Note: Descriptions are shown in the official language in which they were submitted.
1077~48
This invention relates to a novel series of 1,5-disubstituted-2-
pyrrolidones which are prostaglandin-like in chemical structure and biological
character, the processes for making such 2-pyrrolidones and synthetic
¦ intermediates employed in these processes.
I The C20 unsaturated fatty acids, known as prostagl-ndins, form a ,,
i large family of naturally-occurring compounds. These molecules may have as
many as five asym~etric centers and are present in and evoke response from a
diversity of biological tissues. An example of a particular species of the
prostaglandin E genera is PGE2 pictured below.
,. . !
! 1 .
! ~ ' ~ C2H
H0~`
¦ prostaglandin E2
,
I According to the notation usually employed to tescribe the stereo-
chemistry of prostaglandins, a heavy solid line represents the ~ configuration ;
~hich is defined as a bont coming up out of the plane of the paper ant toward
¦¦ the reader. In a like manner, a dotted or hashed line represents the ~ con-
! figuratlon whlch ~s deflned as a bond going behind the plane of the paper and
¦1 away from the reader. Thus, the configuration of the prostaglandin E2, pic-
.
, tured above, is at carbon atom 8 and ~ at carbon atom 12. [S. Bergstrom, et
al., Acta. Che~. Scand., 16, 501 (1962)J.
i ~ .. ", .
.~ 1
.I f
.
7~8
By he same ter=inology, a wavy l~ne represents a r~xt~re t~ the two
¦forms ~ and ~. Thus, a 2-pyrrolidone of the structure: ¦
., ¦ ~ 8 C2H
. I ~
~ -
represents a mixture of the epimers
~2B
. I
I .
I and
: . ~ 8 2
. ~ '~ . I
~ OB
.
''-,
~,'
,'.``
~ '
". li ~,
. Il i
I !
~ 2-
~ 1 I
li , !
!l
- : , - ~ ~
' ' .' , . ~ ' ' :
07794~
¦ By reference to the pyrrolidone of structure ~ and prostaglandin E2
.. !
shown above, a stereochemical comparison can be made between the two sets of
¦ compounds. The stereochemistry at positions 12 and 15 is the same in both
¦ types but that at position 8 is different. rnat is, the configuration of theI C8-C7 bond of the prostaglandin E is a, but that of the N8-C7 bond is in the
plane of the paper according to the representation of the drawing above.
¦ Another way to represent the above two examples which will develop a better
appreciation of this difference in configuration is the edge-on drawing below:
li
h; ~_~ A ~
prostaglandin E pyrrolidone
where A and B stand for the two side chains of the examples. Here the illus-
tration depicts the eclipsing of the A-C8 bond with the C12-H bond and the
¦ eclipsing of the C12-B bond with the C8-H bond in the case of the prostaglandin
E and the bisecting position of the A-N8 bond with respect to the dihedral
angle formed by B-C12-H in the case of the pyrrolidone. This difference in
; conformation is a result of the planarity generated by the amide moiety of
the pyrrolidone. ["Basic Principles of Organic Chemistry", J. D. Roberts and
M. C. Caserio, W. A. Benjamin, New York, 1965, p. 674]
A systematic name for a 1,5-disubstituted-2-pyrrolidone of the
¦ structure:
;
~ 11 -3-
i 11
.,
~ .~,
. ~
10779 4t~ !
'
I ~ ~ C2H
~/ ~
H OH
: ¦l is 1-(6'-carboxyhexyl)-5~-(3"~-hydroxyoct-1"-enyl)-2-pyrrolidone and it also
.- ¦ can be named as a derivative of ll-desoxyprostaglandin El; that is, 8-aza-11-
desoxy PGEl.
. ¦ The corresponding 8-aza-11-desoxy PGE2 compound has the structure:
.' O . j~
~ N ~ C2H
:~ ~~~~~ I
. H OH
:
. where the single bond between C2' and C3' has been replaced by a double bond.
¦ The corresponding 8-aza~ desoxy PGEo compound has the structure:
., I O . `. '.
I ~ N C2H
,., ~
. I H OH
~, I . ~
I where the double bond between Cl" and C2" has been replaced by a single bond.
~.,
` . I .
~: ~
-4-
,., l
jl .
~ ~1
,
,, . 1, , . I
LO779~ ~
l I
The above pyrrolidones have several centers of asymmetry,
and can exist in the racemlc (optically inactive) form and in either of
the two enantiomeric (optically active) forms, i.e. the dextrorotatory (D) and
llevorotatory (L) forms. As drawn above, each pyrrolidone structure represents
1 5 ~he particular optically active form or enantiomer which is derivable in part
from D -glutamic acid. The mirror image or optical antipode of each of the
above structures represents the other enantiomer of that pyrrolidone and is
derivable in part from L -glutamic acid.
¦ For instance, the optical antipode of 1-(6'-carboxyhexyl)-5~-(3"~-
10 ¦hydroxyoct-1"-enyl)-2-pyrrolidone is drawn as:
¦ O C02H
. . ~
HO H
¦ and is called 1-(6'-carboxyhexyl)-5-(3"~-hydroxyoct-1"-enyl)-2-pyrrolidone.
,., I .
The racemic form of the above pyrrolidone contains equal
¦ numbers of a particular enantiomer and its ~irror image. When reference
to the racemate of a compound contained herein is intended, the symbol "rac"
15 I will precede the compound's name. This term will then mean and is properly
¦ represented by an equimolar mixture of the D and the L or enantiomeric forms.
~ A pair of optical isomers which are optical antipodes or enantiomers i
¦ are related through inversion of the absolute conflguration at all of their
1l centers of asym~etry. Contrastingly, when the relationship is an inversion ofl
20 11 absolute configuration at one or more but not all of the centers of asymmetry, !
the pair of isomers are epimers or diastereomers. For instance, 1-(6'-
carboxyhexyl)-5~-(3"-hydroxyoct-1"-enyl)-2-pyrrolidone and 1-t6'-carboxy-
I
, -5-
1,
I, .
:
, ~ , ? ~ ~
hexyl)-5~-(3"~-hydroxyoct~ enyl)-2-pyrrolidone are diastereomers related by
~m inversion of configuration about the C5 atom and are shown respectively
I ~s
- N ~ ~ ~ C 2
~N ~ C2H
I I l"",~~~
H OH
It is a fact that chemical experimentation on either member of an
enantiomeric pair or upon a mixture of the two will produce the same and iden-¦
tical results.
¦ As pointed out earlier, substitution of a nitrogen for the carbon atl
C8 causes a dramatic change in the three dimensional conformation of the resulj
I tant prostaglandin. Because structure is related to biological activity and
10 ¦ often a subtle change in structure such as a conformational change will have a
¦ profound efiect upon the biological activity, such molecular modification of
I prostaglandins by substitution of heteroatos has been investigated recently.
¦ Nbst compounds are atte~ptsat investLgation of heteroatom substitutions at the C9 an~
Cll prostaglandin positions and include such examples as 9-o~aprostaglandins
15 ¦ [I. Vlattas, Tetrahedron Let., 4455 (1974)]; ll-oxaprostaglandins [A. Fougerou~se,
¦ Tetrahedron Let., 3983 (1974)] and S. Hanessian et al., Tetrahedron Let., 3983 !
j (1974) and 9-thiaprostaglandins [I. Vlattas, Tetrahedron Let., 4459 (1974)].
T~o 8-aza-11-desoxy prostaglandin E's with the natural ~-side
I chain, that is, compounds with the aza substitution at C8 of ll-desoxy pros- !
20 ll taglandin El and E2 have also been reported in the litcrature [G. Bolliger
and J. M. Muchowski, Tetralledron Let., 2931 (1975) (Aug. 1975); and J. W.
Bruin~ et al., Tetrahedron Let., 4599 (1975)]. These examples of pyrrolidone
-6-
Il ,
~1 1
!1 1
~.
1077948
compounds are outside of the scopc of the present invention which presents a
higher order of complexity and molecular variation at the Cl prostaglandin
position and in the ~i-side chain. Relatively Iittl-e--biological activity is
reported for these literature examp;es and they can be contrasted in form and
in molecular complexity with the novel compounds of the present invention.
The natural prostaglandins and many of their derivatives such as
the esters, acylates, and pharmacologically acceptable salts, are extremely
potent inducers of various biological responses [D. E. Wilson, Arch. Intern.
Med., 133 (29) (1974)] in tissues composed of smooth muscle such as those of
the cardiovascular, pulmonary, gastrointestinal and reproductive systems, in
cellular tissues such as those of the central nervous, hematologic, reproduc-
tive, gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and
adipose systems and also operate as mediators in the process of homeostasis.
With such a wide range of responses, it is apparent that the prostaglandins are
involved in basic biological processes of the cell. Indeed, this basic impli-
cation of prostaglandins is supported by the fact that they can be found in
cellular tissue of almost all animal organisms.
Often on such a cellular level the actions of closely related natural~
prostaglandins may be opposite. For instance, the effect of PGE2 on human plate-
20 I lets is enhancement of aggregation while that of PGEl is inhibition of aggrega-~
tion.
Such contrasting effects may also bs observed at the tissue level.
For instance, in vivo PGE2 ac~ion on the cardiovascular system of ma;nmals mani~
fests itself by causing hypotension while the in vivo action of PGF2~ is hyper-
25 tension [J. B. Lee, Arch. Intern. Med., 133 56 (1974)j. However, the ability to
predict the biological action of prostaglandin classes based upon such obser- I
vations is largely illusory at present. For instance, ~hile the cardiovascular,
actionsof PGE2 and PGF2 are opposite as described above, their in vivo or in
vitro action on mammalian uterine smooth muscle is the same and is stimulatory
; 30 (causes contraction) [H. R. Behrman, et al , Arch. Intern. Med., 133 77 (1974)).
. I
-7- ~ I
.
... .. . , ...... ,~,~
077948
In the preparation of synthetic pharmaceutical agents, among the
!
principal ob;ects is the development of compounds which are highly selective
in thelr pharmacological activiey and which have an increased duration of acti-
¦ vity over their na~urally occurring relatives, In a series of compounds which1 is similar to the naturally-occurring prostaglandins, increasing selectivity
I of a single compound usually involves the enhancement of one prostaglandin-like
¦ physiological effect and the diminution of the others. By increasing the
¦ selectivity, one would alleviate the severe side effects frequently observed
¦ following adminlstration of the natural prostaglandins; for example, those
¦ gastrointestinal side effects of diarrhea and emesis or cardiovascular side
effec~s when bronchodilator effects are desired. Recent developments directed
toward an increase of biological selectivity include the ll-desoxy prostaglan- ,
¦ dins [N. H. Anderson, Arch. Intern. Med., 133, 30 (1974) Review], 2-descarboxy-
¦ 2-(tetrazol-5-yl)-11-desoxy-15-substituted-~-pentanorprostaglandins (M. R.
