CA1045132A - Phenyl and naphthyl esters of prostaglandins - Google Patents

Abstract

COMPOSITION AND PROCESS
ABSTRACT OF THE DISCLOSURE

Substituted phenyl and naphthyl esters of PGE1, PGE2, PGA1, PGA2, PGF2.alpha., the 15-alkyl and 15(R)-15-alkyl substi-tuted prostaglandin analogs of the above naturally occurring prostaglandins, their racemic forms, and processes for pro-ducing them are disclosed. The compounds are useful for the same pharmacological purposes as the parent free acids and are also useful as a means for obtaining highly puri-fied forms of the free acids.

Description

~,~4~
sACKGROUND OF THE INVENTION
This invention relates to novel substitued phenyl and naphthyl esters of prostaglandln El (PGEl). prosta-glandin E2 (PGE2), prostaglandin Al(~GAl), prostaglandin A2 (PGA2) and protaglandin F2a(PGF2a), the 15 alkyl and 15 (R) - 15 alkyl substituted prostaglandin analogs of the above naturally occurring prostaglandins, their racemic forms and processes for producing them.
PGEl is represented by the formula;
'""'" .
~' ~ COOH

H OH
A systematic name for PGEl is 7-~3~-hydroxy-2~- L (3S)-3- ~-hydroxy-trans-l-octenyl -5-oxo-la-cyclopentyl~ -heptanoic -acid. .
PGE2 is represented by the formula:
' ' ` ~' `, /~oo}~ ' .'' .:

A systematic name for PGE2 is 7- ~3~-hydroxy-2~ S)-3-hydroxy-trans-l-octenyl -5-oxo-la-cyclopentyl3 -cis-5-hep- -- , .
tenoic acid. ~ ~ ~

PGAl is represented by the formula: ;

:, . , ~ ~ - 2 ~
~; ` ~ ,','''"
' ' ' . .
.: .
: ~ , .: . .

.,: .
....

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

~045132 o , .
COOH

` OH 111 A systematic name for PGA1 is 7 - ~2~ - (3S)-3-hydroxy-trans-l-octenylJ -5-oxo-1~ cyclo-3--pentenyl~ heptanoic acid.
PGA2 is represented by the formula: ~

O , :. ,, COOH

~ IV
H OH -~
A systematic name for PGA2 is 7- f2~- (3S)-3-hydroxy- ; :
trans-l-octenyl -5-oxo-lo~-cyclo-3-pentenyl~ ~cis-5 hep- .' tenoic acid. .';

PGF2a is represented by the formula~
HO ''" " ' ~ ' _ COOH V

; H~ ~ ~ ~ - ''' ~ ;
A systematic name~for PGF~2a is~7~-~3~ , 5~ -dihydroxy-2~ :
- .L-C t3S~-3-hydroxy-trans-1-oxtenyl~ -la-cyclopentyl} -c : ~--5-heptenoic acid. ~:': :'' PGEl and~PGE2 are known to be useful for a variety ; '~
of pharmacological and medical;purposes, for example, : ~' ' -labour induction~and: abortion in~`pregnant animals, in-cluding humans, menstruaI regulat1on in both pregnant and~non-pregnant animals, including humans, reduction : -and~control o~gast~r1a~secretlon, and as:a hypotens'ive "'~
agent to~reduce : :
::
~: :

: ` ~ ~ ' '' ~ '"
.
~' ' . .', ~5~32 blood pressure ~n mammals, including humans. See Berg-strom et al., Pharmacol. Rev. 20, 1 (1968) and reference cited therein. As to recemic PGEl and racemic ~GE2 see for example W.P. Schneider et al., J. Am. Chem. Soc, 91 5372 (1969).
PGAl and PGA2 are known to be useful for a variety of pharmacological and medical purposes, for example to reduce and control excessive gastric secretion, to in-crease the flow of blood in the mammalian kidney as in - -case of renal dysfunction, to control spasm and facili-tate breathing in asthmatic conditions, and as a hypoten- ~
sive agent to reduce blood pressure in mammals, inclu- ~ -ding humans. See Bergstrom et al., cited above. As to racemic PGAl, see for example P.W. Ramwell, Nature 221,1251 (1969). As to racemic PGA2, see for example J. Martel et al., Tetrahedron Lett. 1491 (1972).
PGF2a is known to be useful for a variety of pharmacological and medical purposes, for example labor induction and abortion in pregnant animals, including humans, menstrual regulation in both pregnant and non-pregnant animals, including humans, and reduction and ~
,:: ' :
control of gastric secretion. See Bergstrom et al., . .. .
ctled above. As to racemic PGF2a, see for example E.S

Corey et al., J. Am. Chem. Soc., 91 5675 (1969). ' ~ The 15-alkyl-PGEI analog and its 15(R) epimer are :,: ~. .
~ represented by the formula:
'- ',~':
-,, :.:

:

~5~2 ~ ~ _~ ",~,,COOH VI

HO y~

The 15-alkyl PGE2 analog and its 15(R) epimer are represented by the formula: ;

O .
. . .
,~~== ~ COOH Vll . . ~
~ / , ,.~ ' The 15-alkyl-PGA1 analog and its 15(R) epimer are .. .
represented by the formula ` !` `

O ~ ~ .. . !
~ f-~'~~COOH V I I I ~ "

Y ' . ~ ' '. ':
s .: ~:
' :':'`:~-The 15-alkyl-PGA2 analog and its 15(R) epimer are : :
represented by the formula: :~
. .: ,:

~~`COOH I X ~ -y l , ;
25 ~
The 15-alkyl-PGF2~ analog and its 15(R) epimer are -:
represented by the formula~: ~

~: : ~ `. . "

. : 5 : : .
; . . ' . . .. . ... . i . . .I.. i ~ .. .. .... . . . .. . . .

~ ~ ~ S ~ 3 HO, ~ ,^~==,-~" ~'` COO~I X

HO/ ~
- -;
wherein Y' is CH~ bH, CaHs OH, CH~ OH, or CrH ~ H, 10 following the usual convention wherein broken line attach-ment of hydroxy to the side chain at carbon 15 indicates the natural or "S" configuration and solid line attachment -of hydroxy indicates the epi or "R" configuration. See for example Nugteren et al., Nature 212, 38 (1966) and Cahn, ~J' Chem. Ed. 41, 116 (1964),~ The 15~alkyl- and~l5(R)-15-alkyl-PGE1, -PGE2, and -PGFaa analogs in their optically active and racemic forms are~ known. See for example U. 5.
Patent 3,728,382. The 15-a~l~kyl~~and 15(R)~l5~alkyl~pGA
a~nd~~PGA2 analogs in the~ir optically active and racemic ~20 ~ forms~are known.~ See for~example Belgian Patent 772,584,Derwent Farmdoc No. 19694T. These analogs are also use~
ful~for the above~described~pharmacological purposes.
Esters of~the above;compounds are known, wherein~the ~h~ydrogen atom~of the carboxyl~group is replaced by a hydro-25~ ca~rbyl or substituted hydrocarbyl group. Among these arethe~;methyl ester~of PGE1~(B.~ Samuelsson, J. Biol. Chern.
238,~3229 (1963)), (see also U. S~. Patent ~,069,322), the meth~y~l esters of~l5-methyl~-PGE1~and dl 15-rnethyl-PGE~
(G. L.~Bundy~et~al.,~Ann. N, Y;.~Acad. Sci. 180, 76 (1971)), 30~ the;~eth~yl~ ester of PGE~(R~. Ryhage et al., 8iochem. Biophys.

~ 6-~ ., : ~ . . . .~ .
- ~ , . .

- ~45~3;Z ~: ~
Res. Commun. 19~ 279 (1965)), and the octafluoro-1-pentyl ester of PGE1 (Belgian Patent 775,106, Derwent Farmdoc No.
33705T); themethyl esterof PGEz (B. Samuelsson, J. Biol.
Chem. 238, 3229 (1963))J themethyl ester of15-methyl-PGE
(E. W. Yankee et al., J. Am. Chem. Soc. 94, 3651 (1972)), the decyl ester of PGE2 (Belgian Pat. 765,732, Derwent Farmdoc No. 67580S), the 2-phenoxyethyl ester of PGE2 (Belgian Patent 776~294J Derwent Farmdoc No. 39011T)J the phenyl and alkyl-phenyl esters of PGE2 (British Spec.
1,282,661, see Derwent Farmdoc No. 67438R) and the p-(1,1J3,3-tetramethyl-butyl)-phenyl ester of PGE2, and a (and ~-)naphthyl ester of PGE2, and the 5,6,7,8-tetrahydro~

2-naphthyl ester of PGE2 (Belgian Patent 775,106, Derwent Farmdoc No 33705T); the methyl ester of PGA1 and PGA2 (J.
P Lee et al., Biochem. J. 105, 1251 (1967)); the methyl ester of PGF2~ (B. Samuelsson, J. Biol. Chem 238, 3229 .: .
(1963)), the methyl ester of racemic PGF2a (E. J. Corey et al., J. Am. Chem. Soc 91, 5675 (1969)), the methyl ester of 15-methyl-PGF2a (E W. Yankee et al., J. Am. Chem. Soc -,~
94, 365]. (1972)), the phenyl, alkyl-phenyl~ and 1-naphthyl esters of PGF2a (British Spec. 1,040,544, see Derwent -~
Farmdoc. No. 22,599), and;the a-naphthyl ester of PGF2a ;~
(Belgian Patent 775J106J see Derwent Farmdoc No. ~3705T). ~ :
~ SUMMARY OF THE INVENTlON
It isa purpose ofthis invention toprovide novel ester ~ ;
derivatives ofprostaglandin PGE19 15-alkyl-PGE1, 15(R)-15- ~ ;
alkyl-PGE1,~prostaglandin P6E2, 15-alkyl-PGE2, 15(R~-15-al- -kyl-PGE2, prostaglandin;PGA1,~15-alkyl-PGA1, 15(R)-15-alkyl-~PGAI, prostaglandin PGAa, 15-alkyl-PGA2~ 15(R)-15~alkyl-PGA2, prostaglandin PGF2~, 15-alkyl-PGF2aj 15(R)-15-alkyl-PGF2aJ
and their racemic forms.
~7 3086~F

~0 ~S ~ 3 Z ;
It is a further purpose to provide such esters derived from substituted phenols and naphthols. It is a further purpose to provide such esters in a free-flowing crystal-line Form. It is still a further purpose to provide novel processes for preparing these esters, The presently described esters include co~pounds ~ :
represented by the generic formula:

O ':
Il :~ .. ' , CH2-A-(CH2) 3-C-O~
_ ~) X l "`
H
H/ C-(CH2)~-CH3 :. :
Y ': .,- ,.
wherein ~ is ' H0 H0 ~ -wherei~n A is -CH2CH2- or cis -CH=CH- when ~ is ~ or ~ and H d , . . . .
wherein A is cis -CH=CH- when ~ is .: .

..

wherein Z is the substituted phenyl or naphthyl group defined immediately below and Y is ~8-, ~: , ~ 3086-F ~:
,: "

~)45132 ~ OH, CH3 OH, CH3 OH~ C2H5 OH, or C~Hs OH, i.e. the esters of PGE1, 15-methyl-PGE1, 15(R)-15-methyl- .
PGE1, 15-ethyl-PGE1, 15(R)-15-ethyl-PGE1, PGE2, 15-methyl- .
PGE2, 15(R)-15-methyl-PGE2, 15-ethyl-PGE2, 15(R)-15-ethyl- -PGE2, PGA1, 15-methyl-PGA1, 15(R)-15-methyl-PGA1, 15-ethyl-PGA1, 15(R)-15-ethyl-PGA1, PGA2, 15-methyl-PGA2, 15(R)-15-methyl-PGA2~ 15-ethyl-PGA2, 15(R)-15-ethyl-PGA2, PGF2~, 15-methyl-PGF2a, 15(R)-l5-methyl-pGF2a~ 15-ethyl-pGF2a~
15(R)-15-ethyl-PGF2~ and the racemic compounds represented .: . .
by each respective formula and the mirror image thereof;
Z being represented by , - .. .

~ NH C-Chl3 A ~ ~
,.,': :,...: .. .

