Method for preparing 7-oxabicycloheptyl substituted bromooxazole amide prostaglandin analog intermediates useful in the preparation of anti-thrombotic and anti-vasospastic compounds

A method is provided for preparing bromooxazole intermediates of the structure ##STR1## wherein a vinyl compound of the structure ##STR2## wherein X.sup.1 and X.sup.2 are independently H and Br, is treated with a metal halide such as cupric bromide, and a base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The resulting bromooxazole may be hydrolyzed and hydrogenolyzed to the final anti-thrombotic-anti-vasospastic compounds.

FIELD OF THE INVENTION 
The present invention relates to a method for preparing a novel 
7-oxabicycloheptyl substituted bromooxazole amide prostaglandin analog 
intermediate by cyclization of a corresponding vinyldiamide or 
vinylbromide compound employing a metal halide such as cupric bromide, in 
combination with a base such as DBU. The resulting oxazole may be 
hydrolyzed and hydrogenolized to a final anti-thrombotic-anti-vasospastic 
product. 
BACKGROUND OF THE INVENTION 
U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl 
substituted heterocyclic amide prostaglandin analogs which are thromboxane 
A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 
receptor antagonist/thromboxane synthetase inhibitors useful, for example, 
in the treatment of thrombotic and/or vasospastic diseases, and have good 
duration of action. Examples of compounds disclosed in Misra et al have 
the structural formula I 
##STR3## 
and including all stereoisomers thereof, wherein 
m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; 
R.sup.1 is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl, 
cyclo-alkylalkyl, or amide 
##STR4## 
wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl, cycloalkyl, or 
cycloalkylalkyl); 
R.sub.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 
together with the nitrogen to which they are linked may form a 5- to 8- 
membered ring. 
Misra et al disclose that these compounds may be prepared from the 
oxazoline XV' 
##STR5## 
which is made to undergo oxidation using manganese dioxide, or nickel 
peroxide, or preferably cupric bromide and 
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form the oxazole I. 
##STR6## 
The cupric bromide oxidation is carried out at a temperature of within the 
range of from about 20.degree. C. to about 70.degree. C., employing a 
molar ratio of cupric bromide to XV' of within the range of from about 2:1 
to about 6:1 and a molar ratio of cupric bromide to DBU of within the 
range of from about 1:1 to about 1:3 in an inert solvent, preferably ethyl 
acetate/chloroform (1:1, v/v). 
The so-formed oxazole may then be hydrolyzed by treatment with an aqueous 
solution of alkali metal base and then aqueous acid to form the 
corresponding acid. 
In Example 1 Part O of Misra et al, the methyl ester of the final product 
is prepared together with the corresponding bromooxazole as a side product 
(6% yield). 
DESCRIPTION OF THE INVENTION 
In accordance with the present invention, a method is provided for 
preparing oxazoles of formula I (as set out above in the Misra et al 
patent) which includes the step of treating a vinyl compound, such as a 
vinyl diamide, vinyl bromide, or vinyl dibromide of the structure II 
##STR7## 
wherein X.sup.1 and X.sup.2 are independently selected from H and Br and 
wherein m, n, R.sup.1 and R.sup.2 are as defined below (and as in the 
above-mentioned Misra et al patent), with a metal halide such as cupric 
bromide, cuprous bromide or ferric bromide, preferably cupric bromide, and 
a base which is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 
1,5-diazabicyclo[4.3.0]non-5-ene (DBN), preferably DBU, in the presence of 
an inert organic solvent such as dichloromethane, chloroform, ethyl 
acetate/chloroform, or dimethylformamide (DMF), to form the corresponding 
bromooxazole III 
##STR8## 
The so-formed bromooxazole III may be subjected to hydrogenolysis, for 
example, by treatment of III with hydrogen in the presence of a catalyst 
such as Pd-C, and an alcohol solvent such as ethanol or methanol, to form 
the corresponding oxazole ester I. 
In the above formulae I, II and II compounds, 
n is 0, 1, 2, 3 or 4; 
m is 1, 2 or 3; 
R.sup.1 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, 
cycloalkylalkyl or an amide 
##STR9## 
wherein t is 1 to 12 and Ra is lower alkyl, aryl, cycloalkyl or 
cycloalkylalkyl); 
R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or 
R.sup.1 and R.sup.2 together with the N to which they are linked form a 5- 
to 8-membered ring which contains only the single N heteroatom. 
Oxazole ester I may be hydrolyzed to the corresponding acid by treatment of 
I with alkali metal base and then with aqueous acid as described in U.S. 
Pat. No. 5,100,889. 
Alternatively, bromooxazole ester III may be hydrolyzed by treatment with 
an alkali metal hydroxide such as NaOH, KOH or LiOH and then strong acid 
such as HCl, H.sub.2 SO.sub.4 or phosphoric acid, to form the 
corresponding bromooxazole acid IIIA. 
##STR10## 
Bromooxazole acid IIIA may then be subjected to hydrogenolysis by treating 
IIIA with weak aqueous base such as sodium bicarbonate, potassium 
bicarbonate, sodium carbonate and the like and with hydrogen in the 
presence of a reduction catalyst such as Pd-C, to form the corresponding 
salt which may be treated with acid such as HCl to form the corresponding 
acid. 
Alternatively, bromooxazole acid IIIA may be directly hydrogenolized to the 
acid product of the invention I by treating IIIA with hydrogen in the 
presence of a reduction catalyst such as Pd-C. 
DETAILED DESCRIPTION OF THE INVENTION 
In carrying out the method of the invention, the reaction of the vinyl 
compound II, namely, vinyl diamide, vinyl bromide or vinyl dibromide of 
the structure II, with the metal halide is carried out at a temperature 
within the range of from about 20.degree. C. to 70.degree. C., preferably 
from about 10 to about 25.degree. C., preferably under an inert atmosphere 
such as argon or nitrogen. 
The metal halide is employed in a molar ratio to vinyl compound II of 
within the range of from about 2.5:1 to about 5:1, preferably from about 
3:1 to about 4:1, and most preferably about 4:1; and the base is employed 
in a molar ratio to vinyl compound II of within the range of from about 
2.5:1 to about 5:1, preferably from about 3:1 to about 4:1, and most 
preferably about 4:1. 
The above reaction will be carried out for a period of from about 5 to 
about 150 hours, preferably from about 18 to about 48 hours. 
In the above method, the preferred metal halide is cupric bromide, the 
preferred base is DBU and the preferred solvent is dichloromethane. 
The starting vinyl compound II wherein one of X.sup.1 and X.sup.2 is H and 
the other Br, that is vinyl bromide IIA. 
##STR11## 
is prepared as follows. 