Johnson et al., U.S. 3,932,389) where certain modifications are cited as pro- '
. ducing selective vasodilator, antiulcer, antifertility, bronchodilator and anti
ypertensive properties, 16-phenoxy-16-~-tetranor prostaglandins having anti-
fertility activity (U.K. 1,350,971) and l-imide and l-sulfonimide prostaglandins;
~, .
;~ (U.S. 3,954,741).
:. i
I '
,, I
.,
~ I
,''', . 11
.,
: 11
:
,
. 1~ .
Il -8-
Ii
,,~y, ~
', . ' , :
1' 1`07794~ ~
I
!
The present invention comprises novel prostaglandin-like compounds
~which have selective and potent biological activity and which have the struc- ¦
ture:
S j and the C5 epimer thereof wherein: O
O Q is selected from the group consisting of COR3, tetrazol-5-yl and
-CNHR4;
A is a single or cis double bond;
B is a single or trans double bond;
U is H~3~ OH or HO~ 'H ;
'' , I
; . R2 is selected from the group consisting of ~-thienyl, phenyl, I
: phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents¦
being selected from the group consisting of chloro, fluoro, phenyl, methoxy,
trifluoromethyl and alkyl having from one to three carbon atoms;
15R3 is selected from the group consisting of hydrogen, alkyl having
from one to five carbon atoms, phenyl and p-biphenyl;
R4 i8 selected from the group consisting of -CR5 and -SO2R5, said R
being selected from the group consisting of phenyl and alkyl having from one
to five carbon atoms;
20iland the alkali, alkaline earth and ammonium salts of those compounds
having a carboxylate or tetrazol-5-yl group.
. ~
1.
I~.,
1 1
10'7794~, .
In addition the present invention comprlses intermediates which willj
. allow the preparation of the final products above and which have the structure :
L~W
. and the C5 epimer thereof wherein W is selected from the group consisting of
-COR3, tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl having from two to five
5 ¦ carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl and N-(tetrahy-
dropyran-2-yl)tetrazol-5-yl, and A, B, R2 and R3 are each defined as above;
G~,' --w
¦1 and the C5 eF Lter ehereof wherein W and A are defined as above;
. I ~ N ~ ~ N" ~`CHO
s'~ ! and ~ ~ OH
H H
and the C5 ep ~er thereof.
10-
,, I
. ~1
~...
1~779~
In accordance with the present invention, there
is provided a process for the preparation of a novel 1,5-
disubstituted -2-pyrrolidone compound having selective pro-
staglandin - like activity and having the formula:
.\5~--Rl . I
H . ll
or the C5 epimer thereof, wherein Q is -COOH or -COOR, R
is alkyl of from one to five carbon atoms; W is a single
or cis double bond; Z is a single or trans double bond;
M is ~ ~OH or HO ~H and R' is phenyl or phenoxy, which
comprises reducing a 3"oxo-pyrrolidone intermediate of
the formula:
.~=\-~`R~
11
o ~ . . I I
wherein Q, W, Z and R' are as defined above, to convert
to oxo substituent at the 3"-position to ~ hydroxy or
~-hydroxy.
107794~
: l I
l I
Especially preferred for their selective biological actlvity are: I
¦ 1-(6'-carboxyhexyl)-5~-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone
. ¦ and the methyl ester and 5 epimer thereof,
,~ ¦ 1-(6'-carboxy-hex-2'-enyl)-5~-(3"a-hydroxy -4"-phenylbut-1"-enyl)-2-
5 I pyrrolidone and the 5 epimer thereof,
1-(6'-carboxyhexyl)-5~-(3"-hydroxy-4"-phenylbutanyl)-2-pyrrolidone
, ¦ and the 5 epimer thereof,
.~ i 1-(,6'-carboxyhexyl)-5~-(3"-hydroxy-4"-phenoxybut-1"-enyl)-2-pyrrolidone
,~ I and the 5 epimer thereof,
1 1-(,6'-carboxyhex-2'-enyl)-5~-(3"-hydroxy-4"-phenoxybut-1"-enyl)-2-
, pyrrolidone and the 5 epimer thereof,
,, 1-(6'-carboxyhexyl~-5~-(3"~-hydroxy-4"-phenoxybutanyl)-2-pyrrolidone
and the 5 epimer thereof,
. , the compounds wherein 6t-(tetrazol-5-yl) replaces the 6'-carboxy
,1 group of each of the above especially preferred compounds,
, I and the compounds wherein a 3"~-hydroxy replaces the 3"-hydroxy
gro~p of esch of the abo~o 6'-carboxy a~d 6'-(tetrasol-5~ l) c =po~ds.
~ ¦ !
. I
. l l
,, . ~.
1 i
~.
q
Il 107794~ ,
' . I
The pyrrolidone compounds of the present invention of prostamimetics
are prepared in an optically active form by six step sequence which attaches
j the two side chains, the or top side chain and the ~ or bottom side chain,
to the pyrrolidone ring and starts ~ith a resolved amino acid, D- or L-glutamic
acid. It is noted that the choice of the route starting from D- or L-glutamic
acid establishes the absolute confirmation of C5 of the 2-pyrrolidone ring and j
pre-empts the necessity of resolving this position at the end of the synthesis.
; In the examples and discussion to follow, the D-configuration is shown. The L-
¦ configuration compounds are prepared by the same sequence from L-glutamic acid.
The synthetic sequence shown by Scheme A illustrates the methods by
which the chain is attached to the 2-pyrrolidone nucleus. It will be noted
that the methods prepare in each instance a pyrrolidone intermediate 19
I differing only at the C2'-C3' bond, The final products of the present invention
are then synthesized from intermediate 19 according to the methods presented in
Sche=es B, C a-~ D.
`- I!
.,' l
~; ! 13
1~ i
' ' , ' ' '
i1 ~077948
¦ SCHEME A - cl CHAIN ATTACHMENT
' I
~N2
¦ (a) lo
~H
~ 1l7 L~ w ~oY 18
.~ ¦ ' CH20T ~ CH2T
(d~ ~OU _ = 5
o (8 `1 Ph 31'-CU ( CU2 ) 3W
¦l ~N ~--W
¦l !
1077948
A brlef summary of the steps in Scheme A is as follows. The first
step, marked (a), illustrating the cyclization of D-glutamic acid to methyl D-
pyroglutamate and the reduction of the pyroglutamate to 5-D-hydroxy-2-pyrroli-
done is known ~V. Bruckner et al., Acta. Chim. Hung. Tomus, 21, 106 (1959)].
The second step (b) is the protection of the hydroxymethyl group with protec-
ting agent T which can be any group suitable for the protection of the hydroxyl
¦ against alkylation; for instance, benzyl, dimethyl-t-butyl silyl, acetyl, 1-
ethoxyethyl~ or especially tetrahydropyranyl. Steps (c) and (e) illustrate the
Alkylation of the sodium or lithium salt of pyrrolidone 1 by alkylating agents
of the formula
X~~W
or XCH2CH(OY)2, respectively, wherein X is Cl, I, or especially Br; W is C02X3,
N-acyloxymethyl)tetrazol-5-yl having from two to five carbon atoms in the acyl_
oxy group, N-(phthalidyl)tetrazol-5-yl, N-(tetrahydropyran-2-yl)tetrazol-5-yl
or tetrazol-5-yl; Y is alkyl having from one to three carbon atoms, and A and R3
are definet as above. Step ~d) is the removal of protecting group T, the method
of which will depend upon the identity of T. Step (f) is the deprotection of
the pyrrolidone compound 18 to produce in situ 1-(ethan-2'-al)-5-hycroxymethyl-
2-pyrrolidone which can exist in intimate equilibrium with the hemi-acetal
I compound 5. Step (g) is a Wittig reaction of the equilibrium mixture contain-
! ing bicyclo[4,3,0]nonan-5-one 5 with a phosphorane of the structure Ph3P-
CH(CH2)3W wherein W, definet above, i9 unprotected to produce the corresponding
2-pyrrolidone compound 19 wherein A is a double bond.
;
'' ~', ' ,.
Ii . -<,5 .
11,
Ij ;
, , I ,, , .~_~
. ' '
1~794~ 1
. I
; The reactions necessary to produce the products of the invention
I are arranged in order so that no epimerization of the optically active center
¦at C5 will occur. Therefore, by starting with either of the two enantiomers of
I glutamic acid, the same configuration at the asymmetric centers is preserved
5 I in the products. Also by starting with racemic glutamic acid, the racemic or
rac products are produced.
The C5 position of the intermediates and products of the present in-
vention will be drawn in the ~ configuration but the ~ configuration at the
C5 position is applicable also, provided that the starting glu~amic acid has
the proper configuration. I
- The first two steps of the reaction sequence are the condensa- ¦
tion and esterification of D-glutamic acid to produce the corresponding D- l
methyl pyroglutamate of the structure: ¦
H C2Me ~
','
[E. Hardegger, et al., Helv. Chem. Acta., 3O, 312 (1955); E. Segel, J. Am. Chem.
1 j Soc~, 74-, 851 (1952~]. '
The third,and knowl4step of the sequence shown in Scheme A as step (a)
is the reduction of the 5-carboxymethyl group of D-methylpyroglutamate to
produce 5-D-hydroxymethyl-2-pyrrolidone. This reaction is most conveniently
! conducted by employing a variation of the method reported by V. Bruckner, et
20 I al.[Acta. Chem. Hung. Tomus, 21, 106 (1959)].
l l
. . , ,~
~-
1077948
The D-methyl pyroglutamate is stirred with litllium borohydride in dry tetra- !
hydFofuran or other ethereal solven~ until the reduction is substantially co-.n-
plete. Isolation of the product in the reported manner gives 5-D-hydroxymethyl
2-pyrrolidone of the structure:
, 1,
CH20H
, . H
. ' ' 1~
- In order to alkylate the amide nitrogen of 5-D-hydroxymethyl-2-
pyrrolidone, it is appropriate to protect the labile 5-hydroxymethyl hydrogen
with the known tetrahydropyranyl group. Thls protection (Scheme A, step (b))
is most conveniently accomplished by contacting 5-D-hydroxymethyl-?-pyrrolidone
with dihydropyran in the presence of an organic acid such as p-toluene sulfonic
acid and in an inert solvent such as methylene chloride, chloroform, tetrahydro-
furan or diethoxy ethane. The appropriate temperature range for this reaction
is from that of an ice bath to that of refluxing solvent and preferably ambient.
~fter the formation of 5-D-(tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone 1 is
Fubstantially complete, usually overnight, it is isolated by first removing the
frganic acid by basic extraction and removing the solvent and any excess dihydro
yran by vacuum evaporation t~chniques. The product is most commonly purified
~y col~mn ~hromat raphy
,~
J~
'. ''
... . .
7794l~ I
,. . I
j Other protecting agents that can be employed with equal facility
include at~y which will protect the hydroxyl from alkylation. Some examples
are benzyl, acetyl, dimethyl-t-butyl silyl and l-ethoxyethyl. These protecting
¦ agents are readily available and can be attached to the 5-hydroxymethyl group
I by known methods. Their selection for synthetic purposes will depend upon the
¦ protecting group at C7'. For instance, if it is desired to employ N-tetrahydro-
pyran-2-yl as a protecting`group for the acidic hydrogen of a C7' tetrazol-5-
yl (W), appropriate C3" hydroxyl protecting groups (T) would oe acetyl or
d~=ethyl-t-bu:Lsilyl.