NH-C ~ B

; ; ~ NH-Il ~ NH-C-CH9 C ,~

NH-C ~ NH-C ~ D

25 ;~
NH-I-NH~ E

NH-C-NH ~ F

-9- :

~io86- F

~)45~3Z `~

~=~ G

~3C- (C~H5 )3 H
,., .' ' ,' `

O : ':
~3 CH2 - CH- C- NH2 NH- ~j- CH3 :
O ,.' ~-:. ' ' O
~CH2- ICH-~-NH2 J ~ .
NH- C- C~iH5 :~
O ,.": ~
` ' `., .

~=~ CH= N- NH - C- NH2 K
:: 20 ~3C-CH3 L

': : : o ~ ` : `.

29 ~ 431~ M

Ol ~ ' ~C-NH2 N

~ . .
~:~ 30 .,'. ~, :
- 10 - '., ~ , ' .. ... . .
;

. '' 5132 ~

ol , - . .
C-NH ~ C-(C~Hs ) 3 0 ~ ~ :

C-O-CH3 .P

~3 c~ Q `~ ~' o C `~

~ O~C ~ NH-C-CH~ R

~ NH-C-CH3 S

NH- jCI - CH3 ~ NH-C-CH3 T

- ~ O .~
NH-C ~ U

25 ~ : ~ NH~C~NHa ~ ~ ' :;For example, PGFz~, p-acetamidophenyl ester~ is repre~
sented hy formula XI wherei:n ~ is ~;

,. .

~o86- F

~)451~Z

HO
~X .i HO
A is cis -C~CH-~ Y is ~ OH '`

and Z is A, i.e. ~'', ''" ' ' ' ' O .'.
~ NH-C-CH3 , and is conveniently identified herein as the PGF2~ ester , ' , of formula Xl-A. Racemic compounds are designated by the ':
prefix "racemic" or "dl"; when that prefix is absent, the ''',`,,, "' intent is to designate an optically active compound. , '~
Racemic 15-methyl PGE1, p-benzamidophenyl este,r, corres-ponds to ~ormula Xl wherein D is .
. .

~ ~
/ --, .;.:

~ HO " ,"
A is-CH2CH2-/ Y is ''"' ', ~' ,, ~ ,, .
CH3~ OH

and Z is B, i.e.
.. :.

~ ~ NH C ~ ,;

,' '.'`.

1045~32 including of course not only the optically active iSOmer represented by formula XI but also its mirror image.
The novel formula-XI optically active prostaglandin analogs and corresponding racemic compounds of this inven-tion are each useful for the same purposes as describedabove for PGE1J PGE2, PGA1, PGA2, and PGF2a and are used for those purposes in the same manner known in the art, including oral~ sublingual, buccal, rectal, intravaginal, -intrauterine, or topical administration.
For many applications these novel prostaglandin esters which are obtained from certain specified phenols and naphthols have advantages over the corresponding known -~
. .
prostaglandin compounds. Thus, these substituted phenyl -and naphthyl esters are surprisingly stable compounds hav- ~ ;
ing outstanding shelf-life and thermal stability. In con-trast to the acid form of these prostaglandins, these ` ;
~esters are not subject to acid-catalyzed decomposition . ; . .
either by elimination of water or by epimerization. Thus ;-these~compounds have improv~ed stability either in solid, ;~
liquid, or solution form. In oral administration these ~; ;esters~have shown surprisingly greater efficacy than the ~`
corresponding free acids~or lower alkyl esters, whether ~;
because of longer duration of biological activity or .~. , .
because of improved lipophil~icity and absorption 7s not `~
certain. These esters offer a~further advantage in that they have low soiubility~in water and the body fluids and are therefore retained longer at~the site of administra- `
tion.
A particularly outstanding advantage of many of these substituted phenyl and naphthyl esters is that they are ~ 1 3 ~
-, , .
' :'.

1~5~32 obtained in free-flowing crystalline form, generally of moderately high melting point, in the range 90-180 C.
This form is especially desirable for ease of handling, administering, and purifying. These crystals are highly stable, for example showing practically no decomposition at accelerated storage tests at 65 C., in comparison with the corresponding liquid alkyl esters or the free acids of the PGE's and PGA's. This quality is advantageous because the compound does not lose its potency and does not be- :
come contaminated with decomposition products. ~;
These crystalline esters also provide a means of purifying PGE1, 15-methyl-PGE1, 15(R)-15-methyl-PGE1, 15-ethyl-PGE1, 15(R)-15-ethyl-PGE,J PGE2, 15-methyl-PGE2, 15(R)-15-methyl-PGE2, 15~ethyl-PGE2g 15(R)-15-ethyl-PGE2, PGA~, 15-methyl-PGA1, 15(R)-15-methyl-PGA1, 15-ethyl-PGA1~ i 15(R)-15-ethyl-PGA1, PGA2, 15-methyl-PGAz, 15(R)-15-methyl- - -PGA2, 15-ethyl-PGA2, 15(R)-15-ethyl-PGA2, PGF2~g 15-methyl-PGF2~, 15(R)-15-methyl-PGF2a, 15-ethyl-PGF2a, or 15(R)-15-ethyl-PGF2~ which are first converted to one of these es-ters, recrystallized until pure, and then recovered as the free acid. One method of recovering the free acid is by ~enzymatic hydrolysis of the ester, for example with a lip-ase. See German Patent 2,242,792, Derwent Farmdoc No.
23047U. - ~ ~ -To obtain the optimum combination of stability, dura-tion of biological activity, lipophilicity, solubility, and crystallinity, certain compounds within the scope of formu-la Xl are preferred. ~`
; . . .
One preference is that Z is limited to either ~
: :, -.~
-14- `
::: ' :' '"'~ "' ' '" '' ''' ;. .' '"' ~ ' ' .'.' "' '' ' ',: , ' ~ ''; ' "' '' ' ,' ' ,' , . ''' ' " . ' ' .

~o86-F

~S13Z
ol ~;
NH-C-CH3 .
:;
.~ '.
O .
~ NH-C ~ ;
.;, :
..
O ` ~ :
~ NH- e~ :H- C- CH~

o o j,~
NH-C ~ NH-C ~ ''~
: ', ;.' O .'' ''. -"
: ~ NH-C-NH2 .`

o : ,,-~ ~ NH-C-NH ~

:`
o :, 20~ ~ CH2-,H-e~NH2 :: 25~ CH2-lH-C-NH2 NH-C-C~H5 30 ~ ~ C~N~~e N~la .. . . . . .. . . . ... . . ..

.
' ~ 101 :

O , ~ C

~ C-NHz o : ' ' C-NH ~ C-(C~Hs)~

~ C-0-CH3 ~~1~ ~

, 20 ~ O~C ~ NH-C-CH3 ~' o .
.
25 ~ NH-I-CH3 O

;~ 30 -16- `

~o86- F

~ 513Z

- ~NH~

.
` O
~NH-C-NH2 ~ " '' ~ ' Another preference is that Z is further 1 imited to ~,' O
(1) ~NH-C-Rl whe re i n Rl i s .:
~: :
--CH
... .

2 0 ~ : , O .:, .. ~ -~NH-C-CH3 ~ ~

.

29 ~ ~IH-C~

'. ; '.
.
--NH2 or .:

~30 ~ NH~

-: : ; ~' :' ' -17~
~, : ',, ' ~o86- F . -~0~5~l3Z
.. ~...........

(2 ) 4~NH- C-CH3; or ~=/ ',, NH- IC- CH3 .

~: .

O ' '

(3) ~ NH-C-R2 6~) "' , wherein R2 is .: .
-:

~3 o r ~ ;
.. .. .

. .:
20 ~ --NH2 .
Another preference is that ~ is 1 imited to : .:
o ~CH2- ICH-C-NH2 25NH- IC- CH3 ". ;
~:
. .
: ~ o ',~
CH2-~lH-C-NH2 NH- I C~H5 .
: : 0 o r :
- :L 8 -~()45~3;~
o ~ CH=N-NH-C-NH2..

Another preference is that Z is limited to : .

(1) ~ C-R3 ,: ' ::
wherein R3 is :
: . ~ .. .
'''': ' '' ~ " . "

' ~
: , . .
: -: '` ! ` .
.. -~ -. .. . . .
: - NH
-, ~ NH ~ C-~(C~H=)3 or .

o: :
I ~
(2~ ~ 0- ~-:R

where~in R~;~is~

` 3086- F

10~5~L3Z `

~ or ~ NH-I-CH3. , -... ...

Especially preferred are those compounds which are in ,' ' .
free-flowing crystalline form, for example: ' ' p-acetamidophenyl ester of PGE1 , p-benzamidophenyl ester oF PGE1 .'- , , p-acetamidophenyl ester of PGE2 ~ ' p-benzamidophenyl ester of PGE2 ,':,'.
p-(p~cetamidobenzamido)phenol ' ' ,', 'I . ' '.'' :
p-hydroxyphenylurea ester of PGE2 :,,",: , p-biphenyl ester of PGE2 p-hydroxybenzaldehyde semicarbazone ester of PGE2 ,. ~'':' p-acetamidophenyl ester of 15-methyl PGE2 ,.,,~ ;
p-benzamidophenyl ester of 15-methyl-PGE2 `i:'''.
p-benzamidophenyl ester of 15(R)-15-methyl-PGE2 p-hydroxybenzaldehyde semicarbazone ester of 15(R)-15- ', ',:
: methyl-PGE2 ~ -' p-benzamidophenyl ester of PGA1 : . ' p-ureidophenyl ester of PGA1 2-naphthyl ester of PGA1 -' p-benzamidophenyl ester'of PGA2 ;~' : p-(p-acetamidobe:nz,~m,i~o)phe~ol- : , ~
a-semicarbazono-p-tolyl ester of PGA2 , , p-acetamidophenyl ester of PGF2a p-benzamidophenyl ester of PGFZa .
, p-ureidophenyl ester of PGF2~ `;

' .

~04S~3Z
p-(3-phenylureido)phenyl ester of PGF2a

4-biphenylyl ester of PGF
p-tritylphenyl ester of F'GF2a p-(2-acetamido-2-carbamoylethyl)phenyl ester of PGF
p-(2-benzamido-2-carbamoylethyl)phenyl ester of PGF2~
a-semicarbazono-p-tolyl ester of PGF2a ~-p-acetylphenyl ester of PGF2~
p-benzoylphenyl ester of PGF2a p-carbamoylphenyl ester of PGF2a o-carbamoylphenyl ester of PGF2a p-(methoxycarbonyl)phenyl ester of PGF2a 2-naphthyl ester of PGF2a

5-sulfamoyl-1-naphthyl ester of PGF2a g-oxofluoren-4-yl ester of PGF2a The substituted phenyl and naphthyl esters of PGE1J
15-alkyl-PGE1, 15(R)-15-alkyl-PGE1, PGE2, 15-alkyl PGE2, 15(R)-15-alkyl-PGE2, PGA1, 15-alkyl-PGA1, 15(R)-15-alkyl- ~
PGA1, PGA2, 15-alkyl-PGA2, 15(R)-15-alkyl-PGA2~ PGF2a, 15- ~ -alkyl-pGF2a~ 15(R)-15-alkyl-PGF2a encompassed by formula Xl wherein Z is defined by ester groups A through V are pro-duced by the reactions and procedures described and exem-. . ~ .
~plified hereinafter. For convenience, the above prosta- ~;
glandin or prostaglandin analog is referred to 25 "the PG
compound". The term "phenol" is used in a generic sense, `
inciuding both phenols and naphthols.
Various methods are available for preparing these ., esters, differing as to yield and purity of product. Thus~
by one method, the PG compound is converted to a tertiary amine salt~ reacted with pivaloyl halide to give the mixed acid anhydride and then reacted with the phenol. Altern- ~ , ,,. ;

