentenyl;
3-oxo-4-(m-trifluoromethylphenoxy)-trans-1-pentenyl;
3-oxo-4-(p-fluorophenoxy)-trans-1-pentenyl;
3-oxo-4-methyl-4-phenoxy-trans-1-pentenyl;
3-oxo-4-methyl-4-(m-chlorophenoxy)-trans-1-pentenyl;
3-oxo-4-methyl-4-(m-trifluoromethylphenoxy)-trans-1-pentenyl;
3-oxo-4-methyl-4-(p-fluorophenoxy)-trans-1-pentenyl;
3-oxo-5-phenyl-trans-1-pentenyl;
3-oxo-5-(m-chlorophenyl)-trans-1-pentenyl;
3-oxo-5-(m-trifluoromethylphenoyl)-trans-1-pentenyl;
; 3-oxo-5-(p-fluorophenyl)-trans-1-pentenyl;
3-oxo-4-methyl-5-phenyl-trans-1-pentenyl;
3-oxo-4-phenyl-5-(m-chlorophenyl)-trans-1-pentenyl;

!

~249 ~069S20 3-oxo-4-methyl-5-(m-trifluoromethylphenyl)-trans-1-penteny !;
3-oxo-4-phenyl-5-(p-fluorophenyl)-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-phenyl-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-(m-chloropheny!)-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-(m-trifluoromethylphenyl)-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-(p-fluorophenyl)-trans-1-pen-tenyl;
3-oxo-4-fluoro-5-phenyl-trans-1-pentenyl;
3-oxo-4-fluoro-5-(m-chlorophenyl)-trans-1-pentenyl;
3-oxo-4-phenyl-5-(m-trifluoromethylphenyl)-trans-1-pentenyl;
3-oxo-4-phenyl-5-(p-fluorophenylJ-trans-1-pentenyl;
3-oxo-4,4-difluoro-5-phenyl-trans-1-pentenyl;
3-oxo-4,4-difluoro-5-(m-chlorophenyl)-trans-1-pen-tenyl;
3-oxo-4,4-difluoro-5-(m-trifluoromethyl)-trans-1-pentenyl;
3-oxo-4,4-difluoro-5-(p-fluorophenyl)-trans-1-pen-tenyl;
3-oxo-trans-1-cis-5-octadienyl-4-methyl-trans-1-cis-5-octadienyl;
3-oxo-4,4-dimethyl-trans-1-cis-5-octadienyl;
3-oxo-4-fluoro-trans-1-cis-5-octadienyl; or 3-oxo-4,4-difluoro-trans-1-cis-5-octadienyl, there is obtained respectively, the corresponding 2,3,4J5J6-penta-nor-PGF~a-type cGmpoundJ as follows:
16-methyl;
16J16-dimethyl;

~249 9~ZO

16-fluoro;
16,16-difluoro;
16-phenoxy-17,18,19,20-tetranor;
16-(m-chlorophenoxy)-17,18,19,20-tetranor;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor;
16-(p-fluorophenoxy)-17918,19,20-tetranor;
16-phenoxy-18,19,20-trinor;
16-(m-chlorophenoxy)-18J19,20-trinor;
16-(m-trifluoromethylphenoxy)-18J19J20-trinor;
16-(p-fluorophenoxy)-18,19J20-trinor;
16-methyl-16-phenoxy-18J19J20-trinor;
16-methyl-16-(m-chlorophenoxy)-18J19J20-trinor;
. 16-methyl-16-(m-trifluoromethylphenoxy)-18J19J20-trinor;
16-methyl-16-(p-fluorophenoxy)-18J19J20-trinor;
17-phenoxy-18,19J20-trinor;
17-(m-chlorophenyl)-18J19,20-trinor;
17-(m-trifluoromethylphenyl)-18J19J20-trinor;
17-(p-fluorophenyl)-18j19J20-trinor;
16-methyl-17-phenyl-18J19,20-trinor;
16-methyl-17-(m-chlorophenyl)-18,19,20-trinor;
16-methyl-17-(m-trifluoromethylphenyl)-18~19,20-trinor;
16-methyl-17-(p-fluorophenyl)-18J19,20-trinor;
16J16-dimethyl-17-phenyl-18J19J20-trinor;
16J16-dimethyl-17-(m-chlorophenyl)-18J19J20-trinor;
16,16-dimethyl-17-(m-trifluoromethyl)-18J19J20-trinor;
16J16-dimethyl-17-(p-fluorophenyl)-18J19J20-trinor;
16-fluoro-17-phenyl-18J19J20-trinor;
16-fluoro-17-(m-chlorophenyl)-18,19,20-trinor;
16-fluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor;