'
~' I ''
'~. I . , ' ' . 1,
',~
,~,.',
:- . I
~1 .
, ' jl .
'
. , ,~
. ~ 18
1~
. .
.. . ~
~ 1(177948 ~1
~ ' I
l The l-(alkylated)-2-pyrrolidone compounds (17 and 18 Scheme A) are
! prepared by a combination of two reactions which are performed upon 5-D-(tetra-l
hydropyran-2'-yloxymethyl)~2-pyrrolidone 1 of any of its T group analogs. First,
the sodium or lithium salt of pyrrolidone 1 is prepared by contacting a solu-
tion of compound 1 in an inert organic solvent such as tetrahydrofuran, di- ¦
. ethoxyethane or dioxane with a base such as n~butyl` lithium, phenyl lithium or
especially sodium hydride. The appropriate temperature range for this salt forj
mation is ambient to that of refluxing solvent and preferably ambient. All base!
¦must be reacted before starting the alkylation which usually requires times of ¦
l to 4 hours. Then, the desired l-(alkylated)-2-pyrrolidone compounds 17 and 1
are respectively formed by contacting the above prepared lithium or sodium salt
~of 2-pyrrolidone compound 1 with an alkylating agent of the structure:
! ~ I
! X W or XCH2CH(OY)2 ll
. I :
wherein X is Cl, I and especially Br, !
W and A are each defined as above and
15 j Y is alkyl having from one to three carbon ato~s. This second part
¦of the alkylation procedure is usually conducted by additlon of a mixture of
¦the alkylating agent in the inert organic solvent previously defined or es?eci-
ally by addition of a mixture of the alkylating~agent in a polar aprotic organic
solvent such as dimethylformamide or dimethylacetamide to the above formed mix-
ture of the sodium or lithium salt of pyrrolidone 1 ln an inert organic solventand then by allowing contact between the mixture of alkylating agent and 2-
pyrrolidone sodium or lithium salt at temperatures of ambient to solvent reflux
until the alkylation is substantially complete, usually overnight.
Of course, the alkylated 2-pyrrolidone resulting from use of XCH2C~-
tOY)2 can also be prepared by employing XCH2C02Et as the alkylating agent fol-
lowed by selective conversion of the ester group of the resultant 1-(2'-ethyl
acetate)-5-(substituted)-2-pyrrolidone to aldehyde.
,~
,...
107794~
l~len there is the possibility of having an acidic hydrogen present in
~1, the alkylation procedure is most conveniently executed by protecting or
otherwise ren~oving that acidic hydrogen. For example, in the case where R3 is
hydrogen, the best method is employment of an ester derivative which can then
be removed by alkaline hydrolysis at the end of the synthetic sequence. In the!
case where W is tetrazol-5-yl, the best method is replacemel~t of t~e acidic
hydrogen by an acyloxyme~hyl as defined above, a phthalidyl group ~'. v.Daehne,
J. I~ed. Chem., 13, 607 (1970j; I. Isaka, et al., Chem. Pharm. Bull., 24, 102
(1976)~ or a tetrahydropyran-2-yl group. l`he first two groups ror tetrazol-5-
yl protection will also be removed by alkaline hydrolysis at the end of thesynthesis (Scheme B) but the l~lP group will be removed by acidic hydrolysis.
It will be assumed in the ensuing discussion tnat the acidic hydrogen of the
W group has been protected unless otherwise stated.
The character of the C2~-C3' bond of the 2-pyrrolidone compound 17
obtained from the alkylation step is determined by the nature of A in the
¦ alkylating agent
.' I X~W
¦
The selection of A will also determine the unsaturated or saturated character
of the a-side chain of the final product of the synthesis; that is, whether the
I final product will be an 8-aza-11-desoxy PGEl or an 8-a~a-desoxy PGE2.
Obviously, the selection of A only causes a difference in the charac-;
ter of the C2'-C3' bond of the a-side chain and in fact, conversion from pyrro-'
lidone compounds where A is a double bond to those where A is a single bond is
¦possible at the pyrrolidone compound 17 stage of the synthesis. For instance,
the 2-pyrrolidone compound 17 with the double bond at A may be converted to the
2-pyrrolidone compound 17 with the single bond at A by hydrogenation over a
noble metal catalyst such as palladium on carbon at ambient temperature until
1 equivalent of hydrogen is absorbed.
.' I
~ I
...'
l 10779~
~ ~ I RN~ W 2 ~----U
Compound 17 A = double bond Compound 17 A = single bond
., l
I
In either case, the protecting group T is removed (step d, Scheme A~ ~
by methods known to those familiar with the art in anticipation of the forma- ¦
; tion of the ~-side chain. The resulting 2-pyrrolidone compounds of the structure: u
,
Compound 19 -
wherei~ W and A are each defined as above, are then carried through Schemes B,
C and D to produce the novel final products of the present invention.
The above 2-pyrrolidone compound 19 can also be prepared by contact-
; ¦ing the hydrolyæed form of the 2-pyrrolidone of the structure:
~i I ~OY
Compound 18
wherein Y and T are defined as above with a phosphorane of the structure:
. ~.
. I I . Ph3P~CH(CH2)3W
; 10 llwherein ~, defined as above, is unprotected, e.g. C02H or tetrazol-5-yl. The
Ilsynthesis of the tetrazol-5-yl phosphorane will be found in U.S. 3,953,466.
: . i
.. ~
." .
,~
.. , . . .
, Ii . .~
.. , ~ - . .
. 1077948
Thi6 subset of reactions, illustrated by steps (f) and (g) of Scheme¦
A, can be executed in the following manner. If the preferred T proteeting
- group, tetrahydropyran-2-yl, is used in compound-18, then acid hydrolysis of
compound 18 according to the usual method for acetal removal such as acetic ac~d
in water at ca.40C. will-cleave both the tetrahydropyran-2-y~ and the acetal ~o
form l-(ethan-2'-al~-5~-hydr~xyme~hyl-2-pyrrolid~o~e which can exist in intimat
equilibrium with 4-aza-2-hydroxy-1-oxa-bicyclo[4,3,0]nonan-5-one 5.
~ ~ ,,OH
nonanone 5
The equilibrium mixture containing hemiacetal 5 can then be contacted wi~ about
equivalents of phosphorane as defined above in a polar apro.ic solvent such as~
dimethylsulfoxide or a mixture of an ethereal and polar aprotic solvent such a
tetrahydrofuran and dimethylsulfoxide at temperatures of 0C. to 60, usually
overnight, to produce 2-pyrrolidone 19 wherein A is a double bond. It will be
not-ed that ~he acidic hydrogen or group W ~an then be p.oteGted as an ester in
the case of the carbo~ylic acid or as an N-acyloxymethyl, N-phthalidyl ~or N-
u
. 19 1~
tetrahydropyran-2-yl group in the case of tetrazal-5-yl. This 2-pyrrolidone 13
with A as a double bond can, if desired, be converted to 2-pyrrolidone 19
wherein A is a single bond by the hydrogenation method described above.
Several of the final products of the present invention, the 2-
pyrrolidone compounds 22, carb. a~d tet.~ are prepared by oxidat~Qn of ~he 5~-
l ~ hydroxym-thyl o~p qE 2-pyrrol~dqne 19 aqd Norn~r-Wl~lE re=c~ion oE ~he ~h~s
10779~ ,
formed 5~-formyl-2-pyrrolidone compound 20 with the sodium or lithium salt of
¦~ a phosphonate of the structure (MeO)2PCH2C~12R2 wherein R2 is defined as above,
j followed by reduction of the thus formed 5-(4"-substituted-but-1"-er.-3"-onyl)
moiety of 2-pyrrolidone 21.
Scheme B illustrates this outlined process, the method of which
~ttaches th w-chain.
.
~ ~
','
,~
7`:
'
: i I
il ,
.,., ~ ! ` . __
,j ` .
7794~
SCHEME B
~-CHAIN ATTAC~IENT
.' ~
! 19 H
~¦ 1 oxidation
L ~
1 (leo)2pc~d2~cl2R2
~: I ~
!-
21 O
: ¦ reduction
2 3 1 ¦
22-carb. H OH 2
A IH
~11 1
. .
~y
r~
. 1CI177941~ I
The aldehyde 20 is obtained from tl~e 5~-hydroxymethyl-2-pyrrolidone
compound 19 by a modification of the Pfit~ner Moffat~oxidation [K. E. Pfitzner
and M. E. Moffatt, J.Am. Chem. Soc., 87, 5661 (1965)~ which avoids contact of
the 5~-formyl compound 20 with water. For example, stirring a slurry of 1-(7'-
methylheptanato ~-5~-hydroxymethyl-2-pyrrolidone or other appropriate 5~-hydrox _
methyl-2-pyrrolidone in an inert, hydrocarbon solvent such as toluene, xylene
or especially benzene with dimethyl sulfoxide, a weak acid such as acetic acid
or especially pyridinium trifiuoroacetate and a water soluble diimide such as
diethyl carbodiimide or especially dimethylaminopropylethylcarbodiimide or,if
desired, its hydrochloride salt, at temperatures of 0C. to ambient for 1 to 4
I hours, will oxidize the primary alcohol 19 to aldehyde 20. Alternate methods
to achieve oxidation include the usual Pfitzner-Moffatt reaction and oxidatio,n
with chromium t~ioxide-pyridine complex [R. Ratcliffe, et.al., J. Org. Chem., 35~,
4000 (1970)] although the method of choice is the reaction described above.
The 5~-(4"-substituted but-1"-en-3"-onyl)-2-pyrrolidone compound 21
is prepared by contacting the 5~-formyl-2-pyrrolidone compound 20 with the sodi-um or lithium salt of a phosphonate of the structure:
'O O ~ I
(MeO)2PCH2CCH2R2
., . . ,. I
wherein R2 is defined as above in a solution or slurry with an ethereal solvent ¦
fiuch as tetrahydrofuran, dimethoxyethane or dioxane at temperatures from 0 to
~C. until the reaction is essentially complete- as determined by reaction
monitoring methods. The isolation of product from this Horner-Wittig reaction, ,the method of which is known to those familiar with the art, is accomplished in
the usual fashio~ by chromatography. Other-methods include high pressure liquid
ohromatography and in some cases fractional recrystallization. The method for
the preparation of the phosphonates will be found in U.S. 3,932,389.
. . I
,
1077948
Reduc on a~d, lf desired, alk~llnc or acidlc hydrolysis of the 2-
pyrrolidone compound 21 produces several of the final products of the invention I
wherein Q is C02R3 or tetrazol-5-yl. The reagent of choice for conducting the rer
duction is lithium triethylborohydride, but other selective reduction reagents ¦
S which will reduce the ketone but no other groups,e.g. zinc borohydride or sodium¦
borohydride, can be employed with equal facility. ~he usual solvents employed
are ethereal in nature such as tetrahydrofuran and diethyl ether. The temper-
ature selection will be based upon the activity of the reducing agent and in
most cases it is convenient to employ a dry ice/acetone bath.