~0~5132 ately, instead of pivaloyl halide, an alkyl or phenylsul-fonyl halide is usedJ such as p-toluenesulfonyl chloride.
See for example B~lgian patents 775,106 and 776,294, Der-went Farmdoc Nos. 33705T and ~9011T
Still another method is by the use of the coupling reagent, dicyclohexylcarbodiimide. See Fieser et al., :
"Reagents for Organic Synthesis", pp. 2~1-2~6, John Wiley ~;
and Sons, Inc., New York (1967) The PG compound is con-tacted with one to ten molar equivalents of the phenol in the presence of 2-10 molar equivalents of dicyclohexyl- ~ -carbodiimide in pyridine as a solvent. -~
The preferred novel~process for the preparation of these esters~ however, comprises the steps (1) forming a mixed anhydride with the PG compound and a chloroformate ester, e.g. isobutylchloroformate in the presence of a ter-tiary amine and (2) reacting the anhydride with an appro- ;
priate phenol or naphthol.
The mixed anhydride is represented by the formula:
-o o 20 ~ ~CH3 CH2 - A - ( CH 2 ) 3 - C - O - C - O - C Hz - C H~ .; . ' ~' H X I I ~,:
~ ~5- ( CH2) 9 -CH3 ~ `
~

: Y ,''' .s ' .' .
~ for the optically active PG compounds, ~ , A and Y having the same definitions as above.
The~anhydride is formed readily at temperatures in the range -40 to +60 C.~, preferably at -10 to +10 C. so that .
the rate is reasonably fast and yet side reactions are mini-~ mized.~ The isobutylchloroformate reagent is preferably ~ ~ -22-~45~l3~
used in excess, for example 1.2 molar equivalents up to 4.0 per mole of the PG compound. The reaction is preferably done in a solvent and for this purpose acetone is pre~erred, although other relatively non~-polarsolvents are used such as acetonitrile, dichloromethane, and chloroform The - -reaction is run in the presence of a tertiary amine3 ~or example triethylamine, and ~he co-formed amine hydrochlor-ide usually crystallizes out, but need not be removed ~or -the next step.
The anhydride is usually not isolated butis reacted directly in solution with the-phenol~ preferably in the presence o~ a tertiary amine such as pyridine.
The phenol is preferablyused in equivalent amounts or in excess to insure that all of the mixed anhydride is con-verted to ester. Excess phenol is separat~d from the pro-duct by methods described herein or known in the art, for example by crystallization. The tertiary amine is not ~
only a basic catalyst for the esteri~ication but also a ; -convenient solv-ent. Other examples of tertiary amines use-ful for thi 5 pU rpose include N-methylmorpholine, triethyl- ~ i amineJ diisoprQpylethylamine, and dimethylaniline. Although ; ;
they may be us~d, 2-methylpyridine and quinoline result in a slow reaction. A highly hindered amine such as 2~6- ;
~dimethylpy~idine is not useful because o~ the slowness o~
the reaction.
The reaction with the anhydride proceeds smoothly at room temperature (about 20 to ~O C.) and can be followed ..
in the conventional manner with thin layer chromatography (TLC), usually;being found complete within 1-4 hours.
~0 The reaction mixture is worked up to yield the ester `~
; ',"' .. , -2~- ~
: : ',,`,-'.. ' ~o86-F

1()45~3;Z
following methods known In the art, and the product is pur-ifiedJ for example by silica gel chromatography.
, .
Solid esters are converted to a free-flowing crystal-line form on crystallization from a variety of solvents, including ethyl acetate, tetrahydrofuran, methanol, and acetone, by cooling or evaporating a saturated solution of , the ester in the solvent or by adding a miscible non-solvent such as diethyl ether, hexane, or water. The crystals are then collected by conventional techniques, e.g. filtration or-centrifugation, washed with a small amount oF solvent, and dried under reduced pressure. They may also be dried in a current of warm nitrogen or argon, or by warming to about 75 C. Although the crystals are normally pure enough s for many applications, they may be recrystallized by the ~;
same general techniques to achieve improved purity after each recrystallizat-ion.
.. , . ~ .
DESCRI PTI ON OF THE PREFERRED EMBODIMENTS -The invention can be more fully understood by the following examples.
All~temperatures a~re in~degrees centigrade.
Silica gel chromatography, as used herein, is under-stood~ to include chromatography on a column packed with silica gel, e~lutionJ collection of fractions, and combi~
~ nation oF those fractions shown by thin layer chromatography (TLC) to contain the desired product Free oF starting materia~l and impurities.
"TLC", herein~ refers to thsn layer chromatography, Prepara~ion 1 p-Benzamidophenol ::...................................................................... .. ... ... : . .
A solution of p-hydroxyaniline (20 g.) in 200 ml.
pyridine is treated with benzoic anhydride (20 g.). A~ter -24~

~o86- F

10~5~l32 hr. at about 25 CO~ the mixture is concentrated under reduced pressure and the residue is taken up in 200 m1.
of hot methanol and reprecipitated with 300 ml. of water The product is recrystallized from hot acetonitrile as white crystals/ 8.5 9.J m.p. 218.0-218~5 c.
Preparation 2 p-(p-Acetamidobenzamido)phenol A solution of p-acetamidobenzoic acid (12 5 g. ) in 250 ml. of tetrahydrofuran is treated with tri~thylamine (11.1 ml.). The mixture is then treated with isobutyl-chloroformate (10~4 ml.) and, after 5 min. at about 25 c., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine.
After 40 min. the crude product is obtained by addition of ~i 2 liters of water. The product is recrystallized from 500 ml. of hot methanol by dilution with 300 ml. of water as ~`
. . .
white crystals, 5.9 g., m.p. 27sio-277.0 c~ -Exam~le 1 p-Acetamidophenyl Ester of PGEl (Formula Xl-A). -A solution of PGE1 (o.450 g. ) and triethylamine (0 214 ml.) in 20 ml. of acetone is treated at -20 C.
with isobutylchloroformate (~? ml ) whereupon t~riethyl-amine hydrochloride is precipitated. After 5 min. the mix-ture is treated with~p-acetamidophenol (0.260 g.) in 10 ml.
of pyridine for 2 hr at about 25 c. The solvent is removed under reduced pressure and the residue is dis- i~
solved in ethyl acetate and washed with water. The 25 organic phase is dried over sodium sulfate, concentrated, ~and subjected to silica gel chromatography, eluting with -ethyl acetate followed by acetonitrile The residue ob-~tained by concentration of sel~ected fractions, a solid on ;
.,.
chilling, is the title compound, o.600 g., having Rf 0.3 (TLC~on silica gel in ethyl acetate~acetic acid, g7:3) , ~' '', ~ .

It is recrystallized from ethyl acetate-hexane as white free-flowing crystals, m.p. 133.8-136.3 C.
Example 2 p-~enzamidophenyl Ester of PGE1 (Formula Xl-B) --Following the procedure of Example 1 but using 0.490 g. of PGE1, 0.230 ml. of triethylamine, 0 216 ml. of iso-butylchloroformateg and 0 400 g. of p-benzamidophenol there is obtained a crude solid residue This residue is ;
subjected to silica gel chromatography, eluting with ethyl acetate, then ethyl acetate-acetonitrile (1~ and finaliy acetonitrile. The residue obtained by concentrat;on of selected fractions, o.496 g~, is crystallized from acetone diluted with 1 5 volumes of hexane as the title compound, o.356 g , white free-flowing crystals, m.p. 150 8-~54 8 C., having Rf o.6 (TLC on silica gel in ethyl acetate).
Example 3 p-Acetamidophenyl Ester of PGE2, (Formula Xl-A).
A solution of PGE2 (0.215 g.) and triethylamine (0 165 ml.) in 20 ml. of acetone is treated at -10 C. with isobutylchloroformate (0.~159 ml.) whereupon triethylamine hydrochloride is precipitated. After 5 min. the mixture is treated with p-acetamidophenol (o.659 g ) in 5 ml. of pyridine for 3 hr. at about 25 C. The solvent is removed under reduced pressure and the residue taken up in aceto-~nitrile and again concentrated. The crude residue Is dis~
.
solved in ethyl acetate and washed with aqueous citiric ; , acid (2~) and water. The organic phase is dried over so-. .
dium sulfate, concentrated, and triturated in hexane to a pasty solid. The product is subjected to silica gel - ;
chromatography, eluting with ethyl acetate followed by -acetonitrile. The residue obtained by concentration of ,.
selected fractions, a solid on chilling, is the title com-~. .

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

~o86-F

~Q4S~3Z

pound, 0.192 g., having Rf 0.~ (TLC on silica gel in ethyl acetate-acetic acid, 97:~). It is recrystallized from ethyl acetate-diethyl ether as white free-flowing crystals, ;
m.p. 112 3-113.0 C.
Example 4 p-Benzamidophenyl Ester of PGE2, (Formula Xl-B) A solution of PGE2 (0.26 g.) and triethylamine (0 206 ml.) in 20 ml. of acetone is treated at -5 C. with iso-butyl chloroformate (0.194 ml.), whereupon triethylamine hydrochloride is-precipitated The mixture is then treated with p-benzamidophenol (Preparation 1, o.8 g ) in 8 ml. of ~ -pyridine for 4 hr. at about 25 C. The solvent is removed under reduced pressure and the crude residue is subjected to silica gel chromatography~, eluting with ethyl acetate -~ollowed by acetonitrile The residue obtained by con-centration of selected fractions is recrystallized from tetrahydrofuran-hexane (1:1~ to yield the title compound~ ;
white free-flowing crystals, 0.269 g., m.p 132.8-135.0 ` ~;~
C., having Rf 0.5 (TLC on silica gel in ethyl acetate);
recrystallized from tetrahydrofuran-diethyl ether, m.p.
138 ~ 9.5 C.
Example 5 `~p-(p Acetamidobenzamido)phenyl Ester of PGE2 (Formula Xl-C) A solution of PGE2 (0.25 g.) and triethylamine (0.186 :
mi.) in 15 ml. of acetone is treated at -10 C. with iso-25 ~ ~ butylchloroformate (0.202 ml.) and, after 5 min. at 0 to ~;
~-5~C., with a solution of p-(p-acetamidobenzamido)phenol (Preparation 2~ o.g6 g.): in 10 ml. of pyridine for 4 hr at about 25 C. The solvent 7s removed under reduced pressure ~: . , , , :
and the residue is partitioned between 100 ml. of ethyl ~0 ~ acetate and lOO ml, o~ 0.1 N, aqueous monosodium dihydrogen ~ ~ ~ ' '''',' , -27~ ~
~ .

'::
10~5~L3Z ~ ~
. , orthophosphate. The organic phase is dried over sodium sul-fate and concentrated. The residue is taken up in 25 ml.
of ethyl acetate, filtered, and the solution concentrated.
The crude residue is dissolved in 1 ml. of dimethylformamide 4 and 4 m'. of ethyl acetate and the solution subjected to silica gel chromatography, eluting with 3-8~ methanol in ethyl acetate. The residue obtained by concentration of selected fractions is recrystallized from methanol-acetone -(1:5) on addition of water, to yiëld the title compound, white free-flowing crystals, estimated 0.09 g., m.p. .
173.2-176 2 C , having Rf 0.5 (TLC on silica gel in ethyl acetate-methanol 92:8).
Example_6 p-Hydroxyphenylurea Ester of PGE2 (Formula Xl-E) Following the procedure of Example 3 but using 0.453 9 f PGE2, 0.27 ml. of treithylamine, 0.254 ml. of isobutyl-chloroformate, and 1 0 g. of p-hydroxyphenylurea, there is obtained a brown oily crude residue. This residue is dis-solved in 100 ml. of ethyl acetate and 10 ml. of methanol, extracted with 0 1 N. aqueous hydrochloric acid and water, and the organic phase dried over sodium sulfate. The res-idue-left on concentrating is subjected to silica gel chromatography, eluting with ethyl acetate-acetone~ (7:3) and ethyl acetate-acetone (2:3). The residue obtained by concentrati.on of selected fractions, 0.56 9~J ;S recrys- ' tallized from 10 ml. of ethyl acetate on addition of one ml. of hexane as the title compound, white free-flowing -crystals, o.396 g., m.p. 105 3-108.3 C., having Rf 0.5 (TLC;on silica gel in ethyl acetate-acetone, 1:1), Exampie 7 p-Biphenylyl Ester ofPGE2., (Formula Xl-G) -~
Following the procedure of Example 3 but using 0.51 g - 2 ~3 - :` . .
,: ,'~ ' ' ' ,. ;. ,, , , I ,.. ,.. " . .. ,., . , ., . . , ,, ... .. ,~. ` . .. . . .

