SOLID SUPPORTED SYNTHESIS OF SULFONATED 2-OXOPIPERAZINES

SYNTHESE SUR SUPPORT SOLIDE DE 2-OXOPIPERAZINES SULFONEES

English Abstract

The subject invention involves processes for making 2-oxopiperazine and
homologous compounds using a solid support resin by (a) removing the
protecting group from a N-protected amino acid ester of the resin (if
present), (b) reacting the resulting unprotected resin ester with a sulfonyl
chloride, (c) reacting the resulting intermediate with a N-protected amino
alcohol, (d) removing the N-protecting group from the N from the amino
alcohol, and (e) cleaving/cyclizing the product from the resin.

French Abstract

La présente invention concerne des procédés qui permettent de fabriquer des composés de 2-oxopipérazine et homologues au moyen d'un résine support solide et qui consistent à: (a) retirer le groupe protecteur de l'ester d'aminoacide protégé N (le cas échéant), (b) faire réagir la résine non protégée qui en résulte avec un chlorure de sulfuryle, (c) faire réagir le produit intermédiaire avec un alcool amino N-protégé, (d) retirer le groupe de protection-N de N de l'alcool amino et (e) séparer le produit de la résine.

Claims

13
1. A process for making compounds having the structure:
<IMG>
wherein R1 is hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl amine,
aryl
amine, alkyl , or aryl ester; R2 is hydrogen, alkyl. aryl,heterocycle,
heteroaryl, alkyl amine, aryl amine, alkyl ester, or aryl ester; R3 is
hydrogen,
alkyl, aryl, heterocycle, heteroaryl, alkyl amine, aryl amine, alkyl acyl,
aryl acyl,
alkyl ester, aryl ester, alkyl sulfonyl, or aryl sulfonyl; and R4 is alkylene
or
heteroalkylene; n is an integer from 0 to about 5; m is an integer from 1 to
about 5;
and B1 is a N-protecting group; the process comprising the following steps:
(a) from a N-protected amino acid ester of a solid-support resin:
<IMG>
removing the N-protecting group B1 and substituting therefor a
hydrogen to give an unprotected amino acid ester of a solid-support
resin; or starting with such unprotected resin ester;
(b) reacting the unprotected resin ester from step (a) with sulfonyl
chloride:
R2-SO2C1
to provide:

14
<IMG>
(c) reacting 3 with a N-protected alcohol:
<IMG>
to provide.
<IMG>
(d) removing the N-protecting group from 5 or 8; and
(e) cleaving and cyclizing 6 or 9 from the resin.
3. The process of Claim 1 wherein a is 0 or 1, and m is 1 or 2.
4. The process of Claim 3 wherein in step (c) the amino alcohol has structure
4~,
resulting in product with structures 6 from step e.

15
5. The process of Claim 3 wherein in step {c) the amino alcohol has structure
7 resulting is product with structure 9 from step e.
6. The process of Claim 4 wherein
(a) R1 is hydrogen or alkyl, the alkyl having from one to about four
carbon atoms and being saturated, linear or branched, unsubstituted
or substituted with one moiety selected from the group consisting
of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
methylamino, ethylamino, dimethylamino, diethylamino, guanido,
carboxy,carbamoyl,phenyl,hydroxyphenyl,indole,and imidazo;
(b) R2 is selected from the group consisting of hydrogen, alkyl, aryl.
and heterocycle;
(c) R3 is hydrogen or alkyl, the alkyl having from one to about four
carbon atoms and being saturated, linear or branched, unsubstituted
or substituted one moiety selected from the group consisting
of hydroxy, methoxy, ethoxy, thio, methylthio. ethylthio, amino,
methylamino, ethylamino, dimethylamino, diethylamino, guanido,
carboxy, carbamoyl, phenyl hydroxyphenyl, indole, and imidazo;
and

16
(d) R4 is saturated alkylene having from about three to about
four carbon atoms, the alkylene being unsubstituted or substituted
with one moiety selected from the group consisting of hydroxy,
methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino,
ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl.
7. The process of Claim 6 wherein step (e) is carried out in an acetic
acid/2-butanol solution.
8. The process of Claim 3 wherein each N-protecting group is Boc or Fmoc,
and steps (a) and (d) are carried out in a TFA solution.
9. The process of Claim 7 wherein each N-protecting group is Boc or Fmoc,
and steps (a) and (d) are carried out is a TFA solution.
10. The process of Claim 3 wherein the main is hydroxymethylpolystyrene.
11. The process of Claim 9 wherein the resin is hydroxymethylpolystyrene.
12. The process of Claim 1 wherein n is 0 and m is 1.
13. The process of Claim 3 wherein n is 0 and m is 1.
14. The process of Claim 6 wherein n is 0 and m is 1.
15. The process of Claim 11 wherein n is 0 and m is 1.