10Under the usual reaction conditions, the reduction of the but-l"-en- ¦
3"-onyl moiety of the pyrrolidone 21 will actually produce-two 2-pyrrolidone
compounds 22, w~ich are diastereomers.
~ W and L ~ W
3"~-hydroxy compound 22a 3"~-hydroxy compound 22b
Thus, these two compounds, which are separable by the common isolation techniques
such as high pressure liquid chromatography, are both prepared by the described
manner; and it is assumed that both are indicated even though the isomer is
shown throughout- If the separation of the two diastereomers is not done, then I
a mixture of the two compounds will result and is indicated as: ¦
A
~ ~ L~W
and is taken to mean a mixture of the ~ epimer and the ~ epimer.
;: . ' ~ I
.. ,~
.
~ 1077948
AfLer isola~ion of the product of thc above reduction reaction in the
usual manner, the protecting group on thc acidic position of the C7 group W, ca
be removed, if desired, using conditions common for~~the removal of such groups.
For instance, if an alkyl ester was selected as W and the acid is desired,
simp]e alkaline hydrolysis with one equivalent of base at ambient temperature
to that of refluxing solvent, usually overnight, will yield after neutralization'
the carboxylic acid. In a like manner 3 the phthalidyl and acyloxymethyl groups
can be removed, but the tetrahydropyran-2-yl (THP) group will be removed with
acid such as acetic acid in water or p-toluene sulfonic acid in methanol at am-
bient temperature to 50 usually overnight.
The products of the present invention wherein A and B are each singlebonds, e.g. compound 23 carb. and tet., are prepared by catalytic reduction of
the 3"-tetrahydropyran-2"'-yloxy derivative of 2-pyrrolidone 22 wherein A is a
single bond. That sequence is outlined in Scheme C.
Alternatively, the pyrrolidone compounds 23 can be produced by cataly-l
tic reduction of the 3"'-tetrahydropyran-2"'-yloxy derivative of 2-pyrrolidone
22 wherein A is a double bond. In this case, A and B will be reduced to single
bondt at the sa time.
.
,
, ~
. .
ll ;
~077948
, I
SCUEME C
~J~N ~ W
A - single bond 2Z ¦ H~ R2
dihydropyran
~N ~~ W
OTHP
2~ Pd/C
1~ L~W
3 H
2 3 ~ N--
~N
~2 L~ R2
Z3 c rb., 23 tet.
~ ! .
` 11 '. . 'i
.~ I
I'
:: .
lom4s
The tetrahydropyran-2"'-yloxy derivative of compound 22 whcrein A i~
a single bond is formed in the same manner as that described for 5-D-(tetra-
hydropyran-2-yloxymethyl)-2-pyrrolidone 1. Then, hydrogenation over noble
metal catalysts such as palladium on carbon or platinum oxide in solvents such
as ethyl acetate, methanol or ethanol at ambient to reflux temperatures until
1 equivalent of hydrogen is absorbed followed by removal of the tetrahydro-
pyran-2"-yl group and, if desired~ the W protecting group by the usual methods
will allow the preparation of the 8-aza-11-desoxy prostaglandin Eo compounds 23.'
The products of the present invention wherein Q is NHR4 are pre?ared
10 from the tetrahydropyran-2"'-yloxy derivatives of compounds 22 and 23 having a
C02H group at W. That synthetic sequence is outlined in Scheme D wherein R5 is
defined as above. These a&id derivatives, compounds 24 and 25, are formed
I according to well-known methods described for imide and sulfonimide preparations
from carboxylic acids. The preferred method is that according to the procedure
of Speziale and Hurd where the acyl or sulfonyl isocyanate is contacted with
the above cited derivatives of compounds 22 and 23 in an inert solvent such as
ether or tetrahydrofuran at temperatures of ambient to solvent reflux, usually
oyernight. See the following: [A. J. Speziale, et.al., J. Org. Chem., 30, 4306
tl965~, C. D. Hurd and A. G. Prapas, J. Org. Chem., 24, 388 (1959); reactions of
isocyanates with carboxylic acids in "Survey of Organic Synthesis", C. A. Beuhler,
D. E. Pearson, Wiley Interscience, New York, 1970, N-acylation of amides and
imides, J. March, "Advanced Organic Chemistry: Reactions, ~echanism and Struc-
; ture", McGraw-Hill, New York, 1968, p. 340l. ¦
,'.', , 1l
. .
:' ..
. I
. ` ~77948
I I
1 There are also several other methods to prepare the
,products of the present invention wherein Q is CONHR4. The
~first alternate route comprises treating the 5 -(4"-substituted-
I.but-l"-en-3"-onyl)-2-pyrrolidone compound 21 wherein W is COOH
s ''with an acyl or sulfonyl isocyanate under the conditions des-
,cribed above for the procedure of Speziale and Hurd. The C-15
~Iketo group of resulting aminated or sulfonaminated pyrrolidone
¦! intermediate is then reduced to an hydroxyl group using the
ljprocedure described for the reduction of pyrrolidone compound 21 to
lipyrrolidone compound 22.
¦ The second alternate route comprises condensing nonanone
. ¦compound 5 with a phosphorane of the structure Ph3 P = CH(CH2)3-
'CONHR4 using the procedure described for the analogous prepara-
¦.tion of pyrrolidone 19 from nonanone 5. After optional hydrogena-
lltion of the resulting C5-C6 double bond, this route produces a
pyrrolidone intermediate of the structure
CONHR4
H CH2H ¦
1'' . ,
The above pyrrolidone carboxamide intermediate is analogous to
pyrrolidone compound 17 and can become carried through the
I,subsequent steps illustrated in Srheme B to prepare the compounds
Ilof ~he present inventlon wherein Q is CONHR4.
,~
10779~
The ester products of the present invention wherein
Q is carboalkoxy, carbophenoxy and carbo-para-biphenoxy can
be prepared from the corresponding acid products of the
present invention wherein Q is COOH by well-known methods of
esterification including reaction with diazoalkanes of from
one to five carbon atoms, and the reaction of phenol or
p-biphenol with the acid and dicyclohexylcarbodiimide.
In addition to forming the 8-aza prostaglandins
as described by Schemes A through C, they may be synthesized
from Intermediate 18 through initial attachment of the bottom
side chain and then formation of the top side chain. The
reactions used for this synthetic sequence are shown by
Scheme E. They have been previously described in detail in
Schemes A through C. Reaction l is the cleavage of the
dimethyl-t-butyl silyl protecting group annotated as T in the
scheme and is described on pages 16, 22 and 41. Reaction 2
is the oxidation of the primary alcohol group to an aldehyde
group which forms the handle for attachment of the bottom
side chain. This reaction is described on page 26 lines l
through 14. Reaction 3 is the Honer-Wittig reaction described
on page 26 lines 15 through 25. It employs a same type of
,' phosphonate used throughout the main synthesis. Reaction 4-l
is the reduction of the enone moiety of the bottom side chain
to an allyl moiety. It is described on page 27 lines l
through 20. Reaction 4-2 is the protection of the hydroxyl
, function of the allyl moiety formed in Reaction 4-l. It is
described on Page l9. Reaction 5 is the deprotection of the
, acetal group which forms the handle for the top side chain.
It is a simple hydrolysis and is described on Page 40.
Reaction 6 is the usual Wittig reaction used to form the top
side chain of prostaglandins and is described on Page 23
. lines 8 through 12 and Page 42. Reaction 7 is again the
deprotection of the hydroxyl group and is analogous to
Reaction 1. The symbols Y, T, R2 and Q have the meanings
given above.
,, .
,
- 29B -
077948 ) ` ~ I
, . ' . . , I
¦; RCI~E~IE D - IMIDE ARD SULFONI~IIDE DERIVATIFE~
3 ~--C0211
R5C \ R5S02XCO
-O ~ _ _o ~
. . 1 A O O O 11 A O O
. ~ N ~ ` `- ~ COCNHCR5 f N~ cocNHso2R5
L H OTHP _ . ~ B ~' ~ R2 _
021 l -C0
o o . . o 1
: ~ N ~ CNHCR5 ~ N~Se~=~cNHso2R5
~R2 ~R2
H OTHP H OTHP
H~ ~ H~
. o 1 A Q ~ ,
~ ~ N ~ / OCNH,OCR5 ~ ~N ~ CNHS02R5
~ R2 ~ R2
. .H OH H OH ' !
24 25
. ' I
~'.' . I
~ ,1
~, ~3
.
7794,~
SC~IE~'ME ~
alccrr;iate ri~ctiori scheme for 8 a:~a pxost:aglandin synthesis
R
C~ Y)2 Y=21e,Et
C ~liO r ~S~Ie2tBu
4 (reag~t)
C t~ Y),2
CH~ol~
co r~
MSO ~eagent ~ .
-e~ c~ yi~
\--~cuo ~'~\R2
3 ¦ R2~2~2P~) (~e)2/ 7. t n-Bu411F (rea~ t)
~ o
/\~\R2 ~\F~2
4. ¦ 1. JiBet3H -78~ 6. tP~3~{~2)3Q
2. Me2t-BuSiCl (phosphorane`i l
\~ ~ . o~ ~2
. ' ' ', 1.
,. ~ 30~9 - 1'
.
~ $~77948
. '
In numerous in vivo and in vitro tests it has been demonstrated that
; the new prostaglandin analogs possess physiological activitles of greater selec-
tivity, potency, and duration of action than those ex~ibited by the natural
prostaglandins. These tests include, among others, a test for effect on isolated
smooth muscle from guinea pig uterus, inhibition of histamine-induced broncho-
spasm in the guinea pig, effect on dog blood pressure, inhibition of stress-
induced ulceration in the rat, diarrheal effect in the mouse, and inhibition of
stimulated gast~ic acid secretion in rats and dogs.
The physiological responses observed in these tests are useful in de- l
termining the utility of the test substance for the treatment of various natural¦
. and pathological conditions. Such determined utilities in~lude: vasodilator
; activity, antihypertensive activity, bronchodilator activity, antifertility~
activity and antiulcer act;vity.
The novel 8-aza-11-desoxy prostaglandins of the instant invention
possecshighly selective activity profiles compared with the corresponding
naturally-occurring prostaglandins and, in many cases, exhibit a longer duration
of action. For instance, the novel prostamimetic pyrrolidones of the present
invention having tne substitutions of aryl (including phenyl, substituted phenyl
and -thienyl~ at R2 and carboxylic acid, carboxylic ester or
tetrazol-5-yl at Q possess useful vasodilator activity. Prime examples of the
therapeutic importance of these pyrrolidone compounds are the efficacies of 1-(6j-
carboxyhexyl)-5~-(3"-hydroxy-4"-phenylbut~ enyl)-2-pyrro~idone and 1-(6'-car-
boxyhexyl)-5a-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone which exhibit hypo
tensive activity o~ a similar potency compared with PGE2 itself when ad~inistered
;; 25 intravenously to anesthetized dogs according to the procedure of U.S. 3,956,2~4.~
` At the same time, other activities such as b'ronchodilation and antiulceration arq
greatly diminished compared to PGE2 as measured by the procedure described in
l~S-j,956,294.
