N-alkyl-N-alkoxycarboxamides and methods of use in prostaglandin synthesis

Novel N-alkyl-N-alkoxycarboxamides useful for prostaglandin synthesis are disclosed. Also disclosed are novel synthetic methods for preparing the novel intermediates of the present invention.

The present invention is directed to novel intermediates useful in 
prostaglandin synthesis. More specifically, the invention is directed to 
N-alkyl-N-alkoxycarboxamides and methods for the synthesis of 
prostaglandins. 
BACKGROUND OF THE INVENTION 
Naturally occurring prostaglandins arc biologically active in a myriad of 
ways including hormone action, muscular contraction/relaxation, platelet 
aggregation/inhibition, intraocular pressure reduction and other cellular 
transduction mechanisms. Prostaglandins are enzymatically produced in 
nature from arachidonic acid. The arachidonic acid cascade is initiated by 
the prostaglandin synthase catalyzed cyclization of arachidonic acid to 
prostaglandin G.sub.2 and subsequent conversion to prostaglandin H.sub.2. 
Other naturally occurring prostaglandins are derivatives of prostaglandin 
H.sub.2. A number of different types of prostaglandins have been 
discovered including A, B, C, D, E, F and I-Series prostaglandins. These 
descriptions delineate substitution patterns of the various cyclopentane 
group central to all prostaglandins. Still other naturally occurring 
derivatives include thromboxane A2 and B2. 
Due to their potent biological activity, prostaglandins have been studied 
for possible pharmaceutical benefit. However, due to potency of these 
molecules, as well as the ubiquitous presence of these agents and 
receptors and other biologically responsive tissue sites to their 
presence, numerous side effects have prevented the exploitation of the 
naturally occurring prostaglandins. It has also been difficult to 
pharmaceutically exploit the naturally occurring prostaglandins due to the 
relatively unstable nature of these molecules. As a result, researchers 
have been preparing and testing synthetic prostaglandin analogs, known as 
"prostanoids," for several decades. 
In general, prostanoids can be described generically as consisting of (1) 
an alpha chain; (2) an omega chain; and (3) a cyclopentane group (or a 
heterocycle or other ring structure), as shown in formula (I). 
##STR1## 
In general, the R' groups of the ring structure are independently hydroxy, 
oxy, halogen and hydrogen groups. The omega chain has generally consisted 
of linear carbon backbones of varying lengths. The omega chains have also 
been of varying degrees of saturation, containing optional hetero-atoms 
and have terminated with a variety of alkyl and cycloalkyl groups. Alpha 
chains have consisted of numerous linear moieties and have involved 
various degrees of saturation. The alpha chains generally consist of a 
seven carbon chain and generally terminate with a carboxylic acid group or 
a variety of corresponding esters. 
Another set of prostaglandins of particular interest are known as the 
"3-oxa-prostaglandins" or "3-oxa-prostanoids," which contain an oxygen 
atom at the three position, according to formula (II): 
##STR2## 
wherein, R' is oxy, hydroxy, halogen, protected hydroxy or hydrogen; and 
the omega chain is generally five to twelve carbons in length with various 
substitutions including substitutions of hetero-atoms within the chain. 
The compounds of formula (II) are typically synthesized by methods outlined 
in Scheme A, below, similar to methods disclosed in Buchmann et al., 
Tetrahedron Letters, volume 31, page 3425 (1990) and European Patent No. 
0299914. 