The diamide IV 
##STR12## 
wherein m, n, R.sup.1 and R.sup.2 are as defined above is treated with a 
bromine source such as Br.sub.2 or N-bromosuccinamide followed by 
treatment with an amine base, such as triethylamine, diisopropyl 
ethylamine or tributylamines, at a reduced temperature, under an inert 
atmosphere, such as argon, to form the vinyl bromide compound IIA (one of 
X.sup.1 and X.sup.2 is H and the other is Br)d, which is then employed as 
described above to form oxazole I. 
The starting vinyl compounds II wherein each of X.sup.1 and X.sup.2 are Br, 
that is vinyl dibromide IIB 
##STR13## 
are novel compounds and are prepared as follows. 
A solution of vinyl bromide compound IIA (wherein one of X.sup.1 and 
X.sup.2 is Br and the other H) in a dry inert organic solvent, such as 
dichloromethane, chloroform or dichloroethane is cooled to a temperature 
within the range of from about -40.degree. to about -80.degree. C. and 
treated with bromine and organic bases such as triethylamine, 
diisopropylethylamine or tributylamine to form the vinyl dibromide 
compound IIB. 
In carrying out the above reaction, Br.sub.2 is employed in a molar ratio 
to IIA of within the range of from about 1:1 to about 1.5:1, preferably 
from about 1:1 to about 1.2:1. 
The starting diamide IV may be prepared as follows. 
Hydroxymethyl compound of the structure V 
##STR14## 
(prepared as described in Misra et al U.S. Pat. No. 5,100,889) is treated 
with methanesulfonyl chloride (mesyl chloride) in the presence of an 
organic base such as triethylamine, diisopropylethylamine or 
tributylamine, to form the mesylate VI 
##STR15## 
and mesylate VI is subjected to a displacement reaction wherein VI is 
treated with an alkali metal salt such as lithium chloride or a quaternary 
ammonium salt such as benzyltributyl ammonium chloride, to from the 
chloromethyl amide VII 
##STR16## 
In an alternative method for preparing the chloromethyl amide VII, an amide 
of the structure VIII (formed from the corresponding amide) 
##STR17## 
wherein Pro represents a protecting group, such as t-butyloxycarbonyl, 
benzyloxycarbonyl and the like, and R.sup.1 and R.sup.2 are as defined 
above, is treated with an organic base such as triethylamine, 
diisopropylethylamine or tributylamine, and methanesulfonyl chloride at a 
reduced temperature to form the mesylate IX 
##STR18## 
Mesylate IX is subjected to a displacement reaction wherein IX is treated 
with an alkali metal salt such as lithium chloride or a quaternary 
ammonium salt such as benzyltributyl ammonium chloride, at an elevated 
temperature of from about 40.degree. to about 65.degree. C. to form 
chloromethyl compound X 
##STR19## 
Chloromethyl compound X is treated with a deprotecting agent to form the 
chloromethyl amine XI 
##STR20## 
and XI is coupled with acid XII 
##STR21## 
in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 
1-hydroxybenzotriazole (HOBT), in the presence of N-methylmorpholine 
(NMM), to form the chloromethylamide VII. 
Alternatively, the acid XII can be converted to the corresponding acid 
chloride by treatment with oxalyl chloride, preferably in the presence of 
a catalytic amount of N,N-dimethylformamide, which acid chloride is 
treated with amine XI in the presence of an acid scavanger such as 
triethylamine or DBU, or sodium bicarbonate (when employing aqueous 
conditions) to form chloromethylamide VII. 
The chloromethyl amide VII is treated with DBU under an inert atmosphere, 
such as argon, to form the vinyl diamide IV which is then employed as 
described above, in accordance with the present invention, to form oxazole 
I. 
Preferred vinyl compound starting materials will comprise those of Formulae 
II, IIA, IIB or IV wherein m is 1 or 2 and n is 1, 2 or 3, R.sup.1 is 
alkyl of from 3 to 7 carbons and R.sup.2 is hydrogen or alkyl of from 3 to 
7 carbons. 
Where the starting vinyl bromide IIA (wherein one of X.sup.1 and X.sup.2 is 
Br and the other is H) is prepared starting with vinyl diamide IV, diamide 
IV which is treated with a bromine source such as Br.sub.2 or 
N-bromosuccinamide, preferably Br.sub.2, at a reduced temperature of 
within the range of from about -80.degree. to about -40.degree. C., and 
preferably from about -80.degree. to about -60.degree. C., under an inert 
atmosphere such as argon or nitrogen, preferably argon, employing a molar 
ratio of bromine source to diamide IV of within a range of from about 1:1 
to about 2:1 and preferably from about 1:1 to about 1.1:1. The organic 
base, which may be triethylamine, DBU, Hunig's base (diisopropylethyl 
amine), collidine, dimethylamino pyridine or pyridine, preferably 
triethylamine, will be admixed with the reaction mixture at a temperature 
of within the range of from about -78.degree. C. to about 25.degree. C. 
and preferably from about -20.degree. C. to about 0.degree. C. The above 
reaction will be carried out in the presence of an inert organic solvent 
such as methylene chloride, chloroform, tetrahydrofuran (THF), 
acetonitrile, or acetone, preferably methylene chloride. 
In a first method for preparing starting vinyl diamide IV (employing 
chloromethyl amide VII), hydroxymethyl compound V (prepared as described 
in U.S. Pat. No. 5,100,889) will be treated with mesyl chloride employing 
a molar ratio of mesyl chloride to amide VII of within the range of from 
about 1:1 to about 3:1, and preferably from about 1:1 to about 1.5:1, in 
the presence of an organic base such as triethylamine or pyridine, 
preferably triethylamine, in the presence of an inert organic solvent such 
as methylene chloride or THF, at a temperature of within a range of from 
about -78.degree. C. to about 0.degree. C. and preferably from about 
-20.degree. C. to about 0.degree. C. to form mesylate VI. 
The mesylate VI will be subjected to a displacement reaction by treatment 
with an alkali metal salt such as lithium chloride, sodium chloride, 
potassium chloride, lithium bromide or sodium iodide, preferably lithium 
chloride, or with a quaternary ammonium salt such as benzyltributyl 
ammonium chloride, tetra-n-butylammonium bromide, or tetra-n-butylammonium 
iodide, employing a molar ratio of salt to VI within the range of from 
about 2:1 to about 10:1, preferably from about 2:1 to about 5:1, the above 
reaction being carried out in the presence of an inert organic solvent 
such as dimethylformamide, THF, acetone, chloroform or methylene chloride, 
preferably dimethylformamide or methylene chloride. 
Where the starting diamide IV is prepared starting with the 
chloromethylamide VII, DBU will be employed in a molar ratio to amide VII 
of within the range of from about 1:1 to about 4:1, preferably from about 
1:1 to about 2:1, and the reaction will be carried out under an inert 
atmosphere such as argon or nitrogen. 