1~
.. 1 . I
! .....
i 107794~
Another outstanding instance of the therapeutic importance of pyrroli-
dones o~ the instant invention is the selective anti-ulcer activity of compoundsl
having the substitutions of aryloxy (including phenoxy~and substituted phenoxy) ¦
at R2 andcarboxylic acid, carboxy~ic ester or imide, tetrazol-5-yl
or sulfonimide at Q. For example, 1-(6'-carboxyhex)Tl)-5~-(3"-hydroxy-4"-phenoxyL
but-l"-enyl)-2-pyrrolidone displays outstanding.and~selective antisecretory
ac~ivi , wheD ad nlseere o lly ~o dogs.
.. . , 1.
,' . . I
. , .... . . . .. . . I
I I ~Q7794~
¦l The new compounds of this invention can be used in a variety of phar-
¦maceutical preparations ~hich contain the compound or a pharmaceutically accep-
Itable salt thereof. They may be administered by a variety of routes which will '
¦depend upon the type of ailment and the condition of the individual. l ¦
¦ The 8-aza-11-desoxy-16-aryl-~-tetranorprostaglandin compounds of the
present invention and the epimers thereof are useful vasodilator agents. For
Itreatment of hypertension, these drugs can appropriately be administered as an
lintravenous injection at doses of about 0.5-10 mg./kg. or preferably in the fon~
¦of capsules or tablets at doses of 0.005 to 0.5 mg./kg./day.
The 8-aza~ desoxy-16-aryloxy-~-tetranor prostaglandin compounds
of the present invention and the epimers thereof are useful anti-ulcer agents;
~ For treatment of peptic ulcer, these drugs may be administered in the form of
; capsules or tablets at doses of 0.005 to 0.5 mg./kg./day.
Pharmacologically acceptable salts useful for the purposes descri~ed
above are those with pharmacologically acceptable metal cations, ammonium, amine
cations, or quaternary = onium cations.
Especially preferred metal cations are those derived from the alkali
¦metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals,
le.g., magnesium and calcium, although cationic forms of other metals, e.g.,
~aluminum, zinc, and iron, are wichin the scope of this invention.
Pharmacologically acceptable amine cations are those derived from
Iprlmary, secondary, or tertiary amines. Examples of suitable amines are methyl-,
¦amine, dimethylamine, triethylamine, ethylamine, dibucylamine, triisopropylamine,
jlN-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclo-
Ipentylamine, dicyclohexylamine, benzylamine, dibenzylamine, -phenylethylamine,
~-phenylethylamine, eehylenediamine, diethylenetriamine, and other aliphatic,
¦Icycloaliphatic, and araliphatic amines containing up to and including about 18
;icarbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine,
!Ipyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methyl-
20 ¦I pyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well
'1 3~
; . ~
. .."..~
. I
~.~,.-. j, .
~9~'~ `'q
107794~ ,
as amines containing water-sol.ubilizing or hydrophilic groups, e.g., mono-, di-,~
and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2 amino-l-butanol,,
2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-~-propanol, tris(hydroxymethyl~?-
aminomethane, ~-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine,
galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,
epinephrine, procaine, and the like. .
. Exa~pl.es of suitable pharmacologically acceptable quaternary ammoniu~ I
., cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium,
:. phenyltriethylammonium and the like. I
To prepare any of the numerous formulations possible, various reaction-
. . inert diluents, excipients or carriers may be employed. Such substances include',
for example, water, ethanol, gelatins, lactose, starches, magnesium stearate,
talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum
jelly, cholesterol and other known carriers for medicaments. If desired, these
ipharmaceutical compositions may contain auxiliary substances such as preserving
agents, wetting agents, stabilizing agents, or other therapeutic agents such as
antibiotiCs~ !
The following examples are merely illustrative, and in no way limit
the scope of the appended claîms. The spectral data were obtained on a Varian
T-60 or an A-60 ~IR, a Perkin-Elmer Grating Infrared Spectrometer and an LKB-
9000 mass spectrometer. The infrared data are given in reciprocal centimeters
and the ~R data are given in ~ parts per million using T~S as a standard. I
In general, the tem?eratures of the reactions described in the examples,
when unspecified, will be taken to mean ambient or room temperature which varied
l~f~ot 15~ t~ 30~C
'' ~ ' . ' . I
,-
'', i ~3 '` ' . I
,, , ~
1~7794J~ ~ j
The time requirement of the reactions described in the examples,
unless otherwise stated, was determincd by monitoring with thin layer chroma- I
tography (TLC). The usual TLC system was silica gel- on glass ( E. Merck Silica !
Gel plates~ E. Merck Dormstadt, W. Germany) with benzene/ether or methanol/
chloroform as eluants and vanillin/ethanol or iodine as developers. ["Intro-
duction to Chromatography" J. M. Bobbitt, A. E. Schwarting, R. J. Gritter, Van
Nostrand-Reinhold, N.Y. 1968~. As a general rule, the reaction in question was ;
deemed essentia~ly complete when the TLC Spot representing the critical startingl
'
I
, I
~, .. . 1,~
,
1.
:
.. . ... , '~
' ' . ' ~ ' ' , ' ' ~ " ' '
1~ 1
107794~ ~
:' , . I
I EXAMPLE 1
15B-(Tetrahydropyran-2~-yloxymethyl)-2-pyrrolidone 1
,Into a flame dried flask under a nitrogen atmosphere was put
1 2.54 g. (22.1 mmoles) 5-D-hydroxymethylene-2-pyrrolidone, prepared according
S I to the method of V. Bruckner et. al., Acta Chim. Hung. Tomus, 21, 106 (1959),
and 50 ml. methylene chloride. To this solution at 0C to 5 C was then added
3.72 g. (44.2 mmoles) redistilled dihydropyran and 0.2 g. p-tolenesulfonic
¦ (tosic)acid. The solution was then allowed to warm to room temperature
¦ and to stir overnight. After dilution of the reaction with 20 ml. ethyl
10 I acetate, the solution was extracted with 2 x 5 ml. saturated sodium bicarbo-
nate solution and 1 x 10 ml. saturated brine. The organic layer was dried
with magnesium sulfate, filtered to remove the drying agent, and the solvent
¦ was removed in vacuo to give 4.1 g. yellow oil. This oll was chromatographed ~
I on a 50 g. column of Merck silica gel packed in chloroform. Elution with ~ -
15 j lL. chloroform removed less polar impurities. Elution with 2% methanol
; I in chloroform and collection of 10 ml. fractions separated and
purified the product. Combination of product fractions and removal of
solvent in vacuo gave 3.95 g. of the title compound 1 as a yellow oil, 90%
yield ~ T-60(DCC13)b.s. C6.60 ppm (lH), m. ~4.60 ppm (lH), m. ~4.05 -
; 20 ~3.25 ppm (5H), m. ~2.50 -~2.10 ppm, m. ~2.00 - ~1.40 ppm (lOH).
IR(CHC13 solution)3425, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm
Addit~onally, the dimethyl-t-butyl silyl protecting group can be
employed in place of the tetrahydropyran-2-yl group by applying the procedure
I of E. J. Corey, et. al.,J. Am. Chem. Soc., 94, 6190 (1974) to 5-D-hydroxy-
I ~ethylene-2-pyrrolidone.
!
!
,. '
,
1, ~
I i
I'
! , . I
` iO7794~ 1
EXAMPLE 2
¦ 1-(7~-(Ethylheptanatoi-5~-(tetrahydropyran-2"-yloxymethyl!-2-pyrrolidone 2
! --
¦ Into a flame dried flask containing a nitrogen atmosphere was put
j 0.725 g. (18.7 mmoles) of 62% sodium hydride dispersion in mineral oil and
i lO ml. dry THF. To this mechanically stirred slurry was then slowly added
¦I dropwise 3.74 g. (18.7 mmoles) of 5-D-(tetrahydropyran-2-yloxymethyl)-2-
- 1I pyrrolidone 1 in lO ml. dry TH~ After the addition was complete, the ¦~
thick slurry was stirred for 30 minutes until all hydrogen evolution had
¦ ceased.
¦ The alkylation of the sodium salt was then performed.
¦ To this slurry at room temperature was then added dropwise 5.34 g.
¦ (22.5 mmoles) of ethyl-7-bromoheptanoate in 15 ml. drY DMF. At the completion¦
¦ of the addition, ca. 15 minutes, the slurry had dissolved and sodium bromide
I slowly started to precipitate from the solution. The reaction was stirred
¦ overnight, then filtered, and the solvent was removed in vacuo from the
j filtrate. To the residue was then added lO0 ml. ethyl acetate and this
: ¦ organic solution was extracted with 2 x 20 ml. water. After drying the
I organic layer with magnesium sulfate and filtering it to remove the drying
¦ agent, the solvent was removed in vacuo from the filtrate to give a yellow
~ oil which was chromatographed on a 120 g. column of ~erck silica gel
packed in chloroform. Elution with: (a) 250 ml. of chloroform; (b) 500 ml. 5% !
¦ ethyl acetate in chloroform; (c) lL. 10% ethyl acetate in chloroform; and
, ¦ automatic collection of lO ml. fractions allowed the separation and
I purification of the product. The product fractionq were co~bined and stripped
I of solvent to yield the title compound 2 as a colorless oil 3.39 g. 51~ yield.
. .
3-
,
1: !
~`~
0779~ I
I
l I
NMR T-60 (DCC13):M ~4.60 ppm (lH), q. ~4.17 ppm Jl = 8 hz.,
m, ~4.00 - 2.70 ppm (9~1), m, ~2.6 - 1.4 ppm, t. ~1.3 ppm Jl ~ 8 hz. (23H)
IR (HCC13) solution) 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200,
1125, 1025 cm 1, ',
S ¦ MS-heated inlet (m/e-%) 356-1%, 355-3%, 310-17%, 240-100%, 194-83%.
I The foregoing procedure can be adapted to the preparation
¦pyrrolidones of the structure below by substitution of the appropriate alkylating
¦agent for ethyl-7-bromoheptanoate and optionally by employment of the dimethyl- t-butyl silyl analog of pyrroli~one 1.
N " " ~7'"--"" X
OT
:
:.
X -- --C02C6,H5
.~ -C02cH3
N-(tetrahydropyran-2-yl)tetrazol-5-yl
N-(acetyloxymethyl)tetrazol-5-yl
¦¦ A - 9ingle or cis double bond.
¦ T ~ THP or dimethyl-t-butyl sllyl
$, I
' I
, I . .