1~4S~l32;
oF PGE2~ 0 24 ml. oF triethylamine, 0.226 ml. of isobutyl- ~-chloroformate, and 0.49 9. of p-phenylphenol, there is ob-tained a crude oily residue which is taken up in ethyl ace-tate and concentrated severa1 times. The brown oil is then subjected to silica gel chromatography~ eluting with ethyl acetate containing 2~ waterO The residue obtained by con-centration of selected fractions, 0.735 g., is recrystal-lized from 6 ml. of ethyl acetate on addition of 12 ml. of hexane as the title compound, white free-flowing crystals, o.585 g., m.p. 91.8-92.8 C., having Rf o.6 (TLC on silica gel in ethyl acetate).
Example 8 p-Tritylphenyl Ester of PGE2, (Formula Xl-H) ..
Following the procedure of Example 3 but using 0.531 : ;. :
9. of PGE2, 0.254 ml. of triethylamine, 0.238 ml. of iso- ~;
butylchloroFormate, and o.760 g. of p-tritylphenol, there is obtained a crude residue. The residue is subjected to ;
silica gel chromatography, eluting with ethyl acetate.
The residue obtained by concentration of selected fractions .
is recrystallized from ethyl acetate-hexane as the title compound, white free-flowing crystals, 0.165 g.) m.p. 96.3-97.8 C.3 having Rf 0.7 (TLC on silica gel in ethyl acetate), Example ~ N-Acetyl-L-tyrosinamide Ester of PGE2 (Formula ;~
..:~., ,. ,.,, ,; . .;, . ..
X I - I ) , :,. ~
Following the procedure oF Example ~ but using 0.531 g oF PGE2, 0.254 ml. of triethylamine, 0 238 ml. o~ iso-.. ..
butylchloro~ormateg and 0.480 g. of N-acetyl-L-tyrosinamide, there is obtained a crude residue. The residue is subjected ~-~
to silica gel chromatography, eluting with methanol~ethyl acetate mixtures. The residue obtained by concentration of selected Fractions is dissolved in 10 ml. of warm ace- ~ ;

- ~o86-F

~n~s~32 ,. . .

tone and diluted with 5 ml. of hexane resulting in crys-tallization of the title compound, as white, free-flowing crystals, 00205 9., m.p. 1~7.3-140 8 C., having Rf 0.2 (TLC on silica gel in ethyl acetate containing 10% methanol), Example 10 N-Benzoyl-L-tyrosinamide Ester of PGE2 (Formula Xl-J) ;
Following the procedure of Example 3 but using 0.531 g. of PGE2, 0.254 ml. of triethylamineJ 0.238 ml. of iso-butylchloroformate, and 0.~42 g. of N-benzoyl-L-tyrosina- `
mide, there is obtained a crude residue. The residue is subjected to silica gel chromatography, eluting with ethyl -~
acetate containing 10~ methanol. The residue obtained by concentration of selected fractions is crystallized from acetone to yield the title compound, white free-flowing ~~`
crystals, 0.240 g., m.p. 160 8-164.8 C., h3ving Rf o.6 -~
(TLC on silica gel in ethyl acetate containing 10 methanol) : . . .
Example 11 p-Hydroxybenzaldehyde Semicarbazone Ester of ~;~
PGE2 (Formula Xl- K) 20 ~ Following the procedure of Example 3 but using 0.516 g. ~of PGE2, 0.264 ml. of triethylamine, 0.249 ml. of iso-butylchloroformate, and 1.4 g. oF p-hydroxybenzaldehyde semî-carbazone, there is obtained a crude oily residue. This residue is dissolved in 25 ml. of acetonitrile and left at about 25 C. until the excess starting phenol crystallizes out and is then filtered off. The fi-ltrate is concentra-, ted and subjected to silica gel chromatographyJ eluting ~
.
with acetonitrile followed by tetrahydrofuran-acetonitrile ~ -.
(3:2) The residue obtained by concentration of seleGted fractions, a white solid, 0.495 g, is recrystallized, .~.
. . . ~ .

, :.
:~O~S13;~
:
first from e-thyl acetate-hexane, then from hot acetonitrile, as the title compound, white free~flowing crystals J 0.328 9., m.p. 125.~-126.5 C., having Rf 0.4 (TLC on silica gel in in tetrahydrofuran-ethyl acetate 3:2) Example 12 p-Hydroxyacetophenone Ester of PGE2 (Formula Xl-L) Following the procedure of Example 3 but using 0.561 g. of PGE2, 0.264 ml. of triethylamine, 0.249 ml. of iso-butylchloroformate, and 00312 9. of p-hydroxyacetophenoneJ
there is obtained a crude oily residue. This residue is :
subjected to silica gel chromatography, eluting with water-ethyl acetate (1:99). The residue obtained by concentra-tion of sel~cted fractions, an oil, is triturated in hexane ~
to yield a solid which is recrystallized from ethyl acetate- : ~ -hexane to yield the title compound, white free-flowing crys-talsJ 0.513 9., m.p. 76.8-77.8 C., having Rf 0.5 (TLC on silica gel in ethyl acetate). ;
,:, ,:
Example 13 p-Hydroxybenzamide Ester of PGE2 (Formula Xl-N) Following the procedure of Example 3 but using 0.561 9. of PGE2, 0.264 ml. of triethylamineJ 0.243 ml. of iso- ~;
butylchloroformateJ and 0.5 g. of p-hydroxybenzamide there is obtained a crude residue. This residue is subject-ed to silica gel chromatographyJ eluting with ethyl ace-.. . . ...
tate-methanol (9:1). The residue obtained by concentra-tion of selected fractionsJ an oilg 0.425 9., is crystall~
;i... .
ized from ethyl acetate-hexane to yield the title compoundJ ~ -. .~ . . .
white crystalsJ 0.294 g.J mOpo 106.3-108.3 COJ having Rf o.6 (TLC on silica gel in ethyl acetate-methanol (g 1))~
. . ~: ., Example 14 p-Acetamidopheny~l Ester of l5-methyl-PGE2 . .
(Formula Xi-A) Following the procedure of Example 3 but using 0.163 ;i,~ .

' ~

I
~)45~3;~ :
g of 15-methyl-PGE2, 0.186 ml. of triethylamine, 0.174 ml.
of isobutylchloroformate, and 0.538 g. of p-acetamidophenol, there is obtained a crude residue This residue is dissolved -in chloroform and left at about 25 C. until the excess starting phenol crystallizes out and is then filtered off -The filtrate is concentrated and subjected to silica gel chromatography, eluting with chloroform-acetonitrile (1 followed by acetonitrile. The residue obtained by concen- '- ~
tration of selected fractions, an oil, o.o67 9., is crys- ~ ~ -tallized from ethyl acetate on addition of hexane as the ~ ~-title compound, white free-flowing crystals, 0.042 g., m.p.
114 3-116.0 C., having Rf 0.6 (TLC on silica gel in ethyl acetate) Example 15 p-Benzamidophenyl Ester of 15-Methyl-PGE2, (Formula Xl-B) ;
Following the procedure of Example 3 but using 0.176 g of 15-methyl-PGE2, 0 133 ml of triethylamine, 0.126 ml. ~ ;
of isobutylchloroformate, and 0.900 g. of p-benzamidophenol, there is~ obtained a crude semi-solid residue This resTdue ~ s partiti;oned~between 100 ml. of chloroform and 75 ml. of 0 1 N~ aqu`eous~monosodi~um dihydrogen orthophosphate The ~organic phase is dried over sodium sulfate and concentrated to~a~white solid. The residue is subjected~to silica gel ~-chromatography~, eluting with chloroform-ethyl acetate (1:1) ' ' ~: ~' ~followed~by acetone-ethyl acetate (1:4) The residue obtained.by~concentration of selected fractions, a colorless oi~l~, 0,~143 g ~ is crystall~i~zed~from ethyl acetate on addi-tion of hexane as the title compound, white free-flowing orystals, 0.126 g., m p. 119.8-121.8 C.~ having Rf 0.7 (TLC : -on silica gel ~in ethyl acetate).
~ : .
: ~ : .~
~.:
-32- `~

~(~45~3;2 Example 16 p-Acetamidophenyl Ester of 15(R)-15-Methyl-PGE2, (Formula Xl-A) Following the procedure of Example 3 but using o 200 g of 15(R)-15-methyl-PGE2, 0.15~ml of triethylamine, 0.142ml, of isobutylchloroformate, andO.45~g. of p-acetamidophenol, there is ob~ained a crude oily residue. This residue is dissolved inchloroformand leftatabout25C.until theexcessstarting ~ ~ --phenol crystallizes out and is then filtered off. The filtrate is concentrated and subjected to silica gel chromatography, elu-ting with chloroform-acetonitrile (3:2). The residue obtained by concentration of selected fractions, an oil, 0.25 9., having Rf 0.3 (TLConsilica gel inchloroform-acetonitrile 3:2).
ExamDle 17 p-Benzamidophenol Ester of 15 (R)-15-Methyl-PGE2 (Formula Xi-B) Following the procedure of Example 3 but using 0,175 g, ~
of 15(R)-15-methyl-PGE29 0.100 ml. of triethylamineJ ~-0.093 ml. of isobutylchloroformate, and o.6 9. of p-benza-midophenol, there is obtained a crude solid residue. This residue is subjected to silica gel chromatography, eluting with chloroform, chloroform-acetonitrile (9:1)9 chloroform-acetonitrile (2:1), and chloroform-acetonitrile (1:3). The ~`
residue obtained by concentration of selected fractions is .' '. :~''. :' rechromatographed to remove traces oF the starting phenol, --thereby yielding a colorless oil, 0 173 9, This oil is -~ crystallized from ethyl acetate on addition of hexane as the title compound, white free-flowing crystals, 0.153 9, m.p. 88.:3-90.3 C., -having RF 0.5 (TLC on silica gel in . :
acetonitrile-chloroform 1 :1 ), ,', " -Example 18 p-Hydroxybenzaldehyde Semicarbazone Ester of 15 (R)-15-Methyl PGE2 (Formula Xl- K) ~33~
~; ; ; '':

~ 3086-F

~45132 - .
Following the procedure of Example 3 but using 0.200 g. of 15(R)-15-methyl-PGE2, o 153 ml. of triethylamine, 0.142 ml. of isobutylchloroformate, and 0.546 g. of p-hy-droxybenzaldehyde semicarbazone, there is obtained a crude oily residue. This residue is dissolved in ethyl acetate `
and washed with aqueous 0.1 N. sodium phosphate buffer at pH 6.o. The organic phase is dried over sodium sulfate and concentrated to a white solid The residue is sub-jected to preparative thin-layer chromatography using . ~
ethyl acetate-methanol ~9:1) and eluting with acetone- ~`
methanol (3:1) to yield a colorless oil. This oil is chromatographed on silica gel, eluting with acetonitrile.
The residue obtained by concentration of selected fractions, a white solid, 0.160 9., is recrystallized from acetone on addition of water to give the title compound, white free-flowing crystals, 0.085 g., m.p. 92 3-93 3 C., having Rf 0.5 (TLC in acetonitrile-methanol 9:1), -Example~l~ p-Acetamidophenyl Ester of PGA1 (Formula Xl-A) ~ -A solution of PGA1 (o.506 9.) and triethylamine (0,250 ml.) in 20 ml. of acetone is~treated at -10 C. with iso~
butyichloroformate (0 236 ml.) whereupon triethylamine hy- -drochloride is precipitated. After 5 min. the mixture is treated with p-acetamidophenol (0.453 g.) in 5 ml. of pyri-dine for 3 hr. at about 25 C. The solvent is removed 25 ~ ~under~ reduced pressure~ and th~e residue is dissolved in ~ -ethyl acetate and washed wi~th ~aqueous citric acid (2%) and `~ ~
water. The organic phase~i~s dried over sodium sulfateJ ;~ ~;
concentrated3 and subjected~to`silica gel chromatography, eluting with chloroform-acetonitrile (7:3) containing 1 water, followed by chloroform-acetonitrile (1:~), The ~: .
-31~ ~
, .
: :

~ 5~32 residue obtained by concentration of selected fractions, an oil, is the title compound, 0.539 9., having Rf 0.4 (TLC on silica gel in chloroform-acetonitrile (7:3)).
Example 20 p-Benzamidophenyl Ester of PGA1 (Formula Xl-B) :.`"!'.'."
Following the procedure of Example 19 but using 0.510 9. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of iso-butylchloroformate~ and oO484 g. of p-benzamidophenol (Prep-aration 1), there is obtained a crude residue, This resi-due is subjected to silica gel chromatography, eluting with chloroform-acetonitrile (85:15). The residue obtained by concentration of selected fractions, 0.505 9., is crystal-lized from ethyl acetate diluted with 2.5 volumes of hexane as the title compound, white free-~lowing crystals, m.p. -96.8-98.3 ~., having Rf o.6 (TLC on silica gel in chloro~
form-acetonitrile (4 Example 21 p-Hydroxyphenylurea Ester of PGA1, (Formula .: - . , .
Xl-E) ~ -~
Following the procedure of Example 19 but using o.506 g. of PGA1, 0,250 ml. of triethylamineJ 0.236 ml. of iso-butylchloroformate, and o.456 g. of p-hydroxyphenylurea, there is obtained a crude residue. This residue is sub-~: :::.'' , . :
jected to silica gel chroma~ography, eluting with ethyl acetate-acetonitrile-water (94:5:1). The res~idue obtained by concentra~ion of selected fractions, o.646 g., is crys-tallized from ethyl acetate as the title compound, white free-flowing crystals, m.p. 96.3-98.3 C., having R~ 0.4 (TLC on silica~gel in ethy1 acetate-acetonitrile (95:5~).
~ ~Example 22 p-Acetylphenyl~ Ester of PGA1 (Formula Xl-L3 ; ~ Fol~lowing the procedure of Example 19 but using o.508 9. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of iso- i ;,, ~"

~: ' ,. ' ' ~" " " .