In the alternative method for preparing vinyl diamide IV, the starting 
amide VIII (prepared as described in U.S. Pat. No. 5,100,889) will include 
a protecting group which can be t-butyloxycarbonyl (BOC) or 
trichloroethoxy carbonyl, preferably BOC, and will be treated with an 
organic base such as triethylamine, or pyridine, preferably triethylamine, 
and methanesulfonyl chloride at a reduced temperature of within the range 
of from about -78.degree. C. to about 0.degree. C. and preferably from 
about -20.degree. C. to about 0.degree. C. to form the mesylate IX. The 
methanesulfonyl chloride will be employed in a molar ratio to amide VIII 
of within the range of from about 1:1 to about 5:1, preferably from about 
1:1 to about 2:1. 
The mesylated compound IX will then be subjected to a displacement reaction 
employing an alkali metal salt such as lithium chloride, sodium chloride, 
potassium chloride, preferably lithium chloride, which is reacted with IX 
at an elevated temperature of from about 40.degree. C. to about 
100.degree. C., and preferably from about 40.degree. C. to about 
65.degree. C., to form the chloromethyl compound X. The alkali metal salt 
will be employed in a molar ratio to X of within the range of from about 
2:1 to about 10:1, preferably from about 2:1 to about 5:1. 
The chloromethyl compound X will be deprotected by reaction with a 
deprotecting agent such as trifluoroacetic acid, anhydrous hydrogen 
chloride/dioxane, preferably trifluoroacetic acid, employing a molar ratio 
of deprotecting agent to X of within the range of from about 5:1 to about 
20:1, preferably from about 5:1 to about 10:1 to form the chloromethyl 
amine compound XI. 
Chloromethyl amine XI is coupled with acid XII employing a molar ratio of 
XI:XII of within the range of from about 1:1 to about 3:1, preferably from 
about 1:1 to about 1.5:1. The coupling reaction is carried out in the 
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
(WSC) or dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) 
in the presence of N-methylmorpholine (NMM), employing a molar ratio of 
WSC or DCC:XII of within the range of from about 1:1 to about 3:1, 
preferably from about 1:1 to about 1.5:1. The HOBT will be employed in a 
molar ratio to WSC or DCC of within the range of from about 1:1 to about 
3:1, preferably from about 1:1 to about 1.5:1 while the NMM will be 
employed in a molar ratio to HOBT of within the range of from about 2:1 to 
about 5:1, preferably from about 2:1 to about 3:1. The above reaction will 
be carried out at a temperature within the range of from about -20.degree. 
C. to about 40.degree. C. and preferably from about 0.degree. C. to about 
25.degree. C. 
Alternatively, acid XII may be activated by forming a mixed anhydride, 
mixed carbonate, or preferably acid chloride (by known literature 
methods), using a slight excess (of from about 10 to about 50%) of amine 
and acid scavanger relative to the acid chloride. A reaction temperature 
of from about -78.degree. C. to about 0.degree. C. will be employed. 
The term lower alkyl or "alkyl" as employed herein includes both straight 
and branched chain radicals of up to 18 carbons, preferably 1 to 8 
carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 
isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 
2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various 
branched chain isomers thereof, and the like as well as such groups 
including 1, 2 or 3 halo substituents, an aryl substituent, an alkyl-aryl 
substituent, a haloaryl substituent, a cycloalkyl substituent, or an 
alkylcycloalkyl substituent. 
The term "cycloalkyl" includes saturated cyclic hydrocarbon groups 
containing 3 to 12 carbons, preferably 3 to 8 carbons, which include 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 
cyclodecyl and cyclododecyl, any of which groups may be substituted with 
substituents such as halogen, lower alkyl, and/or alkoxy groups. 
The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic 
aromatic groups containing from 6 to 10 carbons in the ring portion, such 
as phenyl or naphthyl. Aryl (or Ar), phenyl or naphthyl may include 
substituted aryl, substituted phenyl or substituted naphthyl, which may 
include 1 or 2 substituents on either the phenyl or naphthyl such as lower 
alkyl, trifluoromethyl, halogen (Cl, Br, I or F), alkylsulfonyl, and/or 
arylsulfonyl. 
The term "alkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein refers 
to lower alkyl groups as discussed above having an aryl substituent, such 
as benzyl. 
The term "lower alkoxy", "alkoxy" or "aralkoxy" includes any of the above 
lower alkyl, alkyl or aralkyl groups linked to an oxygen atom. 
The term "halogen" or 'halo" as used herein refers to Cl, Br, F or I, with 
Cl preferred. 
The compounds prepared by the method of this invention have four centers of 
asymmetry as indicated by the asterisks in formula I. However, it will be 
apparent that each of the formulae set out above which do not include 
asterisks still represent all of the possible stereoisomers thereof. All 
of the various stereoisomeric forms are within the scope of the invention. 
The various stereoisomeric forms of the compounds prepared by the method of 
the invention, namely, cis-exo, cis-endo and all trans forms and 
stereoisomeric pairs may be prepared by employing starting materials and 
following the procedures as outlined in U.S. Pat. No. 4,143,054 and are 
fully disclosed in U.S. Pat. No. 5,100,889 which is incorporated herein by 
reference. 
The nucleus in each of the compounds prepared by the method of the 
invention is depicted as 
##STR22## 
for matter of convenience; it will also be appreciated that the nucleus in 
the compounds of the invention may be depicted as 
##STR23## 
The compounds prepared by the method of this invention are thromboxane 
receptor antagonists and as such are useful as inhibitors of thromboxane 
receptor mediated actions. The term "thromboxane receptor antagonist" 
includes compounds which are so-called thromboxane A.sup.2 receptor 
antagonists, thromboxane A.sup.2 antagonists, thromboxane A.sup.2 
/prostaglandin endoperoxide antagonists, TP-receptor antagonists, or 
thromboxane antagonists. 
The compounds prepared by the method of the invention are also thromboxane 
synthetase inhibitors and thus are useful as inhibitors of thromboxane 
production. 
Examples of various utilities of the compounds prepared by the method of 
the invention are set out in U.S. Pat. No. 5,100,889. 
The following Examples represent preferred embodiments of the present 
invention. Unless otherwise indicated, all temperatures are expressed in 
degrees Centigrade.