' ' i
.1
. 1 3:
~q ~
~l ~ l l
; 1 ~77948
., ." , I
As stated the l-(substituted)-5~-(tetrahydropyr~n-2"-yloxymethyl or di~ethyl-t-l
¦ butyl silo~y methyl)-2-pyrrolidones can be prepared by substitution of the appro-
¦ priate alkylating agent for the ethyl-7-bromoheptanoate. For instance, if 1-(6'l
I carboxymethylhex-2'-enyl)-5~-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone is ~o
¦ be prepared, the alkylating agent will be methyl-7-bromohept-5-enoate. If 1-(6'~
l'~'-acetyloxymethyltetrazol-S' "-ylhexyl)-5~-(tetrahydropyran-2"-yloxymethyl)-
2-pyrrolidone is to be prepared, the alkylating Pgent will be 6-bromo-1-(l'-
acetyloxymethyltetrazol-5'-yl)-n-hexane.
1-(2,2-Diethoxyethyl)-5~-(tetrahydropyran-2"-yloxymethyl)-2-
pyrrolidone 3 can also be prepared by the same procedure by employing 2-bromo-
acetaldehyde diethyl acetal as the aIkylating agent.
The preparation of 6-bromo-1-tetrazol-5'-yl-n-hexane can be accom-
plished by the following method.
A mixture of 2.98 g. (23.5 mmoles) 7-hydroxyheptanenitrile, 1.60 g.
t30.0 l~moles) ammonium chloride, 0.032 g. (0.76 mmole) lithium chloride?
l.9i g. (29.3 mmoles) sodium azide and 50 ml. dimethyl formamide can be heated
;~ to 120 under nitrogen with stirring for 18 hours or until the reaction is
essentially complete. The dimethyl formamide can then be removed ln vacuo
and the resulting residue can be purified by one of several methods such as
chromatography or extraction. This product, 6-hydroxy-1-(tetrazol-5-yl)hexane,
can then be treated with phosphorus tribromide under appropriate conditions
to produce 6-bromo-1-(tetrazol-5-yl)hexane. The N'-acetyloxymethyl group
can be attached by employing the method of W. V. Daehne et. al. opt. cit.
, while the N-tetrahydropyran-2-yl group can be attached according to the method
j of Example 1.
.,j.~ I .
1.
.': I
,~
,',
I
~07794~
Treatment of 7-(tetrahydropyran-2'-yloxy)hept-5-ynenitrile in the
I sa~e manner as above will allow preparation of 6-(tetrahydropyran 2'-yloxy)-
¦ l-(tetrazol-S'-yl)hex-4-yne. This material can then be converted into 6-bro -
¦ l-(tetra701-5'-yl)hex-4-ene according to the procedure of Ger. Offen. 2,121,361
I (C.A. 76.24712d). Of course, the starting hept-5-ynenitrile can also be
hydrogenated to the olefin before converting the nitrile to the tetrazole,
essentially by following the same procedure. Again the protecting groups
for the acidic hydrogen of the tetrazol-5-yl can be attached by the above
methods.
I _,"' _
I
I1 ~0~94~ 1
I I
EXA~LE 3
(7~-Methylheptanato)-5~-hydroxymethyl-2-pyrrolidone 4
To a solution of 200 ml. methanol and 3.99 g. THP-pyrrolidone 2
~ was added 79 mg p-toluene sulfonic (tosic) acid and the solution was
5 ¦ refluxed overnight. After work up as described below, an N~ spectrum
o:E the reaction mlxture revealed the presence of a small amount of starting
ethyl ester. Therefore, the reaction mixture was redissolved in 1~0 ml.
methanol, .080 g. tosic acid added, and the reaction again refluxed overnight.
Removal of the solvent in vacuo from the reaction gave a yellow oil which
was dissolved in ethyl acetate and extracted with 1 x 10 ~1. of a 1:2 nix-
¦ ture of saturated sodium bicarbonate and half saturated Rochelle's salt
¦ solution. The organic phase was dried over magnesium sulfate, filtered
and the solvent evaporated to give the title compound 4 as a clear yellow
oil. 2.528 g (88%).
NMR A-60 (DCC13) s. ~3.86 ppm, m. ~4.00 - 3.33 ppm, m. ~3.Z0-
~2.70 ppm (13H), m. ~2~50 - ~2.00 ppm, m. ~1.90 - ~1.20 ppm (lOH), partial
spectrum. ~ -
IR (HCC13 solution) 3550-3100, 2980, 2910, 2840, 1720, 1650, 1450,
¦ 1425, 1410, 1250-1190 cm
20 I MS, LKB 9000, solid inlet (m/e-%)70eV 226-26%, 194-19.8% 74-10070
¦ 13eV 257-3.3%, 226-100% 168-24.6%.
Alternatively the tetrahydropyran-2 " '-yl group can be removed
by hydrolysis in a 65:35 mixture of glacial acetic acid:water for ca. 18
~ hours essentially according to the procedure of Example 14.
25 I In this case, the ethyl ester group of pyrrolidone 2 will be kept
¦ intac~.
_
il I
~ l ~ l
: 1 1077~4~
The foregolng acetic acid, water hydrolysis procedure can also be
used to remove the tetrahydropyranyl protecting group from the other
pyrrolldone products of Example 2 which then will produce the corresponding
l-(substituted)-5~-hydroxymethyl-2-pyrrolidones. However, if the tetrazol-5-yl
protecting group is tetrahydropyran-2-yl, then it will be appropriate to
............... employ the dimethyl-t-butyl silyl group as T. This silyl group can be
¦selectively removed with tetra n-butyl ammonium fluoride according to the
. ¦method of Corey, opt. cit.
On application of the acetic acid procedure to 1-(2~2-diethoxyethyl)-
5-(tetrahydropyran-2~'-yloxymethyl)-2-pyrrolidone 3 of Example 2~ removal of the
.: ~tetrahydropyranyl group will be accompanied by cleavage of the acetal and cycli-
zation~ to yield as product an equilibrium mixture Of the open form and 4-aza-
. 2-hydroxy-1-oxa-bicyclo[3,4,0]nonan-5-one 5.
~ N ~A~CH0~
j ¦ ~ Od ~ ~ O
:
: i'. rhe equilibrium mixture containing compound S can be converted to l-(substi- j
15 ¦tuted)-5~-ùydr xy=ethyl-2-pyrrolidones by the follo~ing procedore.
/,
i. ,
,., ! ~
. . ~ ~
1~ i
.
-
~, 1077~4~ ,
~1 i
¦ To a solutl~n of 23.04 g. (52.0 mmoles) of 5-triphenylphoxphonio-
pentanoic acid (bromide salt) in 46 ml dry dime~hyl sulfoxide can be added
dropwise 49.3 ml. (98.6 mmoles) of a 2.0N solution of sodium methyl-
sulfinylmethide in dimethyl sulfoxide. To the resultant red solution can
I then be added over the course of l.0 hour 3.27 g. (20.8 mmoles)
¦ of 4-aza-2-hydroxy-l-oxa-bicyclo[3,4,0]nonan-5-one 5 in dry dimethyl
sulfoxide (63 ml.). After being stirred for an additional half hour
¦ or until substantially complete, the reaction can be poured into 600 ml. of
I ice-water and then can be extracted with 2 x 300 ml. of ethyl acetate. The I i
10 I cold aqueous layer can be covered with ethyl acetate and acidified to pH~3 wit~
10% hydrochloric acid after which the aqueous layer can be extracted with
¦ 2 x 200 ml. of ethyl acetate. The combined organic extracts are washed
¦ with water, followed by brine, and the organic layer can be dried over
ll anhydrous sodium sulfate. Concentrating the filtered organic layer will ll
afford crude 1-(6'-carboxyhex-2'-enyl)-5~-hydroxymethyl-2-pyrrolidone which ',
can be.chromatographed. .The acid can then be esterified with diazomethane.
This procedure can also be used to prepare l-(substituted)-
5~-hydroxy~ethyl-2-pyrrolidones;o~ the structure,
,,~ l l
ou
i 't
~ wherein X is the same as that of Example 2, by substituting the appropriate
20 I phosphonium 5alt for 5-trlphenylphosphonopentanoic acid and then protecting
the acidic hydrogen with an N-acyloxymethyl group accord~ng to the procedure
jl described by W. V, Daehne et. al.,~op. cit., with an N-tetrahydropyran-2-
¦l yl group sccording to the procedure of Example l or by esterifying in the case.
j of the carboxy acid.
, I
'.
' ~077948
I
,, ~ , EXAMP.E 4
1-(7'-21etLy1heptanato~-53-formyl-2-pyrrolidone 6
To a flame dried flask containing ~ nitrogen a~mosphere was added
0.1286 g. (0.5 mmoles) 1-(7'-methylheptanato)-5~-hydroxymethyl-2-pyrrolidone 4
in 5 ml. dry benzene. To this solution 0.1286 g. (1.5 mmoles) dimetl;~,~l~mino-
I propylethylcarbodiimide hydrochloride (DAPC) and 0.142 ~1. (2 mmoles) dimethy'l
:' sulfoxide were added followed after five minutes by 0.108 g. (0.55 mmoles) of !
I pyridinium trifluoroacetate. The reaction was stirred under a nitrogen at-
I mosphere at room temperature for 1.75 hours, then the benzene was decanted
10 I and the viscous second phase which had formed at the bottom of the flask was
¦ washed with 3 x 5 ml. benzene. The benæene solutions were combined and the
solvent was removed in vacuo to give 0.152 g. of the title compound 6 as-a
clear yellow oil. The crude product was used immediately and without further !
! purif$cation in the next reaction.
15 ¦ NMR T-60 (DCCl~, d. ~9.72ppm Jl=3hæ(IH~ m. ~4.37 - ~4,07ppm (lH), s. 53.70ppm !
I (3~ partial spectrum
; I The foregoing procedure can also be used to oxidize the other 1-
~substituted)-5~-hydroxymethyl-2-pyrrolidones of Example 3 to the corresponding
1- (sub6tltut d)-55-tormyl-2-pyrrolidonec,
. - I ' . . ,
,: l ll
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;
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107794~
Il
¦i F.X.~MP~E 5
1-(7~-~1ethylheptana~o~-5B-(4"-pherlylbu~-l"~en-3"-onyl)-2-pyrrolidones 7
Into a flame dried flask containin~ a nitro~en atmosphere was put
1 0.1188 g. (2.97 mmoles) of a 60% sodium hydride mineral oil dispersion and 5 m .
S ' THF. To this slurry was added a solution of 0.7815 g. (3.24 mmoles) of di-
methyl(3-phenylpropan-2-onyl)phosphonate in 5 ml. THF. After the evolution
of hydrogen ceased, a white suspension occurred which was stirred for fifteen I
minutes. To this suspension was added 0.6894 g. (2.70 mmoles) of 1-(7'-
I methylheptanato)-5~-formyl-2-pyrrolidone 6 in 10 ~1. THF over a period of 1
10 I minute. ~ithin five minutes, the reaction became a clear yello-~ solution and ¦
¦ was stirred for an additional two hours. The reaction was quenched with
glacial ace~ic acid to pH 5. The solvent was removed in vacuo and the residue
I was taken up in 100 ml. ethyl acetate. The organic solution w~s extracted ~it
2 x 10 ml. saturated aqueous sodium bicarbonate, 3 ~ 10 ml. water and 1 x 10 ml.
saturated brine. The organic layer was dried over magnesium sulfate, filtered¦
¦ and the solvent removed in vacuo to give 1.141 g. yellow oil. This crude
I product was chromatographed on a 35 g. column of E. Merck silica gel packed in
- I ethyl acetate. Elution with ethyl acetate and automatic collection of 10 ml.
j fractions allowed the purification of the product. The product fractions were
20 I com~ined and the solvent removed in vacuo to give 0.614 g. of the title com-
¦ pound 7 as a colorless oil (61% yield from the starting alcohol).