~45~3Z
butylchloroformate) and oO309 g of p-hydroxyacetophenone, there is obtained a crude residue. This residue is sub-jected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3)J followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.500 g./ an oil, is the title compound, having Rf 0.4 (TLC on silica gel in ethyl acetate-hexane (1:1)). -Example 2~ p~ Carbamoylphenyl Ester of PGAl (Formula Xl-N) Following the procedure of Example 19 but uslng o.506 ;~
9. of PGA1 0.250 ml. of triethylamine, 0.236 ml. of iso-butylchloroformate3 and 0 412 g. of p-hydroxybenzamide there is obtained a crude residue. This residue is sub-jected to silica gel chromatography, eluting with chloro-form-acetonitrile (6:4). The residue obtained by concen- ;~
tration of selected fractions, 00260 g., an oil, as the title compound, having Rf 0.5 (TLC on silica gel in chloro-form-acetonitrile (3:2)).
Example ?4 p-Benzamidophenyl Ester of PGA2 (Formula Xl-B) A solution of PGA2 (0.310 g.) and triethylamine (0.244) ml.) in 20 ml. of acetone is treated at -10 C. with iso-butylchloroformate (o.2~6 ml.) whereupon triethylamine hy-drochloride is precipitated. After 5 min. the mixture is treated with p-benzamidophenol (0.558 9.) in 5 ml. of pyridine for 0.25 hr. at about 25 C. The solvent is `-25~ removed undel- reduced pressure and the residue is dissolved .
in ethyi acetate and washed with aqueous citric acid (2%) ~and water. The organic phase is dried over sodium sulfateg concentrated, and subjected to silica gel chromatography, elut;ng with acetonitrile-chloroform (1:4) The residue obtained by concentration of selected fractions, a solid .
. ... .
-~6- -- ;.
,:

, . .. , . , . .. , ~ .. .... ~ . . . . . . . . . . .

~ 3 Z
on chilling, is the title compound, 0.293 9., having R~ o.6 (TLC on silica gel in acetonitri1e-chloro~orm (1:4)). It is recrystallized from ethyl acetate-hexane as white free-flowing crystals, m.p. 56,5-57,5 C, Ex_m~le 2~ p- (p-Acetamidobenzamido)phenyl Ester of PGA2 ~
(Formula XI-C) ~-Following the procedure of Example 24 but using o.308 g. of PGA2, 0.244 ml. of triethylamine, 0,236 ml, of iso-butylchloroformate, and 0,714 g. of p-(p-acetamidobenzamido)-phenol (Preparation 2), there is obtained a crude solid residue. This residue is subjected to silica gel chroma- -tography, eluting with ethyl acetate. The residue obtained ~ -by concentration of selected fractions, 0.260 g,, is chro-matographed again on silica gel, eluting with acetonitrile~
chloroform (1:1) to yield 0. 047 g. which is recrystallized ```
from ethyl acetate-methanol-hexane (97:3:10) as the title compound, 0,044 g., white free-flowing crystals, m.p.
159,5-160,0 C,, having Rf 0,42 (TLC on silica gel in ethyl acetate).
Example 26 4- Biphenylyl-~sterofPGA2 (Formula XI-G) Following the procedure of Example 24 but using 0,561 ~ ;
g of PGA2, 0.302 ml. of triethylamine, 0.286 ml. of iso-butylchloroformate, and 0,570 g. of p-phenylphenolJ there is obtained a crude oily residue. This residue is sub-jected to silica gel chromatography, eluting with ethyl ~ i~
acetate-hexane (2:3~ saturated with water The residue : ;
obtained by concentration of selected fractions, 0.381 g.~ ;
an oil, is the title compound, having Rf 0.5 (TLC on silica gel in ethyl acetate-hexane (2:3).
Example 27 a-Semicarbazono-p-tolyl Ester of PGA2 (Formula ~ ~
. .
~-37 '. ', :,.

~0~32 XI-K) Following the procedure of Example 24 but using 00310 g. of PGA2, 0.244 ml. of triethylamine, 0.236 ml. of iso-butylchloroformate, and o.470 g. of p-hydroxybenzaldehyde semicarbazone3 there is obtained a crude solid residue.
This residue is subjected to silica gel chromatography, eluting with tetrahydrofuran-ethyl acetate (~:2) The residue obtained by concentration of selected fractions, o.600 g., is crystallized from acetone-water (1.2) as the title compound, o.7~6 9., as white free-flowing crystals, i An analytical sample recrystallized from acetonitrile has mOp. 128.3-129.0 C. and Rf 0.5 (TLC on silica gel in ethyl acetate-methanol (95:5)). -Example 28 p-Acetamidophenyl Ester of PGF2~ (Formula XI-A) A solution of PGF2~ (0.535 9.) and triethylamine (0.25~ ml.) in 20 ml. of acetone is treated at -10 C.
with isobutylchloroformate (0.238 ml.) whereupon triethyl-amine hydrochloride is precipitated. After 5 min. the mixture is treated with p-acetamidophenol (0.342 g.) in 5 ml. of pyridine for 3 hr. at about 25 C. The solvent is removed under reduced pressure and the residue taken up --in acetonitrile and again concentrated. The crude resi-due is subjected to silica gel chromatography, eluting with ethyl acetate-methanol (90:10) The residue obtained by concentration of selected fractions, a solid on chilling~ -is the title compound 0.285 9., having Rf o.6 ~TLC on sil-ica gel in ethyl acetate-methanol 90:10). It is recrys-tallized from ethyl acetate-hexane as white free-flowing -crystals, m.p. 114-115.8 C.
~0 Example 29 p-Benzamidophenyl Ester of PGF2~ (Formula Xi-B) : : ' .
~ 45~1L3Z
Following the procedure of Example 28 but using 0.535 9. of PGF2C, 0.254 ml. of triethylamine, 0.238 ml. of iso- -butylchloroformate, and 0.481 g. of p-benzamidophenol (Prep-aration 1), there is obtained a crude residue This resi- .
due is subjected to silica gel chromatography, eluting with -ethyl acetate followed by ethtyl acetate-methanol (95:5). -The residue obtained by concentration of selected fractions, 0.220 g., is crystallized from ethyl acetate-methanol .'~!'`.. '.''-~,';';'' ' (100:5) diluted with hexane as the title compound, white free-flowing crystals, m.p. 139.8-143.8 C., having Rf o.8 :
(TLC on silica gel in ethyl acetate-methanol (95:5)).
Example 30 p-Ureidophenyl Ester of PGF2c~ (Formula Xl-E) Following the procedure of Example 28, but using 0.738 g. of PGF2a~ o.~o6 ml. of triethylamine, 0.288 ml. o~ iso-butylchloroformate, and 0.330 g~ of p-hydroxyphenylurea, ~ ;
there is obtained a crude residue. This residue is sub-jected to silica gel chromatography, eluting with ethyl ;
acetate-acetone (4:13. The residue obtained by concentra-tion of selected fractions, 0.488 9., is crystallized from . . . . . .
acetone diluted with one-hal~ the volume of hexane as the title compound, white free-flowing crystals, m.p. 133.8-135.0 C. having Rf 0.5 (TLC on silica gel in ethyl ace- ` ' tate-acetone (4:1)) ExamDle 31 p- (3-Phenylureido)phenyl Ester o~ PGF2a (Form- ~
ula Xl- F) ~
Following the procedure of Example 28 but using o.738 9. of PGF2C~, 0.347 ml. of triethylamine, 0.326 ml. of iso-butylchloroformateJ and 0.705 9. of p-hydroxy-lJ3-diphenyl-urea, there is obtained a crude residue This residue is :
subjected to silica gel chromatography, eluting with ethyl ~ ,. .
''., ~. ' ~39- i :" . ' ~:

3086- f :
l~S~32 acetate-acetone (7 3). The residue obtained by concentra-tion of selected fractions, 0.475 9., is crystallized from hot ethyl acetate as the title compound, white free-flow-ing crystals, m.p. 145 0-147 3 C., having Rf 0.42 (TLC on silica gel in ethyl acetate-acetone (7:3). ' ExamPle 32 p-Biphenylyl Esrer 3f PGF2Q~ (Formula Xl-G) Following the procedure of Example 28, but using o.535 g. of PGF2c~ 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.385 g. of p-phenylphenol, there is obtained a crude residue. - This residue is subject- " ' ed to silica gel chromatography, eluting 'with ethiyl acetate followed by acetonitrile. The residue obtained by concen-tration of selected fractions, 0.270 9., is~crystallized from ethyl acetate diiuted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. '~
114.3-116.8 C. having Rf 0 25 (TLC on silica gel ;n ethyl '~ -' acetate). ~ '' :~ .
Example 3~ p-Tritylphenyl Es$-*r o~ PGF~c~ (Formula Xi-H) Following the procedure of Example 28 but using 0.738 g. of PGFZa~ 0.291 ml. of triethylamine, 0.275 ml. of iso-'; ' butylchloroformate, and o.840 g. o~ p-tritylphenol, there-''' is obtained a crude residue. This residue is isubjected to ~ ' si~lica gel chromatography, eluting with ethyl acetate-water (99~:1) The residue obtained by--concentration of selected 25 ~ fractions, 0.576 g., is crystallized 'from acetone diluted ~; ~ with five volumes of hexane as the title compound, white'' '~
free-~flowing crystals, m.p. 12~.8-129.0, having Rf 0.5 ~' (TLC on~silica gel in et~hyl acetate?.
Example 34 p- (2-Acetamido-2-carbamoylethy'l)phenyl Ester`'~ ~' of PGF2a (Formula Xl~