EXAMPLE 1 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-(pentylamino)ca 
rbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
A. N-Pentyl-N2-[(phenylmethoxy)carbonyl]-L-serinamide 
A 5-L, 3-necked flask was charged with N-CBZ-L-serine (110 g, 0.46 mole) 
(CBZ =carbobenzyloxy) followed by dichloromethane (2.1 L). The resulting 
slurry was stirred under argon and treated with triethylamine (61.7 mL, 
0.443 mole) over several minutes. The resulting hazy solution was cooled 
to an internal temperature of -35.degree. and treated over 10 minutes with 
trimethylacetylchloride (51.06 mL, 0.415 mole) such that the internal 
temperature did not rise above -30.degree.. The reaction was stirred an 
additional 40 minutes at -25.degree. to -30.degree., treated with pyridine 
(35.2 mL, 0.435 mole) over 5 minutes and stirred an additional 10 minutes. 
Amylamine (51 mL, 0.44 mole) was added over 10 minutes while maintaining 
the internal temperature at -25.degree. to -29.degree.. The reaction was 
stirred for 30 minutes while warming to -25.degree.. A precipitate formed 
during this warming. The reaction was further warmed to -10.degree. over 
40 minutes during which time the precipitate redissolved. After stirring 
an additional 20 minutes at -10.degree., the reaction was quenched by the 
addition of 500 mL of 1N HCl. The biphasic mixture was stirred for 20 
minutes and transferred to a separatory funnel. The aqueous layer was 
extracted with dichloromethane (2.times.75 mL). The combined 
dichloromethane solutions were concentrated in vacuo to a weight of 500 g. 
Ethyl acetate (EtOAc) (2.25 L) was added and the organic solution was 
washed with 1N HCl (2.times.400 mL) and 1N K.sub.2 CO.sub.3 (1.times.700 
mL and 2.times.500 mL). The organic solution was dried (magnesium 
sulfate), filtered and concentrated in vacuo to the title compound which 
was used in the next step without purification. 
B. N-Pentyl-L-serinamide, 1:1 oxalate salt 
The Part A compound was evaporated from 95% ethanol (EtOH) to remove 
residual solvents. The residue was dissolved in 95% EtOH (1.28 L) and 
treated under nitrogen with 20% Pd(OH).sub.2 (12.8 g). The mixture was 
stirred and sparged with hydrogen. After 2.5 hours the catalyst was 
filtered off and washed with 95% EtOH. The filtrate was concentrated in 
vacuo to 73.1 g. A portion of this material (36.3 g, 0.21 mole) was 
redissolved in 95% EtOH (221 mL) and added slowly to a stirred room 
temperature solution of oxalic acid dihydrate (31.5 g, 0.25 mole) in 95% 
EtOH (221 mL). After the addition the resulting slurry was further diluted 
with 120 mL of 95% EtOH, stirred an additional 30 minutes and then heated 
to reflux. The slurry was treated with water (29 mL) to afford a clear, 
light yellow solution. After stirring an additional 40 minutes the heat 
was removed and the solution cooled. The resulting slurry was stirred at 
ambient temperature for 18 hours, filtered and washed with 95% EtOH 
(1.times.72 mL, and 1.times.48 mL) and hexane (2.times.48 mL). Drying in 
vacuo produced 42.9 g (77.3%) of the title compound, mp 174.degree. C. 
C. 
[1S-[1.alpha.,2.alpha.,3.alpha.,4.alpha.]]-2-[[3-[[[1-(Hydroxymethyl)-2-ox 
o-2-pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]b 
enzenepropanoic acid, methyl ester 
To a stirred solution of 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[(3-carboxy-7-oxabicyclo[2.2. 
1]hept-2-yl)methyl]benzenepropanoic acid, methyl ester (prepared as 
described in U.S. Pat. No. 5,100,889) (17.6 g, 55.3 mmol) and 
4-methylmorpholine (12.2 mL, 111 mmol) in 100 mL of DMF under argon at 
-10.degree. C. was added dropwise isobutylchloroformate (7.94 mL, 61.2 
mmol) over a 15 minute period. This solution was stirred at -10.degree. C. 
for 50 minutes at which time n-pentyl-L-serinamide (10.6 g, 57.5 mmol) was 
added. The reaction mixture was stirred at -10.degree. C. for 1 hour and 
at room temperature for 16 hours. This mixture was diluted with 2 L of 
ethyl acetate (EtOAc) and washed with 1N HCl solution (2.times.600 mL), 
saturated NaHCO.sub.3 solution (1.times.600 mL) and brine (1.times.600 
mL). The EtOAc layer was dried (MgSO.sub.4), filtered and concentrated in 
vacuo. This was triturated in 600 mL of 1:1 etherhexane to give 25.2 g 
(96%) of title amide. 
TLC: silica gel, 4% CH.sub.3 OH/CH.sub.2 Cl.sub.2, R.sub.f 0.38, Cerium dip 
C.sup.1. Alternative Procedure for Forming C. 
A solution of Part C acid ester starting material (30.27 g, 95.06 mmol) and 
DMF (1.5 mL, 19.37 mmol) in CH.sub.2 Cl.sub.2 (200 mL) was cooled to an 
internal temperature of 0.degree. C. under an argon atmosphere. To the 
above solution was added oxalyl chloride (9.1 mL, 104.57 mmol) over 
.about.2.5 minutes. After 2 hours, gas evolution had ceased. A 75 .mu.L 
aliquot was removed and quenched into MeOH. TLC analysis of this solution 
showed no remaining starting acid, thus indicating complete conversion to 
the acid chloride. Toluene (30 mL) was added to the reaction mixture. The 
crude acid chloride solution was partially concentrated to an oil/solid 
mixture (43.37 g). 
In a separate flask, a suspension of N-pentyl-L-serinamide oxalate salt 
(30.26 g, 114.50 mmol) in CH.sub.2 Cl.sub.2 (200 mL was treated 
sequentially, under argon, with DBU (33.4 mL, 223.28 mmol) and Et.sub.3 N 
(16.0 mL, 114.50 mmol). The resulting solution was cooled to -78.degree. 
C. The crude acid chloride was redissolved in CH.sub.2 Cl.sub.2 (350 mL), 
cooled to 8.degree. C. under argon, and added to the solution of the amine 
via cannula such that the reaction temperature never exceeded -72.degree. 
C. The addition process required 35 minutes. The flask containing the acid 
chloride solution was rinsed with CH.sub.2 Cl.sub.2 (30 mL) which was 
transferred to the reaction mixture. After 45 minutes an aliquot was 
removed and quenched into MeOH. TLC analysis of the solution showed no 
evidence of unreacted acid chloride; only Part C title compound and a 
trace of starting acid were present. The dry ice/acetone bath was removed 
and with vigorous stirring, 1N HCl (500 mL) was immediately added. The 
internal temperature quickly rose to -10.degree. C. After transferring to 
a separatory funnel, additional water (1 L) and CH.sub.2 Cl.sub.2 (250 mL) 
were added. The layers were mixed and split. The aqueous layer was 
extracted with CH.sub.2 Cl.sub.2 (250 mL). The organic phases were 
combined and washed with 1N HCl 250 mL) and saturated aqueous NaHCO.sub.3 
(500 mL). The aqueous NaHCO.sub.3 solution was back-extracted with 
CH.sub.2 Cl.sub.2 (250 mL). The organic solutions were combined, washed 
again with saturated aqueous NaHCO.sub.3 (250 mL) and saturated aqueous 
NaCl (500 mL), dried (MgSO.sub.4), filtered, concentrated, and left under 
high vacuum for 12 hours to give the crude title compound (44.27 g). 