NMR T-60 ~CC13)s. ~7.33ppm (5H), dofd. ~6.73ppm Jl=7hz J2=16hz, d. I
~6~60ppm J2=16hz (2H), m. ~4.27ppm center (lH), s. ~3.93 (2H), s. ~3.73ppm (3H).
i partial spectrum,
25 I IR(CHC13 solution)2980, 2900, 2840, 1725, 1685(sh), 1675, 1625, 1250`
1200 cm 1
MS,LKB9000 ~/e %)70eV 372-20%, 371-82%, 252-96%, 226-24%, 194-35%,
12eV 372-18%, 371-100%, 252-24%, 226-39%.
. !
.~ ' S~3
~!
,j
, ~
,
.
10r7'794~
The other l-(substituted)-5R-formyl-2-pyrrolidone compounds of
Example 4 can be employed in the foregoing procedure in place of pyrrolidone 6
to make the corresponding l-(substituted)-5~-(4"-phenylbut-l"en-3"-onyl)-2-
py~rolidone compounds. In addition, phosphonates of the structure:
(MeO)2lbCH2gCH2Z
Z = -C6H~CH3 (m)
-~-thienyl
-C6H40CH3 (p)
C6H4-C6H5 (m)
-C6H4CF3 tp)
I . -C6H4Cl (?
can be substituted for dimethyl(3-phenylpropan-2-onyl)phosphonate to make the
¦ corresponding l-(substituted)-5~-(4"-substituted but-1"-en-3"-onyl)-2-pyrroli-
¦ done compounds. Hereafter, all pyrrolidones including the 4"-phenyl compounds
15 I shall be known as l~(substituted)-5~-(4"-substituted but-1"-en-3"-onyl)-2-
~yrrolidones.
I
1. ;
~ ~.
1' 107794t~ ~
. 11
E~YAMPLE 6
I 1-(7'-Methylheptanato~-5~-(3"-hydro~y-4"-phenylbut-1"-enyl)-
¦ 2-~yrrolidone 8
To a flame dried flask equipped with a magnetic stirring bar, ther-
¦ mometer and containing a nitrogen atmosphere was added 0.5784 g. (1.56 mmoles)
1-(7'-methylheptanato)-5~-(4"-phenylbut-1"-en-3"-onyl)-2-pyrrolidone 7 in -
20 ml. dry THF. The clear, colorless solution was cooled to -78C. and 1.56 ml.
(1.56 mmoles) lithium triethyl borohydride was added dropwise via syringe,
! needle and serum cap over a 15 minute period. After 1 hour, a TLC showed the
10 I absence of starting e~one so the reaction was quenched with glacial acetic
I acid to pH 5 which was followed by removal of the solvent in vacuo. The resi-¦
i due was dissolved in 50 ml. ethyl acetate and this organic solution was then
¦ extracted with 1 x 10 ml. half saturated aqueous sodium bicarbonate, 4 x 10
¦ ml. water and 1 x 10 ml. saturated brine. The organic layer was dried over
¦ magnesium sulfate, filtered and the solvent was removed in vacuo to give 700
¦ mg. crude product. This product was chromatographed on a 9 g. silica gel col-
; umn packed in ethyl acetate. Elution with ethyl acetat~ and automatic collec-
tion of 5 ml. fractions separated the product from impurities- Combination
¦ of product fractions and removal of solvent in vacuo gave 0.298 g. of the titlje
20 , compound 8 as a colorless oil (51 % yield).
. ~
NMR T-60 ~CC13)s. ~7.37 ppm (5H), d. ~5.72 ppm Jl = 7 hz, d. ~5.62
~ I Jl ~ 7 hz (2H), m. ~4.67-~4.33 ppm, m. ~4.30-~3.83 ppm (2H), s. ~3.73 ppm (3H)~
: j d. ~2.90 ppm J2 ~ 6 hz (2H). partial spectrum.
. 25 j IR ~CC13 solution)3450-3200, 2975, 2900, 2830, 1725, 1665, 1250-1200!
,.~ I -1 i
~, I cm
; 1 The other l-Ssubstituted)-5~-(4"-substituted but-1"-en-3-oyl)-2-
¦ipyrrolidone compounds of Example 5 can be used in the foregoing procedure to
'prepare the corresponding l-(substituted)-5~-(4"-substituted-3"-hydroxybut-1"- ;
enyl)pyrrolidone compounds.
. ~1 1
, .
.. _t`. I' : :
107794f3
¦ EXAMPLE 7
¦ 1-(6~-Carboxyhexyl)-5~-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyr-
rolidone 9
To a solution of 69 mg. (0.185 mmoles) 1-(7-methylheptanato)-5~-(3- i
hydroxy-4-phenylbut-1-enyl)-2-pyrrolidone 8 in 3 ml. methanol was added 0.185~
ml. (0.185 ~eq) lN sodium hydroxide~ The reaction solution was then refluxed ¦
overnight and then neutralized to p~ 4 by addition of glacial acetic acid.
The solvent was removed in vacuo and the oily residue was dissolved in 15 ml.
ethyl acetate. The organic solution was extracted with 2 x 2 ml. water and 1
2 ml. saturated brine, dried with magnesium sulfate and filtered. The solvent
was removed in vacuo to give the title compound 9 as a yellow oil; 59.4 mg.,
89% yield.
NMR,T-60,DCC13, s. ~7.33 ppm (5H), b.s. ~6.30 ppm center ~H), d.
~5.73 ppm Jl = 7 hz, d. ~5.6 ppm Jl = 7 hz (2H), m. ~4.6 - ~3.2 ppm (4H), d.
~2.93 ppm J2 = 7 hz (2H). (partial spectrum).
I~ HCC13 solution,3500-3100, 2980, 2920, 1700, 1600, 1250-1200 cm .
Employment of the other l-(substituted)-5~-hydroxybutenyl-2-pyrroli-
¦ dones of Example 6 in place of pyrrolidone 8 in the foregoing procedure will
¦ allow cleavage of the methyl ester or the acyloxymethyl protecting groups and
~ will allow the preparation of the following 8-aza-11-deshydroxy prostaglandin j
El and E2 compounds. The N-tetrahydropyran-2-yl protecting group if one was
employed, can be removed by the method of Example 3 orl4.
, , ~X , I
~.' ~ l
~ OH
'X
l ll
` ~ 1~7794~
X ~ -C02H 6 4 3 . .
. -tetra~ol-5-yl -~-thienyl
-C6H40CH3
~ -C ~H4-C 6~5 .
6 4 3
C6H5
. 11 'i~j i
" '.,.... 11 `'
10'77948
EXAMPLE 8
1-(7'-Methylheptanato)-5~-(4"-phenoxybut-1"-en-3"-onyl)-2-
pyrrolidone lO _
Into a flame dried ~lask containing a nitrogen atmosphere was put
22 mg. (0.55 mmoles) of a sodium hydride dispersion in mineral oil and 5 ml.
TEF. To this slurry was added a solution of 0.1549 g. (0.6 mmoles) dimethyl- ¦
(3-phenoxypropan-2-onyl)phosphonate in 5 ml. THF. After the evolution of
hydrogen ceased, there was a clear, pale yellow solution which was stirred for
fifteen minutes. To this solution was added 0.1277 g. (0.5 mmoles) 1-(7'-
methylheptanato)-5~-formyl-2-pyrrolidone 6 in 5 ml. TH~ over a period of 1
minute. Within five minutes, the reaction had become a clear yellow solution
and was stirred for an additional two hours. The reaction was quenched with
glacial acetic acid to pH 5 The solvent was removed in vacuo and the resi-
; due was taken up in 50 ml. ethyl acetate. The organic solution was extrac~ed !
with 2 x 5 ml. saturated aqueous sodium bicarbonate, 2 x 5 ml. water and 1 x
5 ml. saturated brine. The organic layer was dried over magnesium sulfate,
filtered and the solven~ removed in vacuo to give 0.231 g. yellow oil. This
crude product was chromatographed on a 25 g. column of E. Merck silica gel
packed in cyclohexane. Elution with 50% chloroform in cyclohexane and auto- j
20 ¦ matic collection of 10 ml. fractions allowed the purification of the product. ',
! The product fractions were combined and the solvent removed in vacuo to give
- ¦ 53.6 mg. of the title compound 10 (28% from the starting alcohol).
¦ ~MR T-60 ~DCC13), m. ~7.40-6.70 ppm t5H), m. ~6.7-6.33 ppm (2H)
~ ¦ s. ~4.67 ppm (2H), m. ~4.40-3.97 ppm (lH), s. ~3.67 ppm (3H). partial spectru=.
I; ¦ !
'~; I .
, _ '
:~"~
' . ~J~ I li
,._.. , . , . _ ~.
L077948
~ I I
The other l-(substituted)-5~-formyl-2-pyrrolidone compounds of
Fxample 4 can be used in the foregoing procedure in place of pyrrolidone 6 to
¦~ make the corresponding l-(substituted)-5~-(4"-phenoxybut-1"-en-3"-onyl)-2-
¦¦ pyrrolidone compounds. In addition, phosphonates of the structure:
l
5 ~ (MeO)2~cH2lclcH2-o-v
O
V~-C6114C33 (~)
-C6H4CF3 (m)
.C6H4-C6H4 (P)
-C6H40CH3 (p)
lC -C6H4-Cl (o)
6 5
can be substituted for dimethyl(3-phenoxypropan-2-onyl)phosphonate to make
i those corres cnding Z-pyrrolidone ~ompounds.
I
l!
'~ .
Ij .
1 ~7
I, ,
'~ 7
~ .
' 1077948 1
', . ,
EXAMPLE 9
1-(7'-Methylheptanato)-5e-(3"-hydroxy-4"-phenoxybut-l-enyl)-
2-pyrrolidone ll _
To a flame dried flask equipped with a magnetic stirring bar,
5 I the~mometer and containing a nitrogen atmosphere was added 0.1046 g. (0.27
I mmoles) 1-(7'-methylheptanato~-5-(4"-phenoxybut-1"-en-3"-onyl)-2-pyrrolidone
¦ 10 in 5 ml. dry THF. The clear, colorless solution was cooled to -78 C. and !
¦ 0.27 ml. ~0.27 mmoles) lithium triethyl borohydride was added dropwise via I 7
¦ syringe, needle and serum cap over a 15 minute period. After 1 hour, a TLC
10 I showed the absence of starting enone so the reaction was quenched with glacial
¦ acetic acid to p~ 5 which was followed by removal of solvent in vacuo. The
¦ residue was dissolved in 25 ml. ethyl acetate and this organic solution was
I then extracted with 1 x 5 ml. half saturated aqueous sodium bicarbonate, 1 x
¦ 10 ml. water and 1 x 10 ml. saturated brine. The organic layer was dried
15 ¦ over magnesium sulfate, filtered and the solvent was removed in vacuo to give !