. ., ~

, 1~)4S~3~, Following the procedure of Example 28 but using o.738 g. of PGF2a, o.306 ml. of triethylamine, 0.288 ml. o~ iso- ;~
butylchloroformate3 and 0.488 g. of N-acetyl-L-tyrosinamideJ
there is obtained a crude residueO This residue is subject-ed to silica gel chromatography, eluting successively with ethyl acetate-methanol-water (90:10:1) and ethyl acetate-methanol-water (80:20:1). The major fraction is chroma- ~
tographed again, eluting with ethyl acetate-methanol (4:1). -The residue obtained by concentration of selected fractions, 0.242 g. is crystallized from acetone diluted with 1.5 -volumes of hexane as the title compound, white free- Flow-ing crystals, m.p. 109.8-11308 with softening at 105.0 having Rf 0.5 (TLC on silica gel in ethyl acetate-methanol (4:1)) Example 35 p-(2-Benzamido-2-carbamoylethyl)phenyl Ester of PGF2a (Formula Xl-J) `~
Following the procedure of Example 28 but using o.73O8 g. of PGF2a, o.306 ml. of triethylamine, 0.288 ml. of ;so-butylchloroformate, and 0,625 g. of N-benzoyl-L-tyrosina-mide, there is obtained a crude residue. This residue is subjected to silica gel~ chromatography, eluting with ~ ;
ethyl acetate-tetrahydrofuran-water (60:40:1). The resi~
due obtained by concentration of selected fractions, 0.459 g., is crystallized from hot acetonitrile as the title com-pound, white ~Free-flowing crystals, m.p. 142.5-144.3 C., having Rf 0.5 (TLC on silica gel in ethyl acetate-tetra- ;
hydrofu ran (3:2)). ~ ;
Example ~6 a-Semicarbazono-p-tolyl Ester of PGF2a (Form-ula Xl-K) Following the procedure of Example 28 but using 0.535 '~'' ,';

, ~,. , , ~
~' ~ ~S ~ 3 2 g. of PGF~, 0.254 ml. of triethylamine, 0.238 ml. of iso-butyl chloroformate, and 0.405 g. of p-hydroxybenzaldehyde semicarbazone, there is obtained a crude residue. This residue is subjected to silica gel chromatography~ eluting with ethyl acetate-methanol (9:1) and ethyl acetate-methanol (8:2). The residue obtained by concentration of selected fractions, 0,215 9., is crystallized from ethyl acetate-hexane (1:1) as the title compound, white free-flowing crystals, m.p. 110.8-113.3 Co having Rf 0.4 (TLC on silica gel in ethyl acetate-methanol (g:l)).
Example 37 p-Acetylphenyl Ester o~ PGF2a (Formula Xl-L) Following the procedure of Example 28 but using 0.738 g. of PGF2~, o.306 ml. of triethylamine, 0.288 ml. of iso-butylchloroformate, and 0.299 g of p-hydroxyacetophenone, `~
there is obtained a crude residue. This residue is sub- ;
jected to silica gel chromatography,eluting with ethyl acetate-water (99:1) followed by ethyl acetate-acetonitrile (1:1) The residue obtained by concentration of selected fractions, 0 589 9. is crystallized from ethyl acetate diluted with an equal volume of hexane as the title com-pound, white free flowing crystals, m.p. 85.3-86.5 C.
having Rf 0.4 (TLC on silica gel in ethyl acetate-aceto-nitrile (4:1)). - ;
Example 38 p-Benzoylphenyl Ester of PGF2~ (Formula Xl-M) ~ -~ Following the procedure of Example 28 but using 0.738 9. of PGF2~, 0.29l ml. of triethylamine, 0.275 ml. of iso-butylchloroformate, and o.594 9. of p-hydroxybenzophenone, there is obtained a crude residue. This residue is sub- -jected to silica gel chromatography, el~lng with ethyl acetate-water (99:1). The residue obtained by concentra-, `' ; - . ' 10 4S~3,Z
tion of selected fractions, o.492 g., is crystal1ized from ethyl acetate diluted with three volumes of hexane as the title compound, white free-flowing crystals, m p. 73.8-75.8 co~ having Rf 0.5 (TLC on silica gel in ethyl ace-5 tate) Example 39 p-Carbamoylphenyl Ester of PGF2~ (Formula Xl-N) Following the procedure of Example 28 but using 0.738 g. of PGF2~, 0.347 ml. of triethylamine, 0.326 ml. of iso- .
butylchloroformate, and 0.433 g. of p-hydroxybenzamide, there is obtained a crude residue. This residue is sub- `
jected to silica gel chromatography, eluting with ethyl ~ ~
acetate-acetone (3 7). The residue obtained by concentra- ~ -tion of selected fractions, 0.455 g.J is crystallized from 15 acetone diluted with an equal volume of acetonitrile as the title compound, white, free-flowlng crystals, m p.
129.5-130.8 co~ having Rf 0.32 (TLC on silica gel in ethyl acetate-acetone (3 7) ) . --Exame~ 40 p-(Methoxycarbonyl)phenyl Ester of PGF
20 (Formula IX-P) Following the procedure of Example 28 but using o.738 -g. of PGF2~, 0.347 ml. of triethylamine, 0.326 ml. of iso-butylchloroformate, and 0.474 g. of methyl p-hydroxybenzo-. ;. .. .
ate, there is obtained a crude residue. This residue is 25 ~ subjected to silica gel chromatography, eluting with .
ethyl acetate-water (gg:l) followed by ethyl acetate-ace-tone-water (69 30 1). The residue obtained by concentra-tion of selected fractions, o.;678 g., is crystallized from ;~
ethyl acetate d;luted wi~th~an equal volume of hexane as the 30 title compound, white free-Flowing crystals~ m.p. 80.3-~: :

3086 ' F

1~4sl3z 82.0 C., having Rf 0.~ (TLC on silica gel in ethyl ace-i tate).
Following the procedures of Examples 1-40 but employ-ing the racemic ~orms of the PG compoundsJ there are ob-tained the corresponding esters of racemic PG compounds.
Exam~les 41-322 The substituted phenyl and naphthyl and -;-esters of PGE1, 15-methyl-PGE1, 15(R)-15-methyl-PGE1, PGE2J 15-methyl-PGE2, 15(R)-15-methyl-PGEz, PGA1, 15 methyl- `;
PGA1, 15(R)-15-methyl-PGA1J PGA2, 15-methyl-PGA2, 15(R)-15-methyl-PGA2, PGF2a~ 15-methyl-pGF2a~ and 15(R)-15-methyl-PGF2~ of Tables l-XV below are obtained following the procedures o~ Example 1, wherein the prostaglandin compound `
is reacted in the presence of triethylamine and isobutyl-chloroformate with the appropriate hydroxy phenyl or naph-thyl compound, listed in the Table. These phenols or naph~
thols are readily available or prepared by methods described herein or ~known in the art. The crude products, obtained by concentration under reduced pressure, are purified by means described herein or known in the art, including par-.
titioning, solvent extraction, washing, silica gel chroma-tographyJ trituration, or crystallization.
, .:
Following the procedures of Examples 41-322 but em-ploying the racemic ~orms of the PG compounds, the;re are -~ obtained the corresponding esters of the racemic PG com-~, .
pounds.

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

`: ,~ ''' :.' :' ~o86-F

gL~45~32 TABLE I
Esters of PGE
:. Hydroxy Phenyl or Product PGE1 Ex ~ ~thy1 Compound_ ester of fo mula 41 p-(p~acetamidobenzamido)phenolXl-C
42 p-(p-benzamidobenzamido)phenol Xl-D
43 p-hydroxyphenylurea Xl-E
44 p-hydroxy-1J3-diphenylurea Xl-F
p-phenylphenol Xl-G
46 p-tritylphenol X-l-H
47 N-acetyl-L-tyrosinamide Xl-l 48 N-benzoyl-L-tyrosinamide Xl-J
49 p-hydroxybenzaldehyde semicarba- Xl-K
zone 5 p-hydroxyacetophenone Xl-L
51 p-hydroxybenzophenone Xl-M
52 p-hydroxybenzamide Xl-N
5~ N- (p-tritylphenyl:)-p-hydroxybenzam;de Xl-0 , . . . .
~ 54 p-hydroxybenzoic acid, methyl ester Xl-P
20~ 55 hydroquinone benzoate Xl-Q
56 hydroquinone, p-ac:e~amidoben~oic Xl-R
acid ester '~ 57 2,4-diacetamidophenol ~ Xl-S
~: 58 :~ 1-acetamido-4-hydroxy-naphthalene Xl-T
59 1-benzamido-4-hydroxy-naphthaleneXi-U
.
~ ~60 1-hydroxy-4-ureido-na~phthalene Xl-V ~ ~

., :
,. ~ ., :, .
; .
~, ", , , , :,:

~ :, . :,, , 1045~
TABLE ll :
Esters of PGE2 Hydroxy Phenyl or Product PGEz Ex. Naphthyl Com~ound Ester of formula: :
61 p-(p-benzamidobenzamido)phenol Xl-D
62 N-(p-tritylphenyl)-p-hydroxy- Xl-O
benzamide

6~ p-hydroxybenzoic acid, methyl Xl-P
ester 64 hydroquinone benzoate Xl-Q
65 hydroquinone, p-acetamido- Xl-R
benzoic acid ester ; ::
66 2,4-diacetamidophenol Xl-S
67 1-acetamido-4-hydroxy-naphthalene Xl-T
68 1-benzamido-4-hydroxy-naphthalene Xl-U
69 1-hydroxy-4-ureido-naphthalene Xl-V

,`. .'",'-'""
;'- ' ' .: . .
... ..

~ . .
. ' .
' "

.. : . . . . .

;.~
, .
: : . :
. , .
, -46- .:~
:, .,.' ' :
;, ~

. 3086-~ .

l~S~3Z
TABLE lll Esters of PGA1 ~. .
Hydroxy Phenyl or Product PGA1 Ex.__ _ Naphthyl Compound Ester_of formula: :-70 p-acetamidophenol Xl-A
71 p-(p-acetamidobenzamido)phenol Xl-C -72 p-(p-benzamidobenzamido)phenol Xl-D ` ~
73 p-hydroxy~ -diphenylurea Xl-F
74 p-phenylphenol Xl-G
75 p-tritylphenol X:l-H -. ; i~
76 N-acetyl-L-tyrosinamide Xl-~
77 N-benzoyl-L-tyrosinamide Xl-J
78 p-hydroxybenzaldehyde semicarbaone Xl-K .
79 p-hydroxybenzophenone Xl-M
N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 81 p-hydroxybenzoic acid,~methyl ester Xl-P ;~
82 hydroquinone benzoate : Xl-Q -;~
83 : hydroquinone, p-acetamidobenzoic Xl-R

20 ~ 84 2,4-diacetamidophenol~ ~ Xl-S
85 1-acetamido~4-hydroxynaphthalene Xl-T
` 86 : 1-benzamido-4-hydroxynaphthalene Xl-U
87 1-hydroxy-4-ureidonaphthalene XI-V
- ~ ~ . - .

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

.. . .
: 47 :.:., ' ~:

.. . .. ..

1(~4513~2 -TAB_E IV '~
Esters of PGA2 Hydroxy Phenyl orProduct PGA2 :' Ex. _ _,Naphthyl Compound _ _ E,ster of formula-, 88 p-acetamidophenol XI-A
89 p-(p-benzamidobenzamido)phenol XI-D
90 p-hydroxyphenylurea XI-E
91 p-hydroxy-1,3-diphenylurea XI-F
92 p-tritylphenol Xl-H '.
93 N-acetyl-L-tyrosinamide XI-I
94 N-benzoyl-L-tyrosinamide XI-J ,.
95 p-hydroxyacetophenone XI-L
96 p-hydroxybenzophenone XI-M
97 p-hydroxybenzam;de XI-N
98 N-(p-tritylphenyl)-p-hydroxybenzamideXI-0 '. ' 99 p-hydroxybenzoic acid, methyl ester XI-P
100 hydroquinone benzoate XI-Q ~:
101 hydroquinone, p-acetamidobenzoic XI-R :':i;. -'' acid ester 102 2,4-diacetamidophenol XI-S ;~
,.: .
10~ 1-acetamido-4-hydroxynaphthalene XI-T '-' ,~ ,-, 104 1-benzamido-4-hydroxyna~phthalene XI-U
105 -1:-hydroxy-4-ureidonaphthalene XI-V ,',:~' :
' :: .' ,'~`: '' :' -:
. .,.

.-.
.:: .: .

... . .
-48- :::
, . ~ .:
:: , - :.~ .

3086- F :

, TABLE V :
Esters of PGF2~ .
Hydroxy Phenyl or Product PGF
Ex. Naphthyl Compound Ester oF Formula: .
106 p-(p~acetamidobenzamido)phenol Xl-C : ~
107 p-(p-benzamidobenzamido)phenol Xl-D :-108 N-(p-tr:itylphenyl)-p-hydroxyben- Xl-0 zamide . .
109 hydroquinone benzoate Xl-Q -10 110 hydroquinone, p-acetamidobenzoic Xl-R .. -aci~ ester -111 2J 4-diacetamidophenol Xl-S
112 1-acetamido-4-hydroxy-naph~thalene Xl-T
113 1-benzamido-4-hydroxy-naphthalene Xl-U
114 1-hydroxy-4-ureido-naphthalene Xl-V ,;
': -, , , ' .