A portion of this material (38.27 g) was placed in a flask with water (7.25 
mL) and EtOAc (344 mL) and the mixture was brought to a boil. The 
resulting clear yellow solution was allowed to cool to room temperature 
and stand for 22 hours. EtOAc (125 mL) was added to slurry the 
all-engulfing white solid and the crystals were recovered via filtration. 
The white crystals were washed sequentially with EtOAc (2.times.75 mL) and 
hexanes (1.times.200 mL), air dried (1.5 hours), and placed under high 
vacuum for 24 hours to give the title compound (33.87 g). 
Procedure I for D. E. E 
D. 
[1S-[1.alpha.,2.alpha.,3.alpha.(R*),4.alpha.]]-2-[[3-[[[1-[Methylsulfonyl) 
oxymethyl]-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]he 
pt-2-yl]methyl]benzenepropanoic acid, methyl ester 
and 
E. 
[1S-[1.alpha.,2.alpha.,3.alpha.(R*),4.alpha.]]-2-[[3-[[[1-(Chloromethyl)-2 
-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]meth 
yl]benzenepropanoic acid, methyl ester 
To a stirred solution of Part C amide (25.2 g, 53.2 mmol) in 480 mL of dry 
CH.sub. Cl.sub.2 at -10.degree. C. under argon was added, in order, 
triethylamine (Et.sub.3 N) (8.88 mL, 63.8 mmol) and methanesulfonyl 
chloride (4.53 mL, 58.5 mmol). This solution was stirred at -10.degree. C. 
for 15 minutes and diluted with 200 mL of CH.sub.2 Cl.sub.2. This mixture 
was washed with ice-cold 1N HCl solution (2.times.150 mL) and a 1:1 
mixture of saturated NaHCO.sub.3 solution and brine (1.times.150 mL). The 
organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo 
to give solid intermediate Part D mesylate. To a stirred solution of this 
Part D mesylate in 120 mL of DMF was added anhydrous lithium chloride 
(5.58 g, 133 mmol). An exotherm was noted. This solution was stirred at 
room temperature for 18 hours and then diluted with 1 L of CH.sub.2 
Cl.sub.2. The solution was washed with 10% LiCl solution (2.times.250 mL), 
water (2.times.250 mL), saturated NaHCO.sub.3 solution (1.times.250 mL) 
and brine (1.times.250 mL). The organic layer was dried (MgSO.sub.4), 
filtered and concentrated in vacuo to give Part E chloride (26.2 g, 100% 
crude yield). 
TLC: silica gel, 3:1 EtOAc-hexane, R.sub.f 0.72, cerium dip mp 
180.degree.-182.degree. C. 
[.alpha.].sub.D =-5.5.degree. (c=0.9, CHCl.sub.3). 
Anal. Calc'd for C.sub.26 H.sub.37 N.sub.2 O.sub.5 Cl: C, 63.34; H, 7.56; 
N, 5.68; Cl, 7.19, Found: C, 63.39; H, 7.68; N, 5.69; Cl, 7.36. 
Alternative Procedure II for D. and E. 
To a stirred solution of Part C amide (25.2 g, 53.2 mmol) in 250 mL of dry 
CH.sub.2 Cl.sub.2 at -10.degree. C. under argon is added, in order, 
triethylamine (Et.sub.3 N) (8.88 mL, 63.8 mmol) and methanesulfonyl 
chloride (4.53 mL, 58.5 mmol). This solution is stirred at -10.degree. C. 
for 15 minutes and diluted with 100 mL of DMF. To this mixture is added 
anhydrous lithium chloride (5.58 g, 133 mmol) in 50 mL DMF. This solution 
is stirred at room temperature for 18 hours and then diluted with 1 L of 
CH.sub.2 Cl.sub.2. The solution is washed with 10% LiCl solution 
(2.times.250 mL), water (2.times.250 mL), saturated NaHCO.sub.3 solution 
(1.times.250 mL) and brine (1.times.250 mL). The organic layer is dried 
(MgSO.sub.4), filtered and concentrated in vacuo to give Part E chloride. 
Alternative Procedure III for D. and E. 
To a stirred solution of Part C amide (25.2 g, 53.2 mmol) in 350 mL of dry 
CH.sub.2 Cl.sub.2 at -10.degree. C. under argon is added, in order, 
triethylamine (Et.sub.3 N) (8.88 mL, 63.8 mmol) and methanesulfonyl 
chloride (4.53 mL, 58.5 mmol). This solution is stirred at -10.degree. C. 
for 15 minutes and diluted with 200 mL of CH.sub.2 Cl.sub.2. This mixture 
is washed with ice-cold 1N HCl solution (2.times.150 mL) and a 1:1 mixture 
of saturated NaHCO.sub.3 solution and brine (1.times.150 mL). The organic 
layer is dried (MgSO.sub.4), filtered and concentrated in vacuo to give 
solid intermediate Part D mesylate. To a stirred solution of this Part D 
mesylate in 250 mL of CH.sub.2 Cl.sub.2 portionwise is added 
benzyltributylammonium chloride (33 g, 107 mmol). This solution is stirred 
at room temperature for 18 hours and then diluted with 1 L of CH.sub.2 
Cl.sub.2. The solution is washed with 10% LiCl solution (2.times.250 mL), 
water (2.times.250 mL), saturated (1.times.250 mL) and brine (1.times.250 
mL). The NaHCO.sub.3 solution (1.times.250 mL) and brine (1.times.250 mL). 
The organic layer is dried (MgSO.sub.4), filtered and concentrated in 
vacuo to give Part E chloride. 
F. [1S-[1.alpha.,2.alpha.,3.alpha.(R*),4.alpha.]]- 
2-[[3-[[[1-Methylene-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyc 
lo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester 
To a stirred solution of Part E chloride (26.2 g, 53.2 mmol) in 740 mL of 
dry CH.sub.2 Cl.sub.2 under argon was added DBU (15.0 mL, 106 mmol). The 
reaction mixture was stirred at room temperature for 4.5 hours and washed 
with 1N HCl solution (2.times.400 mL), half-saturated NaHCO.sub.3 solution 
(1.times.400 mL) and brine (1.times.400 mL). The organic layer was dried 
(MgSO.sub.4), filtered and concentrated in vacuo to give 26 g of crude 
oil. This crude oil (25 g) was chromatographed on 900 g of Merck silica 
gel K-60 using 2 L of 40% EtOAc in hexane and 6 L of 50% EtOAc in hexane 
as eluants to give 17.4 g (72%) of title olefin as a viscous oil. 