¦ 101 mg. crude product. This product was chromatographed on a 25 g. silica
j gel column packed in benzene. Elution with ethyl acetate and automatic col-
i lection of 5 ml. fractions separated the product from impurities but did not
! separate the two epimers. Combination of product fractions and removal of
20 I solvent in vacuo gave 85.6 mg. of the title compound 11 (82% yield).
~ j NMR T-60 (DCC13) m. ~7.54-6.82 ppm (5H), m. ~5.94-5.73 ppm (2H), ,
;~ Im. ~4.79-4.43 ppm (lH), m. ~4.33-3.94 ppm (3~), s. ~3.70 ppm (3H). partial
¦spectrum. I
IR (CHCl3 solution) 3600-3100, 2980, 2920, 1730, 1670, 1600, 1200- i
25 ¦¦ 1250 cm 1
¦ The other l-(substituted)-5~-~phenoxybutenoyl)-2-pyrrolidone com-
pounds of Example 8 can be qubstituted for pyrrolidone 10 in the foregoing
' procedure and will produce the corresponding l-(substituted)-5~-(4"-pheno~y-
li 3"~hydroxybut-l"-enyl)-2-pyrrolidone compounds.
;~
~ ~2.
:Ij . . I
10~7948
.
, EXAMPLE lO
I !~
¦1-(6~-carboxyhexyl)-5~-(3l~-hydroxy-4t-phenoxybut-ll~-enyl)-2
~Yrrolidone 12
,, ~
To a solution of 50 mg. (0.128 mmoles) 1-(7'-methylheptanato)-5~-(3"
j hydroxy-4~-phenoxybut-1~-enyl)-2-pyrrolidone 11 in 3 ml. methanol was added
0.128 ml. (0.128 mmoles) of lN sodium hydroxide. The reaction solution was
refluxed overnight and then neutralized to pH 4 by addition of glacial acetic 1,
acld. The solvent was removed in vacuo and the oily residue was dissolved in
15 ml. ethyl acetate, The organic solution was ex~racted with 2 x 2 ml. water
and l x 2 ml. saturated brine, dried with magnesium sulfate and filtered. The !
solvent was removed in vacuo to give the title compound 12 as a yellow oil;
48.0 m8. (99% yield).
NMR T-60 ~DCC13) m. ~7.40 6.82 ppm (5H), m. ~6.73-h.17 ppm (2H),
m. ~5.87-5.70 ppm (2H), m. ~4.7-4.4 ppm (lH), m. ~4.23-3.88 ppm (3H). partial
15 Ispectrum.
~ IR(HCC~13 solution) 3600-2900, 2920, 1700, 1670, 1600, 1200, 1250 cm l.
; I Employment of the other l-(substituted)-5~-(hydroxyphenoxybutenyl)- ¦
2-pyrrolidone compounds of Example 9 in place of pyrrolidone 11 in the foregoing~
procedure will allow cleavage of the methyl ester or the acyloxymethyl groups
20 ¦and allow the preparation of the bollowing 8-aza-11-deshydroxy prostaglandin E
., I
~r land E2 compounds. The N-THP protecting group can be cleaved according to the
~r'.' procedure of Example 14
i., ~ O
~:~ I ~ N~'~"^~,--~_~,X
i ~OV ~,
¦ OH
`,.` , '' O
.' . 1~ X
,, jl, ~S--$-`OV
: I! OH
1~ ~
.; . - : -
.
1077948
¦ X ~ -C02H V ~ -C6H4CH3 (p)
¦ -tetrazol-S-yl -C6H4CF3 (m)
-C6H4-C6H4 (~
11 --C6H40CH3 (p)
S -C6H4-Cl (o)
I -C6H5
Il l
.' 11 1
., I
:' .1 ..
: . '.
11 .
i: ~
- I. 5~
.
1, .
. . .
,
.
.. ~ . . .
-` I 107~94~3
I .'
I EXAMPLE 11
.
1-(7~-Methylheptanato)-5R-(3~-tetrahydropyran-2~yloxy-4~-
phenylbut-l-enyl)-2-pyrrolidone 13 __ _
Into a flame dried flask under a nitrogen atmosphere was put 128 mg.¦
(0,342 mmoles) of 1-(7'-methylheptanato)- 5~-~3"-hydroxy-4"phenylbut~1-enyl~- ¦
2-pyrrolidone 9 and 5 ml. methylene chloride. To this solution at 0 C. to 5
C. was then added 0.062 ml. (0.684 mmoles) redistilled dihydropyran and 3 r,lg.
tosic acid. The solution was then allowed to warm to room temperature and to
stir overni~ht. The reaction was worked up by dilution with 10 ml. ethyl
aceta~e, extraction with 2 x 2 ml. saturated sodium bicarbonate solution and
1 x 5 ml. saturated brine. The organic layer was dried with magnesium sulfate
~, filtered and the solvent was removed in vacuo to give 3.135 g. yellow oil.
This was chromatographed on a 15 g. column of Merck silica gel packed in
chloroform. Elution with 1 1. chloroform removed less polar impurities.
Elution with 2% methanol in chloroform and automatic collection of 10 ml. frac
, tions separated and purified the product. Combination of product fractions
and removal of solvent in vacuo gave 0.1756 g. of the title compound 13 as a
~ yellow oil.
,~ NMR T-60 ~CC13) s. ~6.34 ppm (5H), m. ~5.77-5.37 ppm (2H), m. ~5.13-l
4.80 ppm (lH), s. ~3.7 ppm (3H). partial spectrum.
. In addition, the l-(substituted)-5~-(4"-substituted-3"-hydroxybut-1"~
; enyl)-2-pyrrolidones of Exsmple 6, 7, 9 and lO can be employed in this pro-
~ cedure to prepare the corresponding THP derivatives.
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EXA~LE 12
1-(7~-Methylheptanato)-5B-(3''-tetrahydropyran-2'~l-yloxy-4''
phenylbutanyl)-2-pyrrolidone 14
,~ . I
To a solution of 156.5 mg. ~0.342 mmoles) of 1-(7~-methylheptanato)
5B-(3"-tetrahydropyran-2"!-yloxy-4"-phenylbut-1-enyl)-2-pyrrolidone 13
¦ in 10 ml. ethyl acetate was added 31 mg. of 10% palladium on charcoal and the~
. I entire mixture placed on a Parr hydrogen reduction apparatus and shaken underl
I a pressure of 50 lb. hydrogen for 4 hours. The slurry was then filtered through
¦ celite to remove the catalyst and the solvent was removed from the filtrate t~
10 I give 158.2 mg. of the title compound 14.
~MR T-60 ~CC13) s. ~7.33 ppm (5H), m. ~5.13-4.67 ppm (lH), m. ~4.57-
4.33 ppm (lH), s. ~3.73 ppm (3H). partial spectrum.
In addition, the other THP derivatives of Example ll wherein A is
~ a single bond can be employed in this procedure to prepare the corresponding
15 ¦~ hydrogena~ed erivaLives.
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1 07~948
¦1EXAMPLE 13
l I
11-(6'-Carboxyhexyl)-5~-C3"-tetrahydropyran-2"'-yloxy-phenyl-
¦,butanyl)-2-pyrrolidone 15
I To a solution of 1582 mg. (0.342 mmoles) of 1-(7'-methylheptanat)~ ¦
1 5~-(3"-tetrahydropyran-2"'-yloxy-4"-phenylbutanyl)-2-pyrrolidone ~4 in 5 ml.-
~ methanol was added 0.342 ml. (0.342m~oles)of lN sodium hydroxide. The reaction
¦I solution was ~efluxed overnight and then neutralized to pH 4 by addition of
glacial acetic acid. The solvent was removed in vacuo and the oily residue
¦ was dissolved in 15 ml. ethyl acetate. The organic solution was extracted
¦ with 2 x 2 ml. water and 1 x 2 ml. saturated brine, dried with magnesium sul-
¦ fate and filtered. The solvent was removed in vacuo to ~ive the title compoun
15 as a yellow oil; 134.2 mg. (89% yield).
~MR T-60 ~CC13) s. ~7.37 ppm (5H), m. ~4.4-3.2 ppm, m. ~2.92 (2H).
partial spectrum.
I In addition, the other hydrogenated derivatives of Example 12 can be
~employed in this procedure to prepare the corresponding 6'-carboxylic acid and j
6'-tetra~ol-5 yl co~pound~.
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77~48
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EXAMPL~ 14
1-(6~-Carboxyhexyl)-5B-(3"-hydroxy-4-phenylbutanyl)-2-pyrrolidone 16
(8-aza-11-deshydroxy-16-phenyl-16-~-tetranor PGEo 16)
I A solution of 134.2 mg. (0,3 mmoles) of compound 15 was stirred in
I S ml. of a 65:35 mixture of acetic acid:water overnight under nitrogen at
ambient temperature. The solvent was then removed by vacuum evaporation using¦
¦ an oil vacuum pump and the residue azeotroped with benzene. The crude product
¦ was then chromatographed on 15 g. of ARCC7 silica gel by eluting with 2%
; I methanol in chloroform to give 82 mg. of the title compound 16.
I NMR T-60(DCC13) s. ~7.17 ppm (5H), m. ~3.2-4.0 ppm (3H), d. ~2.77 pp~,
JH = 7hz (2H). partial spectrum.
IR (HCCl3 solution) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200,
710 cm l.
In addition, this procedure can be employed to remove the THP pro-
- 15 ¦ tecting group from the 6'-carboxylic acid and 6'-tetrazol-S-yl derivatives of
¦ Example 13 and the hydrogenated derivatives ol Example 12.
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EXAMPLE 15
~ (6'-N-Phenylimidohexyl)-5B-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone
¦ To a solution of 64 mg. (0.171 mmoles) 1-(6'-carboxyhexyl)-5~-(4"-
phenyl-3"-tetrahydropyran-~"'-yloxybut-1"-enyl)-2-pyrrolidone prepared according
to the procedure of Example 11 in 10 ml. of dry tetrahydrofuran can be added
¦ 25.16 mg. ~0.171 mmoles) of benzoyl isocyanate prepared according to the pro-
cedure of A. J. Speziale, J. ~. Chem., 27, 3742 (1962) in 5 ml. of dry THF.
After refluxing overnight, the solvent can be removed in vacuo and the reaction
material deprotected (THP group removed) according to the procedure of Example
14 to give the title compound.
In a similar fashion, the following imide derivatives can be made:
by substituting the other appropriately protected carboxylic acids of
Examples 7, 10 and 14.
A 0 A
~C-Im ~ ~ C-Im
~\OV
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I ¦ Im - NHCPh
I NHCCH3
I :
! z is defined in Example 7
¦l V is defined in Example 10
¦ A is a q$nglç or cis double bond
B is a single or trans double bond
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