,, ': ,:
, ,~
~'. !.

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

:: .-:
~ ' ' ' ~: : : . :
: . :.:. l . .
.: .

,', :, .

:'-' . `~ ;.' 4 5 ~ 3 Z

TABLE Vl Esters of 15-Methyl-PGE1 Product Hydroxy Phenyl or 15-Methyl-pGEl Ex _ Naphthyl CompoundEster of formula:
115 p-acetamidophenol Xl-A
116 p-benzamidophenol Xl-B - :
117 p-(p-acetamidobenzamido)phenol Xl-C
118 p-(p-benzamidobenzamido)phenol Xl-D
119 p-hydroxyphenylurea Xl-E
120 p-hydroxy-1,3-diphenylurea Xl-F ;~
121 p-phenylphenol Xl-G `.
122 p-~ritylphenol Xl-H
123 N-acetyl-L-tyrosinamide Xl-l ~
124 N-benzoyl-L-tyrosinamide Xl-J :~;.
125 p-hydroxybenzaldehyde semicarbazone Xl-K . .
126 p-hydroxyacetophenone Xl-L : -127 p-hydroxybenzophenone :XI-M
128 p~-hydroxybenzamide Xl-N
129 N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 :
. .
130 p-hydroxybenzoic acid, methyl ester Xl-P : :; :
131 hydroquinone benzoate Xl-Q
132 hydroquinone, p-acetamidobenzoic Xl-R
acid ester 133 2,4-diacetamidophenol Xl-S :.
134 1~acetamido-4-hydroxynaphthalene Xl-T
135 1-benzamido-4-hydroxynaphthalene Xl-U
..
: 136 1-hydroxy-4-ureidonaphthalene Xl-V ~ .
: ~ .

..:i. .. . .:
:. : :.
. :.
.....
~ -50-,. '''''.
.

: .
, .
TABLF yll :
Esters of 15-Methyl-PGE2 Product Hydroxy Phenyl or 15-Methyl-pGE2 Ex, __ NaPhthyl Compound Ester of formula:
1~7 p-(p-acetamidobenzamido)phenol Xl-C :
138 p-(p-benzamidobenzamido)phenol Xl-D
139 p-hydroxyphenylurea Xl-E
140 p-phenylphenol Xl-G ;
141 p-tritylphenol Xl-H
142 N-acetyltyrosinamide Xl-l ~.
14~5 N-benzoyltyrosinamide XI-J
144 p-hydroxyacetophenone Xl-L ~ .
145 p-hydroxybenzamide ~ Xl-N .~
..
146 N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 147 p-hydroxybenzoic acid, methyl esterXl-P
I48 hydroquinone, p-acetamidobenzoic: Xl-R
acid ester 149 2,4-diacetamidophenol ~ Xl-S
~150 1-acetamido-4-hydroxynaph.thalen~. Xl-T
29~ : 151~ 1-benzamido-4-hydroxynaph:thalene-. Xl~-U
152 ~ 1-hydroxy-4-ureidonaphthalene : Xl-V

. .

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

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

~o86-F

~4S13;Z
TABLE Vlll Esters of 15-Methyl-PGAl Product -:
Hydroxy Phenyl or 15-Methyl-PGA1 Ex. _ _ NaPhthyl Compound _ Ester of formula 153 p-acetamidophenol Xl-A
154 p-benzamidophenol Xl-B
155 p-(p-ace~amidobenzamido)phenol Xl-C
156 p-(p-benzamidobenzamido)phenol Xl-D - . .
157 p-hydroxyphenylurea Xl-E
158 p-hydroxy-1,3-diphenylurea Xl-F :
159 p-phenylphenol Xl-G ~:~
160 p-tritylphenol Xl-H .
161 N-acetyl-L-tyrosinamide Xl~
162 N-benzoyl-L-tyrosinamide Xl-J :
163 p-hydroxybenzaldehyde semicarbazone Xl-K : .
164 p hydroxyacetophenone Xl-L :
165 p-hydroxybenzophenone Xl-M
~ 166 p-hydroxybenzamide Xl-N
: 167 N-(p-~ritylphenyl)-p-hydroxybenzamide Xl-0 20 ~ ~ 168 p~-hydroxybenzoic acid, methyl ester Xl-P ;~ ~.
169 hydroquinone benzoate Xl-Q ; :
, . . .
: ~ 170 hydroquinone, p-acetamidobenzoic acid Xl-R
ester ~ .
171 2,4-diacetamidophenol Xl-S -~
172 1-acetamido-4-hydroxynaphthalene Xl-T
173 1-benzamido-4-hydroxynaphthalene Xl-U ~.
174 1-hydroxy-4-ureidonaphthalene Xl-V ~:

!,:
" ',~', : '. ' :,'` ' "',' ' , .
-52- :
.:, .~. ..... ...
~, .

10~513;2 TABLE IX
Esters of 15-Methyl-PGA2 Product :
Hydroxy Phenyl or ,~5,-~ethyl~PGA2 Ex._ _ Naphthyl ComPound Ester of formula:
175 p-acetamidophenol Xl-A
176 p-benzamidophenol Xl-B ' ~
177 p-(p-acetamidobenzamido)phenol Xl-C - ' 178 p-(p-benzamidobenzamido)phenol Xl-D , 179 p-hydroxyphenylurea Xl-E ''~
180 p-hydroxy-l,~-diphenylurea Xl-F ;~ , ,, 1&1 p-phenylphenol Xl-G '.;: ~
182 p-tritylphenol Xl-H ~.,""-:
18~ N-acetyl-L-tyrosinamide Xl-l ':.
184 N-benzoyl-L-tyrosinamide Xl-J ''' 185 p-hydroxybenzaldehyde semicarbazone Xl-K -.
186 p-hydroxyacetophenone Xl-L
187 p-hydroxybenzophenone Xl-M
188 p-hydroxybenzamide Xl-N ` '' 189 N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 . .
:190 p-hydroxybenzoic acidJ methyl ester Xl-P : '".: -191 hydroquinone benzoate Xl-Q ~ .
: : 192 hydroquinone, p-acetamidobenzoic Xl-R ,', acid ester 193 2~4-diacetamidophenol Xl-S .~.' : 194 1-acetamido-4-hydroxynaphthalene Xl-T `:, 195 1-benzamido-4-hydroxynaph~halene Xl-U .~
-:, ~: ~ 196 1-hydroxy-4-ureidonaphthalene Xl-V : : ' : ~ ,... ...

.

: ~:
. .
~53~ ,, .
. ~ ,.~: , ; .

1~4S~3~:
TABIE X
Esters of 15-Methyl-PGF2~ -Product Hydroxy Phenyl or 15-Methyl-pGF2a Ex. Naphthyl Compound Ester of formula :::
197 p-acetamidophenol Xl-A
198 p-benzamidophenol Xl-B
199 p-(p-acetamidobenzamido)phenol Xl-C
200 p-(p-benzamidobenzamido)phenol Xl-D ~:
201 p-hydroxyphenylurea Xl-E
202 p-hydroxy-1,3-diphenylurea Xl-F
203 p-phenylphenol Xl-G
204 p-tritylphenol Xl-H
205 N-acetyl-L-tyrosinamide Xl-l ;:~.
206 N-benzoyl-L-tyrosinamide Xl-J ~.
207 p-hydroxybenzaldehyde semicarbazone Xl-K ,.
208 p-hydroxyacetophenone Xl-L ~ .
209 p-hydroxybenzophenone Xl-M ;` ~-: - "
210 p-hydroxybenzamide Xl-N ; ;
211 N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 212 p-hydroxybenzoic acid, methyl ester Xl-P ~.
~ 213 hydroquinone benzoate X! Q
: 214 hydroquinone, p-acetamidobenzoic.:~ Xl-R
~ acid ester ~ :
215 2,4-diacetamidophenol Xl-S .
216 1-acetami:do-4-hydroxynaphthalene Xl-T ::
217 1-benzamido-4-hydroxynaphthàlene Xl-U .
218 1-hydroxy-4-ureidonaphthalene: Xl-V :.`~

, . .:

.
'' ~' -54- :.~
: ' ' ,- ~ , 1(~4~132 TABLE Xl Esters of 15(R)-15-Methyl-PGE

Hydroxy Phenyl or 15-MethUylCtpGE ~ ;
Ex, ~hl~ ComPound Ester of formula~
219 p-acetamidophenol Xl-A
220 p-benzamidophenol Xl-B
221 p-(p-acetamidobenzamido)phenol Xl-C
222 p-(p-benzamidobenzamido)phenol Xl-D ~:
223 p-hydroxyphenylurea Xl-E : : .
224 p-hydroxy-1,3-diphenylurea Xl-F ;~ :
.
225 p-phenylphenol Xl-&
226 p-tritylphenol Xl-H
227 N-acetyl-L-tyrosinamide Xl~
228 N-benzoyl-L-tyrosinamide Xl-J
229 p-kydroxybenzaldehyde semicarbazone Xl-K
:230. p-hydroxyacetophenone ~ Xl-L
2~ p-hydroxybenzophenone ~ Xl-M
232~ p-hydroxybenzamide Xl-N
: 233: N-(p-tritylphenyl)-p-hydroxybenzamide Xl-0 234 p-hydroxybenzoic acid,~methyl ester ~ XI-P~
235~ h~ydroquinone benzoate~ Xl-Q
236 hydroquTnone, p-acetamidobenzo-ic:Xl-R
: acid~ester 25~ 237~ 2,~4-:d~iacetamidophenol ~ Xl-S
~:~ 238 1-acetami:do-4-hydroxynaphthalene Xl-T
239 1-benzamido-4-hydroxynaphthalene Xl-U
240 1-hydroxy-4-ureidonaphthalene Xl-V

-55-~
~: : : ~ .

3086-f ~ -: "
104~3~ -TABLE Xll ~
Esters of 15 (R)-15-Methyl-PGE2 :
Product Hydroxy Phenyl or 15(~)7~5-Methyl-pGE2 :
Ex, ~l Compound Ester of formula:
241 p-(p-acetamidobenzamido)phenol Xl-C ~ ~ :
242 p-(p-benzamidobenzamido)phenol Xl-D ;`~
243 p-hydroxyphenylurea Xl-E
244 p-phenylphenol Xl-G
245 p-tritylphenol Xl-H
246 N-acetyltyrosinamide Xl~
247 N-benzoyltyrosinamide Xl-J .~ ~.
248 p-hydroxyacetophenone Xl-L .
249 p-hydroxybenzamide Xl-N
250 N- (p-tritylphenyl)-p-hydroxybenzamide Xl-0 ;
251 p-hydroxybenzoic acid, methyl ester Xl-P ~ .
!~ ~ ,.'' :, 252 hydroquinone, p-acetamidobenz~ Xl-R
acid ester . ,,. ~ : .
~ 25~ 2,4-diacetamidophenol ~ Xl-S
254~ 1-acetamido-4-hydroxynaphthalene- Xl-T
255 1-benzamido-4-hydroxynaphthalene: Xl-U ' 256: 1-hydroxy-4-ureidonaphthalene Xl-V

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

:
~, :
: : -56- .:
:: ~ .;',''''"' .' ~o86- F

~45~32 . :.
TABLE Xl I I
, Esters of 15(R)-15-Methyl-PGAl Product Hydroxy Phenyl or~5(R)-15-Methy1-PGA
Ex. NaPhth~l ComPoundEster of_formula:
257 p-acetamidophenol Xl-A
258 p-benzamidophenol Xl-B
259 p-(p-acetamidobenzamido)phenol Xl-C
260 p-(p-benzamidobenzamido)phenol Xl-D
261 p-hydroxyphenylurea Xl-E
262 p-hydroxy-1,3-diphenylurea Xl-F
263 p-phenylphenol Xl-G
264 p-tr;tylphenol Xl-H
265 N-acetyl-L-tyrosinamide Xl-l 266 N-benzoyl-L-tyrosinamide Xl-J
267 p-hydroxybenzaldehyde semicarbazone Xl-K
268 p-hydroxyacetophenone Xl-L
269 p-hydroxybenzophenone Xl-M
~ 270 p-hydroxybenzamide Xl-N
271 N-(p-tritylphenyl)-p-hydroxybenzamide Xl 0 272 p-hydro~ybenzoic acid, methyl ester Xl-P
27~ hydroquinone benzoate Xl-Q
~274~ hydroquinone, p-ace~amidobenzoic Xl-R
acid ester . ~ .
275 2,4-diac~etamidophenol Xl-S ~`^; "
276 l-acetamido-4-hydroxynaphthalene Xl-T
277 1-benzamido-4-hydrox~ynaphthaleneXl-U . j 278 1-hydroxy-4-ureidonaphthalene Xl-V