[.alpha.].sub.D =+27.7.degree. (c=1.0, CH.sub.3 OH). 
TLC silica gel, 2:1 EtOAc-hexane, R.sub.f 0.64, cerium dip. 
Anal. Calc'd for C.sub.26 H.sub.36 N.sub.2 O.sub.5 : C, 68.40; H, 7.95; N, 
6.14, Found: C, 68.10; H, 8.12; N, 5.87. 
This olefin was stored at -78.degree. C. under argon. 
G. 
[1S-[1.alpha.,2.alpha.,3.alpha.(R*,Z),4.alpha.]]-2-[[3-[[[1-(Bromomethylen 
e)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl] 
methyl]benzenepropanoic acid, methyl ester and 
H. 
[1S-[1.alpha.,2.alpha.,3.alpha.(R*,E),4.alpha.]]-2-[[3-[[[1-(Bromomethylen 
e)-2-oxo-2-(pentylamino)ethyl]-amino]carbonyl-7-oxabicyclo[2.2.1]hept-2-yl] 
methyl]benzenepropanoic acid, methyl ester 
To a stirred solution of purified Part F olefin (13.8 g, 30.3 mmol) in 500 
mL of dry CH.sub.2 Cl.sub.2 under argon at -78.degree. C. was added 
bromine (1.58 mL, 30.7 mmol). At the end of the addition of bromine the 
reaction mixture became bright yellow. This yellow solution was stirred at 
-78.degree. C. for 15 minutes and treated slowly with triethylamine (16.8 
mL, 121 mmol). The reaction flask was then transferred to a wet ice bath 
and stirred for 40 minutes. The mixture was diluted with 200 mL of 
CH.sub.2 Cl.sub.2 and washed with 2% NaHSO.sub.3 solution (2.times.250 
mL), water (1.times.250 mL) and brine (1.times.250 mL). The organic layer 
was dried (MgSO.sub.4), filtered and concentrated in vacuo. This was 
triturated with 1 L of 3:7 hexane-ether to give 14.9 g (92% or 66% from 
starting methyl ester used in Part C) of 9:1 mixture of title vinyl 
bromides G (major) and H (minor). 
TLC: silica gel, 1:2 hexane-EtOAc, R.sub.f, 0.31, 0.56, UV & cerium dip. 
HPLC: R.sub.T =6.3 minutes (87%) and 7.2 minutes (9.5%), linear gradient of 
72-90% aqueous methanol containing 0.2% H.sub.3 PO.sub.4, 20 minutes, 
detected at 217 nm, YMC S-3 (ODS), 6.0.times.150 mm, 3 micron spherical 
end capped column, flow rate 1.5 mL/minute. 
The product from a smaller scale reaction (1.9 mmol) was purified and 
separated by chromatography on silica gel (150 mL, Merck), eluting with 
ethyl acetate:hexane (1:1 and 1:2) and finally with ethyl acetate to give 
the two isomers G and H. The minor isomer H was obtained as a white solid 
(94 mg, 9.2%). mp 104.degree.-108.degree. C. 
[.alpha.].sub.D =+46.0.degree. (c=0.7, CHCl.sub.3). 
Anal. Calc'd for C.sub.26 H.sub.35 N.sub.2 O.sub.5 Br: C, 58.32; H, 6.59; 
N, 5.23, Br, 14.92. Found: C, 58.18; H, 6.66; N, 4.99; Br, 15.14. 
The major isomer G was also a white solid (877 mg, 86%). mp 
160.degree.-164.degree. C. 
[.alpha.].sub.D =-37.9.degree. (c=1.0 CHCl.sub.3). 
Anal. Calc'd for C.sub.236 H.sub.35 N.sub.2 O.sub.5 Br: C, 58.32; H, 6.59; 
N, 5.23, Br, 14.92. Found: C, 58.28; H, 6.64; N, 4.96; Br, 15.19. 
Alternate G and H preparation 
To a stirred solution of crude Part E olefin (olefin was worked up as 
described in the above preparation and used without purification by column 
chromatography, 1.10 g) in 42 mL of dry CH.sub.2 Cl.sub.2 under argon at 
-78.degree. C. was added bromine over 10 minutes. Bromine was added until 
a bright yellow color appeared and stayed in the reaction mixture. The 
amount of bromine used in this scale was 125 .mu.L. The mixture was 
stirred at -78.degree. C. for 5 minutes and treated with Et.sub.3 N (1.33 
mL, 9.60 mmol). The reaction flask was then moved to a wet-ice bath and 
stirred for 30 minutes. The mixture was diluted with 100 mL of CH.sub.2 
Cl.sub.2 and washed with 2% NaHSO.sub.3 solution (2.times.60 mL), water 
(1.times.60 mL) and brine (1.times.60 mL). The organic layer was dried 
(MgSO.sub.4), filtered and concentrated in vacuo. This was triturated in 
50 mL of ether to give 716 mg (57% from starting acids used in Part C) of 
a 9:1 mixture of vinyl bromides G and H. 
TLC: silica gel 1:2 hexane-EtOAc, R.sub.f, Part G compound, 0.31, Part H 
compound, 0.56, cerium dip. 
TLC of the mother liquor indicated that the vinyl bromides were the major 
components in this mixture. 
I. 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino) 
carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
A suspension of CuBr.sub.2 (0.89 g, 4 mmol) and DBU (1.2 mL, 8 mmol) in 20 
mL deoxygenated CH.sub.2 Cl.sub.2 was stirred mechanically at room 
temperature under argon for 10 minutes. A slurry of the mixture of Part G 
and Part H vinyl-bromides diamides (1.078 g, 2 mmol) in 5 mL CH.sub.2 
Cl.sub.2 was added to the solution of the cupric bromide. After stirring 
for 8 hours, a second batch of reagents, DBU (1.2 mL, 8 mmol) and 
CuBr.sub.2 (0.89 g, 4 mmol), was added. After 24 hours the solvent was 
removed and dark brown oil was treated with 40 mL of a mixture of 
saturated aqueous NH.sub.4 Cl/conc. NH.sub.4 OH (2:1, pH .about.10) and 50 
mL EtOAc. The light orange organic layer was separated and the blue 
aqueous layer was extracted with EtOAc (3.times.50 mL). The combined 
organic extracts were washed with a mixture of saturated aqueous NH.sub.4 
Cl/conc. NH.sub.4 OH (2:1, 3.times.30 mL) and 10% aqueous citric acid 
(3.times.30 mL). The organic extract was washed further with aqueous 
NaHCO.sub. 3 and brine and then dried (MgSO.sub.4). The solution was 
stirred with charcoal (activated carbon, Darco) for 25 minutes and then 
filtered through a pad of MgSO.sub.4. The filtrate was evaporated to give 
0.866 g (yield 81%) of title compound. The product was purified by flash 
column chromatography over silica gel (150 mL). The column was eluted with 
a 1:1 mixture of EtOAc/hexane (1:2) and 25 mL fractions were collected. 