##STR3## 
Generally, a lactone (1), wherein R' can be a hydroxy, halogen, protected 
hydroxy or hydrogen moiety and .omega. is an omega chain as generally 
known in the art, is converted to a hydroxy ester (2). The ester (2) is 
then silylated to give a protected hydroxy ester (3). Reduction of the 
protected hydroxy ester (3) yields a protected hydroxy aldehyde (4) and a 
side product alcohol (5). The protected hydroxy aldehyde (4) is then 
condensed with a trialkyl phosphonoacetate salt to give the unsaturated 
ester (6). Reduction of the ester (6) produces the allylic alcohol (7) 
which is then converted to the protected 3-oxa prostaglandin (8) by 
alkylation of the primary hydroxyl and the deprotected 3-oxa prostaglandin 
(9) by desilyation. The 3-oxa prostaglandin (9) can be further processed 
to yield a 9-keto or 9-halo analog and/or, to give an alpha chain 
terminating ester of choice. 
The protected hydroxy aldehyde (4) is thus a key intermediate in the 
synthesis of 3-oxa prostanoids. The above synthetic route of Scheme A, 
however, is complicated by undesired side reactions which can result in 
poor yields, and the generation of substantial by-products. One problem is 
due to the reversible nature of the lactone ring opening reaction, i.e., 
(1) forming (2). The hydroxy ester (2) is unstable with respect to 
reclosure to lactone (1). In fact, in some cases the lactone (1) is 
preferred over the ester (2), causing poor yields of the protected hydroxy 
ester (3) and hence, poor yields of the protected aldehyde product (4). 
##STR4## 
Another problem with the above synthetic method is the formation of the 
by-product (5), the monoprotected diol. The unwanted by-product (5), which 
can result from uncontrolled reduction of (3), will not convert to the 
desired product (4) without further processing. Thus, low yields of (4) 
result in poor yields of the desired product. See for example, Cooper et 
al., Journal Of Organic Chemistry, volume 58, page 4280 (1993). 
A need has arisen, therefore, to develop superior synthetic methods which 
allow the preparation of the various prostanoids of interest in greater 
yields. 
SUMMARY OF THE INVENTION 
The present invention is directed to novel prostaglandin intermediates and 
novel methods employing those novel intermediates in the synthesis of 
prostaglandins. More specifically, the invention is directed to 
N-alkyl-N-alkoxycarboxamides and methods for the synthesis of 
prostaglandins. The N-alkyl-N-alkoxycarboxamides are prepared by the 
amidation of a lactone and protection of the resulting free hydroxy from 
the opening of the ring. 
The use of the N-alkyl-N-alkoxycarboxamide intermediates obviates 
cyclization problems existing with traditional synthetic methods involving 
ring scission of a lactone. The avoidance of cyclization provides for 
greater yield of the protected aldehyde intermediate. 
The use of the N-alkyl-N-alkoxycarboxamide intermediates also avoids 
alcohol by-product formation typical in 3-oxa prostaglandin synthesis. The 
avoidance of this by-product also provides for greater yield of the 
protected aldehyde intermediate. 
Preferred methods of the present invention employ the novel intermediates 
of the present invention in the synthesis of 3-oxa prostaglandins. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel intermediates of the present invention are those of formulas (IV) 
and (V): 
##STR5## 
wherein, R is C.sub.1-4 alkyl; 
R' is hydroxy, halogen, protected hydroxy or hydrogen; 
R" is a protecting group, e.g., trialkyl(C.sub.1-4)silyl; and 
.omega. is 
##STR6## 
wherein: --- is an optional bond; 
D may be in the .alpha. or .beta. configuration, and is fluorine or 
OR.sup.4, wherein R.sup.4 is H, alkyl, alkoxyalkyl, acyl, or 
Si(R.sup.6).sub.3, wherein R.sup.6 is independently C.sub.1-4 alkyl or 
phenyl; 
X is (CH.sub.2).sub.m or (CH.sub.2).sub.m O, wherein m is 1 to 6; and 
Y is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, 
alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or 
X--Y is (CH.sub.2).sub.p Y.sup.1 ; wherein p is 0 to 6; and 
##STR7## 
wherein: W is CH.sub.2, O, S(O).sub.q, NR.sup.5, CH.sub.2 CH.sub.2, 
CH.dbd.CH, CH.sub.2 O, CH.sub.2 S(O).sub.q, CH.dbd.N, or 
CH.sub.2 NR.sup.5 ; wherein q is 0 to 2, and R.sup.5 is H, alkyl, or acyl; 
Z is H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, 
alkylamino, acylamino, or hydroxy; and 
--- is an optional bond; or 
X--Y is cyclohexyl. 