: `;.:. ' :

'"
, 5 7 . :
" ;. . ~ ~

,~,o86- ~ :

3 ~ ~ :
TABLE XIV
Esters of 15(R)-15-Methyl-PGA2 Hydroxy Phenyl or 15(R)-15-Methyl-PG~
Ex. NaPhthyl CorPound Ester of f~cm~
279 p-acetamidophenol Xl-A ~ .
280 p-benzamidophenol Xl-B ~ : :
. . .. .
281 P-(p-acetamidobenzamido)phenol X!-C ~ .
282 p-(p-benzamidobenzamido)phenol Xt-D ~
283 p-hydroxyphenylurea Xl-:E ~:.
284 p-hydroxy-1,3-diphenylurea Xl-F ~
285 p-phenylphenol Xl-G ..
.- . , 286 p-tritylphenol Xl-H
2~7 N-aoetyl-L-tyrosinamide Xl~
288 N-benzoyl-L-tyrosinamide Xl-J
289 p-hydroxybenzaldehyde semicarbazone Xl-K
290 p-hydroxyacetophenone Xl-L
291 p-hydroxybenzophenone Xl-M
292 p-hydroxybenzamide Xl-N
. .. .
293 N (p-tr:itylphenyl)-p-hydroxybenzamide Xl-0 : . :
. .. .
294 p-hydroxybenzoic acid,:methyl ester Xl-P
295 hydroquinone benzoate Xl Q i .
;296 hydroquinone, p-acetamidobenzoic acid Xi-R ;:~ .
297 2,4-diacetamidophenol Xl-S~
298 1-acetamido-4-hydroxynapht~halene Xl-T
299 1-benzamido-4-hydroxynaphthalene Xl-U -. ~
: 300 1-hydroxy-4-ureidonaphtha-lene Xl-V
~ ... ~ , :-, .. . :,.

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

~8 ~;
',~:! ' , ~6)4S~L3~

TABLE XV `
Esters o~ 15(R)-15-Methyl-PGF2a Product Hydroxy Phenyl or15(~)~15-Methyl PGF2~ :
Ex. NaphthYl CompoundEster of Formu1a- _ :
301 p-acetamidophenol Xl-A
302 p-benzamidophenol Xl-B
30~ p-(p-acetamidobenzamido)phenol Xl-C
304 p-(p-benzamidobenzamido)phenol Xl-~
305 p-hydroxyphenylurea Xl-E ..
306 p-hydroxy-1,3-diphenylurea Xl-F
307 p-phenylphenol Xl-G
308 p-tritylphenol Xl-H
~09 N-acetyl-L-tyrosinamide Xl-l 310 N-benzoyl-L-tyrosinamide Xl-J
311 p-hydroxybenzaldehyde semicarbazone Xl-K
: 312 p-hydroxyacetophenone Xi-L .
313 p-hydroxybenzophenone X:l-M
314 p-hydroxybenzamide Xl-N ; ~ -20 ~ 315 N-(p-tritylphenyl)-p-hyd~r~oxybenzamide Xl-0 ~ `~
~ .
316 p-hydroxybenzoic acid, methyl ester Xl-P .~.
. .. .
317 hydroquinone benzoate Xl-Q ~
.
:318 hydroquinone, p-acetamidobenzoic Xl-R ~;; .
: acid ester .;. .
25~ 319 2,4-diacetamidophenol XI~S ~ `
320 1-acetamido-4-hydroxynaphth~lene. Xl-T
~ 321 1-benzamido-4-hydroxynaphthalen~ Xl-U
: ~ ~322 ~1-hydroxy-4-ureidonaphthalen~! Xl-V : .

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

:

: 59 : ~':'' . '' .,, ,. ,.:,. ~ :. , .

Claims

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

A process for preparing an optical1y active compound of the formula or a racemic compound of that formula and the mirror image thereof, wherein is , or ;

wherein A is -CH2CH2- or cis -CH=CH- when is or and wherein A is cis -CH=CH- when is ;

wherein Z is and wherein Y is , , , or , , which comprises the steps, (1) forming a mixed anhydride from an optically active compound of the formula or a racemic compound of that formula and the mirror image thereof, wherein , A, and Y are as defined above, by reaction with a chloroformate ester in the presence of a tertiary amine, and (2) reacting the anhydride with a corresponding phenol or naphthol.

A process according to claim 1 wherein the chloroform-ate ester is isobutylchloroformate.

A process according to either claim 1 or 2 wherein Y is .

A process aceording to either claim 1 or 2 wherein Y is or .

A process according to either claim 1 or 2 wherein Y is or .

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-acetamidophenol and PGE1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and PGE1 .

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-acetamidophenol and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-(p-acetamidobenzamido)-phenol and PGE 2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyphenylurea and PGE 2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-tritylphenyl and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of N-acetyltyrosinamide and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of N-benzoyltyrosinamide and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzaldehyde semicarbazone and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyacetophenone and PGE2.

A pxocess according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzamide and PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-acetamidophenol and 15-methyl-PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and l5-methyl-PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ster of p-acetamidophenol and 15 (R)-15-methyl-PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and 15(R)-15-methyl-PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzaldehyde semicarbazone and 15(R)-15-methyl- PGE2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-acetamidophenol and PGA1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and PGA1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyphenylurea and PGA1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyacetophenone and PGA1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzamide and PGA1.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and PGA2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-(p-acetamidobenzamido)-phenol and PGA2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzaldehyde semicarbazone and PGA2.

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-acetamidophenol and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-benzamidophenol and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyphenylurea and PGF2.alpha., A process according to claim 1, wherein the optical by active or racemic compound is the ester of p-hydroxy-symdiphenylu-rea and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-tritylphenol and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of N-acetyltyrosinamide and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of N-benzoyltyrosinamide and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzaldehyde semicarbazone and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxyacetophenone and PGF2.alpha..

A process according to claim 1, wherein the optically active or racemic compound is the ester of p-hydroxybenzophenone and PGF2.alpha..

A process according to claim 1, wherein the optical1y active or racemic compound is the ester of p-hydroxybensamide and PGF2.alpha..

A process according to claim 1, with the additonal step of recrystallizing the esters to yield the products in free-flowing crystalline form.

An optically active compound of the formula a racemic compound of that formula and mirror image thereof wherein ,A, Z and Y are as defined in claim 1, whenever pre-pared by the process defined in claim 1 or by the obvious chemical equivalent.

The ester of p-acetamidophenol and PGE 1, whenever prepared or produced by the process defined in claim 6 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and PGE1, whenever prepared or produced by the process defined in claim 7 or by the obvious chemical equivalent.

The ester of p-acetamidophenol and PGE2, whenever prepared or produced by the process defined in claim 8 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and PGE2, whenever prepared or produced by the process defined in claim 9 or by the obvious chemical equivalent.

The ester of p-(p-acetamidobenzamido)phenol and PGE2, whenever prepared or produced by the process defined in claim 10 or by the obvious chemical equivalent.

The ester of p-hydroxyphenylurea and PGE2, whenever prepared or produced by the process defined in claim 11 or by the obvious chemical equivalent.

The ester of p-tritylphenol and PGE2, whenever prepared or produced by the procass defined in claim 12 or by the obvious chemical equivalent.

The ester of N-acetyltyrosinamide and PGE2, whenever prepared or produced by the process defined in claim 13 or by the obvious chemical equivalent.

The ester of N-benzoyltyrosinamide and PGE2, whenever prepared or produced by the process defined in claim 14 or by the obvious chemical equivalent.

The ester of p-hydroxybenzaldehyde semicarbazone and PGE2, whenever prepared or produced by the process defined in claim 15 or by the obvious chemical equivalent.

The ester of p-hydroxyacetophenone and PGE2, whenever prepared or produced by the process defined in claim 16 or by the obvious chemical equivalent.

The ester of p-hydroxybenzamide and PGE2, whenever prepared or produced by the process defined in claim 17 or by the obvious chemlcal equivalent.

The ester of p-acetamidophenol and 15-methyl-PGE2, whenever prepared or produced by the process defined in claim 18 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and 15-methyl-PGE2, whenever prepared or produced by the process defined in claim 19 or by the obvious chemical equivalent.

The ester of p-acetamidophenol and 15(R)-15-methyl-PGE2, whenever prepared or produced by the process defined in claim 20 or by the obvious chemical equivalent.

The ester of p-benzarnidophenol and 15(R)-15-methyl-PGE2, whenever prepared or produced by the process defined in claim 21 or by the obvious chemical equivalent.

The ester of p-hydroxybenzaldehyde semicarbazone and 15(R)-15-methyl-PGE2, whenever prepared or produced by the process defined in claim 22 or by the obvious chemical equivalent.

The ester of p-acetamidophenol and PGA1, whenever prepared or produced by the process defined in claim 23 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and PGA1, whenever prepared or produced by the process defined in claim 24 or by the obvious chemical equivalent.

The ester of p-hydroxyphenylurea and PGA1, whenever prepared or produced by the process defined in claim 25 or by the obvious chemical equivalent.

The ester of p-hydroxyacetophenone and PGA1, whenever prepared or produced by the process defined in claim 26 or by the obvious chemical equivalent.

The ester of p-hydroxybenzamide and PGA1, whenever prepared or produced by the process defined in claim 27 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and PGA2, whenever prepared or produced by the process defined in claim 28 or by the obvious chemical equivalent.

The ester of p-(p-acetomidobenzamido) phenol and PGA2, whenever prepared or produced by the process defined in claim 29 or by the obvious chemical equivalent.

The ester of p-hydroxybenzaldehyde semicarbazone and PGA2, whenever prepared or produced by the process defined in claim 30 or by the obvious chemical equivalent.

The ester of p-acetamidophenol and PGF2.alpha., whenever prepared or produced by the process defined in claim 31 or by the obvious chemical equivalent.

The ester of p-benzamidophenol and PGF2.alpha., whenever prepared or produced by the process defined in claim 32 or by the obvious chemical equivalent.

The ester of p-hydroxyphenylurea and PGF2.alpha., whenever prepared or produced by the process defined in claim 33 or by the obvious chemical equivalent.

The ester of p-hydroxy-sym-diphenylurea and PGF2.alpha., whenever prepared or produced by the process defined in claim 34 or by the obvious chemical equivalent.

The ester of p-tritylphenol and PGF2.alpha., whenever prepared or produced by the process defined in claim 35 or by the obvious chemical equivalent.

The ester of N-acetyltyrosinamide and PGF2.alpha., whenever prepared or produced by the process defined in claim 36 or by the obvious chemical equivalent.

The ester of N-benzoyltyrosinamide and PGF2.alpha., whenever prepared or produced by the process defined in claim 37 or by the obvious chemical equivalent.

The ester of hydroxybenzaldehyde semicaxbazoneand and PGF2.alpha., whenever prepared or produced by the process defined in claim 38 or by the obvious chemical equivalent.

The ester of p-hydroxyacetophenone and PGF2.alpha., whenever prepared or produced by the process defined in claim 39 or by the obvious chemical equivalent.

The ester of p-hydroxybenzophenone and PGF2.alpha., whenever prepared or produced by the process defined in claim 40 or by the obvious chemical equivalent.

The ester of p-hydroxybenzamide and PGF2.alpha., whenever prepared or produced by the process defined in claim 41 or by the obvious chemical equivalent.

An ester according to claim 43 in free-flowing crystalline form, whenever prepared or produced by the process defined in claim 42 or by the obvious chemical equivalent.