TLC homogeneous fractions 3 to 21 were combined and evaporated. The 
residue was dissolved in 10 mL CH.sub.2 Cl.sub.2 and evaporated again to 
remove EtOAc. The residue was dried under vacuum to furnish 0.7 g (yield 
65%) title compound as a colorless viscous oil. 
[.alpha.].sub.D =+19.5.degree. (c=1, CHCl.sub.3). 
Anal. Calc'd for C.sub.26 H.sub.33 BrN.sub.2 O.sub.5 (MW 533.47): C, 58.54; 
H, 6.24; N, 5.25; Br, 14.98, Found: C, 58.77; H, 6.23; N, 5.25; Br, 14.99. 
EXAMPLE 2 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino)c 
arbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
A. 
[1S-[1.alpha.,2.alpha.,3.alpha.,4.alpha.]]-2-[[3-[[[1,1-(Dibromomethylene) 
-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]me 
thyl]benzenepropanoic acid, methyl ester 
A solution of Example 1 Part G and H vinylbromides (0.503 g, 0.94 mmol) in 
20 ml dry methylene chloride was cooled to -78.degree.. Bromine (0.048 ml, 
0.94 mmol) was added to the solution and after 30 minutes additional 
bromine (0.01 ml, 0.2 mmol) was introduced into the reaction mixture. 
After 20 minutes triethyl amine (0.52 ml, 3.78 mmol) was added via syringe 
and stirring was continued for 20 minutes. The mixture was poured into 60 
ml aqueous saturated sodium bisulphite and extracted with 50 ml 
dichloromethane. The organic solution was washed with 30 ml brine, dried 
over potassium carbonate, filtered and solvent was evaporated to give 
0.545 g (yield 94.4%) of title compound. TLC: silica gel, EtOAc/hexane 
3:1, R.sub.f of title vinyldibromide 0.28, visualized by UV and ceric 
sulphate/ammonium molybdate. 
B. 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino) 
carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
A suspension of cupric bromide (CuBr.sub.2) (0.054 g, 0.24 mmol) and 
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.072 ml, 0.48 mmol) in 1.8 ml 
deoxygenated dry methylene chloride (CH.sub.2 Cl.sub.2) was stirred at 
room temperature under argon for 10 min. Solid Part A vinyldibromide 
diamide (0.074 g, 0.12 mmol) was added to the solution of the oxidation 
reagent. The reaction was complete after stirring for 20 hours (TLC: 
Silica gel, ethyl acetate (EtOAc)/hexane (3:1), R.sub.f of 
bromooxazole=0.57, dibromide 0.32, visualized by UV and ceric sulphate, 
ammonium molybdate). The solvent was removed and dark brown oil was 
treated with 10 ml ethyl acetate (EtOAc) and 7 ml of a mixture of 
saturated aq. ammonium chloride (NH.sub.4 Cl)/conc. ammonium hydroxide 
(NH.sub.4 OH) (2:1, pH .about.10). The light orange organic layer was 
separated and the blue aq. layer was extracted with ethyl acetate (EtOAc) 
(3.times.4 ml). The combined organic extracts were washed with a mixture 
of saturated ammonium chloride (NH.sub.4 Cl)/conc. ammonium hydroxide 
(NH.sub.4 OH) (2:1, 3.times.5 ml) and 10% aq. citric acid (3.times.5 ml). 
The organic extract was washed further with aq. sodium bicarbonate 
(NaHCO.sub.3) and brine and then dried magnesium sulphate (MgSO.sub.4). 
The solution was stirred with charcoal (activated carbon, Darco) for 25 
min. and then filtered through a pad of magnesium sulphate (MgSO.sub.4). 
The filtrate was evaporated to give 0.051 g (yield .about.80%) of the 
title compound. 
EXAMPLE 3 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbonyl] 
-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, 
methyl ester 
(Hydrogenolysis of Example 1 bromooxazole to the corresponding oxazole). 
A solution of Example 1 bromooxazole (0.085 g, 0.16 mmol) in ethanol (1 ml) 
and methanol (2 ml) was stirred under argon and 10% Pd-C (0.03 g) was 
added. The mixture was stirred under hydrogen (in a balloon) for 24 hours. 
TLC (silica gel, ethylacetate/hexane (3:1), R.sub.f of bromooxazole=0.57, 
oxazole 0.42, visualized by UV and ceric sulphate, ammonium molybdate) 
showed no starting material. The mixture was filtered through Celite and 
solvent was evaporated to give 0.058 g (.about.80% crude yield) of the 
title compound. 
EXAMPLE 4 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)-2-[[3-[4-[(Pentylamino)carbonyl]- 
2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid 
Aqueous 1N NaOH (5 mL) was added to a solution of Example 3 compound (0.912 
g, 2 mmol) in THF (10 mL) and the reaction mixture was stirred under 
argon. After 4.5 hours, the mixture was evaporated under vacuum to 
.about.5 mL and diluted with 10 mL water. HCl (1N, 2.8 mL) was added to 
the aqueous solution and its pH was adjusted to .about.8.5 with a few 
drops of aqueous NaHCO.sub.3. The solution was washed with EtOAc (15 mL), 
CH.sub.2 Cl.sub.2 (10 mL) and EtOAc (15 mL). The aqueous layer was 
separated and acidified with 1N HCl to pH 6.5. The product was extracted 
with EtOAc (150 mL) and CH.sub.2 Cl.sub.2 (50 mL). Organic extracts were 
combined, dried (MgSO.sub.4) and evaporated to give a white solid. The 
product was dried under vacuum overnight to furnish 0.808 g (yield 92%) of 
title acid, mp 157.degree.-59.degree., [.alpha.].sub.D =+57.5.degree. 
(c=1, CHCl.sub.3). 
Anal. Calc'd for C.sub.25 H.sub.32 N.sub.2 O.sub.5 (MW 440.54): C, 68.16; 
H, 7.32; N, 6.36; H20, 0.0, Found: C, 67.99; H, 7.06; N, 6.33; H20, 0.0 
(KF). 