Preferred intermediates of formulas (IV) and (V) are those having an 
.omega. chain consisting of: 
##STR8## 
wherein R.sup.7 is SiPh.sub.2 t-Bu or tetrahydropyranyl. 
The novel intermediates of formulas (IV) and (V) can be synthesized 
following Scheme B, below: 
##STR9## 
In Scheme B, the lactone (1), wherein R, R' (excluding oxy), R" and 
.omega. are defined as above, is first amidated to give the hydroxy 
(N-alkyl-N-alkoxycarboxamide) (10). The free hydroxy group of (10) is then 
protected with a protecting group R", to yield the protected hydroxy 
(N-alkyl-N-alkoxycarboxamide) (11). Various protecting groups can be 
employed using methods known to those skilled in the art. For example, the 
hydroxy (N-alkyl-N-alkoxycarboxamide) (10) can be protected with a 
trialkyl (C.sub.1-4) silyl group. 
The protected hydroxy(N-alkyl-N-alkoxycarboxamide) (11) can now be prepared 
for prostaglandin synthesis. For example, the carboxamide (11) (formula V) 
can now be reacted with a reducing agent, such as lithium aluminum hydride 
or DIBAL, to form the protected aldehyde (12): 
##STR10## 
The product (12) can now be inserted in place of the protected aldehyde 
product (4) of known methods of 3-oxa prostaglandin synthesis. For 
example, the product (12) can be used to synthesize 3-oxa prostaglandins 
according to Scheme C, below: 
##STR11## 
Generally, the 3-oxa prostaglandins of Scheme C can be prepared by 
reacting the protected aldehyde (12) (generated from the novel 
intermediates and methods of the present invention), wherein R, R' 
(excluding oxy), R" and .omega. are defined above, with a trialkyl 
phosphonoacetate salt to give the unsaturated ester (13). The unsaturated 
ester (13) is then reduced with a metal hydride reducing agent to form the 
allylic alcohol (14). The alcohol (14) is then converted to the protected 
3-oxa prostaglandin (15) by alkylation of the primary hydroxyl group. The 
protected 3-oxa prostaglandin is then deprotected by methods known to 
those skilled in the art, e.g., Greene et al., Protective Groups in 
Organic Synthesis, 2.sup.nd ed., Wiley: New York, 1991; to give the free 
hydroxyl 3-oxa prostaglandin (16). The free hydroxyl of (16) can be 
further processed by methods known in the art to give the corresponding 
9-keto or 9-halo prostaglandin. Further processing can be employed to give 
an analog of (16) containing an alpha chain terminating ester of choice. 
The methods of the present invention are also useful in preparing the 
3-carba prostaglandins of formula (III): 
##STR12## 
wherein, R, R' (and including oxy) and .omega. are defined as above. For 
example, the product (12) can be used to synthesize 3-carba prostaglandins 
according to Scheme D, below: 
##STR13## 
Generally, the 3-carba prostaglandins of Scheme D can be prepared by 
reacting the protected aldehyde (12) (generated from the novel 
intermediates and methods of the present invention) with a phosphorane to 
form the unsaturated acid (17). The acid (17) is then deprotected by 
methods known to those skilled in the art (see, e.g., Greene et al., 
Protective Groups in Organic Synthesis, 2.sup.nd ed., Wiley: New York, 
1991), to give the free hydroxyl 3-carba prostaglandin. The free hydroxyl 
compound (18) can be further processed by methods known in the art to give 
the corresponding 9-keto or 9-halo prostaglandin, and/or further processed 
to give an alpha chain terminating ester of choice.