10~9S'~

16-fluoro-17-(p-fluorophenyl)-18,19,20-trinor;
16,16-difluoro-17-phenyl-18,19,20-trinor;
16J16-difluoro-17-(m-chlorophenyl)-18,19,20-trinor;
16,16-difluoro-17-(m-trifluoromethylphenyl)-18,19,2Q-trinor;
16,16-difluoro-17-(p-fluorophenyl)-18J19,20-trinor;
cis-17,18-didehydro;
16-methyl-cis-17,18-didehydro;
16-16-dimethyl-cis-17,18-didehydro;
16-fluoro-cis-17,18-didehydro; or 16,16-difluoro-cis-17,18-didehydro.

.~ .

Claims

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

A process for highly stereoselectively reducing the side chain oxo moiety of a lactone of the formula wherein L1 is , , or a mixture of , and , wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro;
wherein R7 is (1) -(CH2)k-CH3, wherein k is 2 to 6, inclusive, (2) , wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl, the various T's being the same or different, (3) , wherein T and s are as defined above, or (4) cis-CH=CH2-CH2-CH3, with the proviso that R7 is only when R3 and R4 are hydrogen or methyl, being the same or different; and wherein R13 is a directing group of the formula (1) wherein R1 and R2 are hydrogen, chloro, fluoro, bromo, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, being the same or diffe-rent, or (2) , wherein R1 and R2 are defined above, being the same or different for each phenyl ring;
which comprises:
reducing said lactone with a potassium trialkyl boro-hydride of the formula wherein m is zero, one, 2, or 3, thereby preparing an alcohol of the formula wherein L1, R7, and R13 are as defined above.

A process according to claim 1, wherein said potassium trialkyl borohydride is potassium tri-sec-butyl borohydride.

A process according to claim 2, wherein the directing group (R13) is of the formula , A process according to claim 3, wherein R1 and R2 are both hydrogen for each phenyl ring.

A process according to claim 4, wherein is n-pentyl.

A process according to claim 2, wherein the directing group (R13) is of the formula .

A process according to claim 6, wherein the directing group is phenylcarbamoyl or p-tolylcarbamoyl.

A process according to claim 7, wherein at least one of R3 and R4 is methyl.

A process according to claim 8, wherein one of R3 and R4 is hydrogen.

A process according to claim 9, wherein R7 is -(CH2)-(CH2)k-CH3.

A process according to claim 10, wherein R7 is n-butyl.

A process according to claim 8, wherein R3 and R4 are both methyl.

A process according to claim 12, wherein R7 is -(CH2)k-CH3.

A process according to claim 13, wherein R7 is n-butyl.

A process according to claim 7, wherein at least one of R3 and R4 is fluoro.

A process according to claim 15, wherein one of R3 and R4 is hydrogen.

A process according to claim 16, wherein R3 is -(CH2)k-CH3.

A process according to claim 17, wherein R7 is n-butyl.

A process according to claim 15, wherein R3 and R4 are both fluoro.

A process according to claim 197 wherein R7 is - (CH2)k-CH3.

A process according to claim 20, wherein R7 is n-butyl.

A process according to claim 7, wherein R3 and R4 are both hydrogen.

A process according to claim 22, wherein R7 is .

A process according to claim 23, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.

A process according to claim 24, wherein T is tri-fluoromethyl.

A process according to claim 24, wherein T is fluoro.

A process according to claim 24, wherein T is chloro.

A process according to claim 24, wherein s is zero.

A process according to claim 22, wherein R7 is .

A process according to claim 29, wherein T is chloro, fluoro, or trifluoromethyl and s is zero or one.

A process according to claim 30, wherein T is tri-fluoromethyl.

A process according to claim 30, wherein T is fluoro.

A process according to claim 30, wherein T is chloro.

A process according to claim 30, wherein s is zero.

A process according to claim 22, wherein R7 is cis-CH=CH-CH2-CH3.

A process according to claim 22, wherein R7 is -(CH2)k-CH3.

A process according to claim 36, wherein R7 is n-butyl.

A process according to c1aim 37, wherein Rl3 is .

Page 38 of 38 pages.