EXAMPLE 5 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino)c 
arbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid 
A. Purification of 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino) 
carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
Example 1 compound (prepared as a by-product as described in Example 2 Part 
A(1) in U.S. application Ser. No. 900,384, filed June 18, 1992) (2 g) was 
rechromatographed over flash silica gel (K-60, 400 mL, in a 50 mm. dia. 
column). The column was eluted with 2 1 of 50% EtOAc/hexane and 35 mL 
fractions were collected. Fractions 14 to 18 gave 1.14 g Example 3 product 
which still contained impurities. The product was rechromatographed over 
200 mL flash silica gel. The column was eluted successively with 1L 10% 
EtOAc in hexane, 1L 20% EtOAc in hexane and 2L 30% EtOAc in hexane 
collecting 35 mL fractions. Fractions 60 to 75 were combined and 
evaporated to give 0.91 g purified title compound as a viscous oil. 
B. Saponification of Part A compound to Example 5 compound 
([1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino 
)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoi 
c acid) 
Aqueous 1N NaOH (2 mL) was added to a solution of purified Part A compound 
(0.406 g, 0.76 mmol) in 4 mL THF. The biphasic mixture was stirred under 
argon at room temperature. After 3.5 hours THF was removed on a rotary 
evaporator and the aqueous solution (-10 mL) was extracted twice with 3 mL 
t-BuOMe. The aqueous solution was acidified with 1N HCl to pH 8.5 and 10 
mL EtOAc was added before further acidification to pH 6. The organic layer 
was separated and the aqueous layer was extracted with EtOAc (2.times.4 
mL). The combined organic extracts were washed with brine, dried 
(MgSO.sub.4) and the solvent was removed under vacuum to give 0.54 g of a 
snow-white solid. Crude product (0.5 g) was triturated with 5 mL t-BuOMe. 
The insoluble solid was filtered and dried under vacuum over P.sub.2 
O.sub.5 to give 0.37 g (yield 95%) of title compound; mp 
153.degree.-55.degree.. 
[.alpha.].sub.D =+24.8.degree. (c=1, CHCl.sub.3). 
Anal. Calc'd for C.sub.25 H.sub.31 BrN.sub. O.sub.5 (MW 519.44): C, 57.81; 
H, 6.02; N, 5.39; Br, 15.38; H.sub.2 O, 0.0, Found: C, 58.23; H, 5.94; N, 
5.08; Br, 15.39; H.sub.2 O, 0.0 (KF via desorption). 
C. Recrystallization of 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino) 
carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic 
acid 
Part B Bromoacid (0.32 g) was dissolved in 20 mL hot t-BuOMe and filtered 
through a filter paper. The solution was seeded with crystals of Example 5 
compound at room temperature and let stand with a loose stopper. After 2 
days birefringent crystals (long thin rods) were separated from the 
solvent by decantation, washed with t-BuOMe and dried under vacuum to give 
0.136 g (40.3% yield first crop Example 5 compound); mp 
153.degree.-55.degree. dec. 
Anal. Calc'd for C.sub.25 H.sub.31 BrN.sub.2 O.sub.5 (MW 519.44): C, 57.81; 
H, 6.02; N, 5.39; Br, 15.38, Found: C, 57.97; H, 6.05; N, 5.25; Br, 15.53. 
EXAMPLE 6 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbonyl] 
-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid 
(Hydrogenolysis of Example 5 bromooxazole acid to corresponding oxazole 
(Example 6)). 
Example 5 bromooxazole acid (0.052 g, 0.1 mmol) was added to a solution of 
sodium bicarbonate (0.021 g, 0.25 mmol) in 1 ml water. The solution was 
diluted with ethanol (0.5 ml) and dimethylformamide (0.5 ml). 5% Pd-C 
(0.026 g) was added and hydrogen gas was bubbled through the stirred 
suspension for 3 hours. TLC (silica gel, ethyl acetate (EtOAc)/hexane 3:1, 
R.sub.f of starting material bromooxazole acid= 0.71, product oxazole acid 
0.61, visualized by UV and ceric sulphate, ammonium molybdate) showed no 
starting material. The mixture was filtered and solvent was removed 
completely under vacuum. The colorless residue was redissolved in water (5 
ml) and the solution was acidified with a few drops of 1N HCl to pH 4 to 
give a white precipitate. The mixture was extracted with ethyl acetate 
(EtOAc) (3.times.5 ml) and the organic extracts were washed with water 
(3.times.5 ml), brine (5 ml). The solution was dried, magnesium sulphate 
(MgSO.sub.4) and solvent was evaporated to give 0.044 g (yield 100%) of 
the title compound as a white solid. mp 141.degree.-143.degree. C. Proton 
NMR (270 MHz, CDCl.sub.3) of this product was identical to an authentic 
sample of the title compound. Solvent was removed from the NMR sample and 
the residue was once evaporated from 2 ml chloroform. 
Anal. Calc'd for C.sub.25 H.sub.32 N.sub.2 O.sub.5 .multidot.0.06 H.sub.2 
O.multidot.0.07 CHCl.sub.3 ; MW 440.54/449.98: C 6.92, H 7.21, N 6.23; 
Found: C 6.69, H 7.23, N 6.24. 
EXAMPLE 7 
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[5-Bromo-4-[(pentylamino)c 
arbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic 
acid, methyl ester 
(Cyclization of Example 1 Part F Vinyldiamide to Bromooxazole) 
A suspension of cupric bromide (CuBr.sub.2) (0.196 g, 0.88 mmol) and 
1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (0.263 ml, 1.76 mmol) in 1.1 ml 
deoxygenated dry methylene chloride (CH.sub.2 Cl.sub.2) was stirred at 
room temperature under argon for 10 min. Solid Example 1 Part F 
vinyldiamide (0.1 g, 0.22 mmol) was added to the solution of the cupric 
bromide. The reaction was complete after stirring for 20 hours (TLC: 
Silica gel, ethyl acetate/hexane (3:1), R.sub.f of bromooxazole =0.59, 
dibromide 0.35, visualized by UV and ceric sulphate, ammonium molybdate). 
Ethyl acetate (10 ml) was added and the mixture was washed with a mixture 
of saturated aq. ammonium chloride /conc. ammonium hydroxide (3:1). The 
light orange organic layer was separated and the blue aq. layer was 
extracted with ethyl acetate. The combined organic extracts were washed 
with a mixture of saturated ammonium chloride/conc. ammonium hydroxide 
(3:1) and 10% aq. citric acid (3.times.5 ml). The organic extract was 
washed further with aq. sodium bicarbonate and brine and then dried 
(magnesium sulphate). The solution was stirred with charcoal (activated 
carbon, Darco) for 25 min. The mixture was filtered and the filtrate was 
evaporated to give the crude product title compound which also contained 
20% Example 3 oxazole by NMR.