17
16. A library of compounds having structure:
<IMGS>
or both, wherein R1, R2, R3 and R4 are selected such that the compounds
are stable.
17. The library of compounds of Claim 16, wherein
(a) n is from 0 to 2;
(b) m is from 1 to 3;
(c) R1 is hydrogen or alkyl, the alkyl having from one to about four
carbon atoms and being saturated, linear of branched, unsubstituted
or substituted with one moiety selected from the group consisting
of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
methylamino, ethylamino, dimethylamino, diethylamino, guanido,
carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo;
(d) R2 is selected from the group consisting of hydrogen, alkyl, aryl,
and heterocycle;
(e) R3 is hydrogen or alkyl, the alkyl having from one to about four
carbon atoms and being saturated, linear or branched, unsubstituted
or substituted with one moiety selected from the group consisting
of hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
methylamino, ethylamino, dimethylamino, diethylamino, guanido,
carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and
imidazo; and
(f) R4 is saturated alkylene having from about three to about four
carbon atoms, the alkylene being unsubstituted or substituted with

18
one moiety selected from the group consisting of hydroxy,
methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino,
ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl.
18. The library of compounds of Claim 17 wherein n is 0 and m is 1.
19. The library of compounds of Claim 17 wherein the compounds have
structure 6.
20. The library of compounds of Claim 19 wherein n is 0 and m is 1.

Description

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Solid Supported Synthesis of Sulfonated
2-Oxopiperazines
TECHNICAL FIELD
The subject invention relates to methods for synthesizing sulfonated 2-
oxopiperazine and homologous compounds, including libraries of such
compounds, using a solid-support resin to facilitate purification of
intermediates.
BACKGROUND OF THE INVENTION
Many of the first combinatorial libraries were developed around the well
documented solid supported syntheses of peptides and transformations of amino
acid resin esters. As a consequence, several syntheses of hydantoins and
diketopiperazines have been reported. See a) Gordon, D. W.; Steele, J.;
Bioorg.
Med Chem. Lett., vol. 5 (1995), p. 47; b) Kowalski, J.; Lipton, M. A.;
Tetrahedron Lett., vol. 37 (1996), p. 5839; c) Scott, B. O.; Siegmund, A. C.;
Marlowe, C. K.; Pei, Y.; Spear, K. L.; Mol. Diversity, vol. 1 (1995), p. 125;
d)
Goodfellow, V. S.; Laudeman, C. P.; Gerrity, J. L; Burkard, M.; Strobel, E.;
Zuzack, J. S.; McLeod, D. A.; Mol. Diversity, vol. 2 (1996), p. 97; e) Fresno,
M.;
Alsina, J.; Royo, M.; Barany, G.; Albericio, F.; Tetrahedron Lett., vol. 39
(1998),
p. 2639. The latter class of compounds possesses a rigid scaffold and has
proven
to be an effective screening tool, but also has several limitations,
solubility and
metabolic stability. There are only a few reports on the synthesis of
piperazines
and 2-oxopiperazines on solid support. See a) Goff, D. A.; Zuckremann, R. N.;
Tetrahedron Lett., vol. 37 (1996), p. 6247; b) Dankwardt, S. M.; Sherry, R.
N.;
Krstenansky, J.; Tetrahedron Lett., vol. 36 (1995), p. 4923; c) Goff, D. A.;
Tetrahedron Lett., vol. 39 (1998), p.1473.
SUMMARY OF THE INVENTION

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The subject invention involves processes for making sulfonated 2-
oxopiperazine compounds:
O
R1
HN
N
R3 ~SOZR2
using a solid-support resin, comprising the following steps:
(a) starting with a N-protected a-amino acid ester of a solid-support resin:
R1
7
removing the N-protecting group, and reacting the unprotected ester with a
sulfonyl chloride: R2-S02C1, to provide:
O
R1
\O
NH
S R2
(b) reacting this through a Mitsunobu reaction with a N-protected a-amino
alcohol: B1NHCH(R3)CH20H, to provide:

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O
R~
......: w0
N,'''SOZR2
BINH ~R3
(c) removing the N-protecting group, and cyclizing the above sulfonated 2-
oxopiperazine from the resin.
The subject invention also includes the above processes where the above a-
amino acid ester is replaced by a (3-amino acid ester (or longer homologous
ester)
and/or the above a-amino alcohol is replaced by a (3-amino alcohol (or longer
homologous alcohol), such that the final products are the homologous 7-member
or 8-member (or larger) ring compounds. Also, in the above structures, R3 may
also be attached to the N from the amino alcohol (eliminating the H attached
thereto), thus resulting in a fused-ring product.
DETAILED DESCRIPTION OF THE INVENTION
As used herein unless specified otherwise, "alkyl" means a hydrocarbon
chain which is branched, linear or cyclic, saturated or unsaturated (but not
aromatic),
substituted or unsubstituted. The term "alkyl" may be used alone or as part of
another word where it may be shortened to "alk" (e.g., in alkoxy, alkylacyl).
Preferred linear alkyl have from one to about twenty carbon atoms, more
preferably
from one to about six carbon atoms, more preferably still from one to about
four
carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and
branched
alkyl have from three to about twenty carbon atoms, more preferably from three
to
about six carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but
may
have two, three, or more, fused hydrocarbon rings. Preferred alkyl are
unsaturated
with from one to about three double or triple bonds; preferably they are mono-
unsaturated with one double bond; more preferred alkyl are saturated.
Preferred

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4
substituents of alkyl include alkyl, aryl, aryloxy, alkoxy, alkyl or aryl
ester. More
preferred alkyl are unsubstituted.
As used herein, "heteroatom" means a nitrogen, oxygen, or sulfur atom.
As used herein, "alkylene" means a linear alkyl which is attached to other
moieties both ends of the alkylene, and "heteroalkylene" means an alkylene
having
one or more heteroatoms between carbons or/and at one or both ends of the
alkylene.
As used herein unless specified otherwise, "aryl" means an aromatic
hydrocarbon ring which is substituted or unsubstituted. The term "aryl" may be
used
alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl
have from
six to about ten carbon atoms in the aromatic ring(s), and a total of from
about six to
about twenty, preferably to about twelve, carbon atoms. Preferred aryl is
phenyl or
naphthyl; most preferred is phenyl. Preferred substituents of aryl include
alkyl, aryl,
alkoxy, aryloxy, alkyl or aryl ester, halo, nitro, amino, cyano, acyl, alkyl-
or
arylacyl. More preferred aryl are unsubstituted.
As used herein unless specified otherwise, "heterocycle" means a cyclic
hydrocarbon chain with one or more heteroatoms in the hydrocarbon ring(s). The
rings) may be saturated, unsaturated, or aromatic. Preferred heterocycles have
from
one to about six heteroatoms in the ring(s), more preferably one or two or
three
heteroatoms, most preferably one heteroatom. Preferred heterocycles have from
three to about twelve carbon plus heteroatoms in the ring(s), more preferably
from
three to about seven; and a total of from three to about twenty carbon plus
heteroatoms, more preferably from three to about ten. Preferred heterocycles
have
one ring, but may have two, three, or more, fused rings. Heterocycles are
unsubstituted or substituted. Preferred heterocycle substituents are the same
as for
alkyl.
As used herein unless specified otherwise, "heteroaryl" means an aromatic
heterocycle. Preferred heteroaryls have from one to about six heteroatoms in
the
ring(s), more preferably one or two or three heteroatoms, most preferably one
heteroatom. Preferred heteroaryls have from five to about twelve carbon plus
heteroatoms in the aromatic ring(s), more preferably from five to about nine;
and a
total of from five to about twenty carbon plus heteroatoms, more preferably
from

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five to about ten. Preferred heteroaryls have one ring, but may have two or
more
fused rings, at least one of which contains at least one ring heteroatom.
Heteroaryls
are unsubstituted or substituted. Preferred heteroaryl substituents are the
same as for
aryl.
The subject invention processes use solid-support resins capable of linking
with the carboxy moiety of amino acids. Preferred resins for use in the
subject
processes have hydroxyalkylene linking moieties. Particularly preferred are
Merrifield or Wang resins such as polystyrene based resin Merrifield (100-200
mesh), 2%DVB - catalog number O1-64-0104, available from Calbiochem-
Novabiochem Corp., San Diego, California, a hydroxymethylpolystyrene resin.
N-protected amino acids can be readily esterified to the above-mentioned
resins. Alternatively, such resins are commercially available with N-protected
amino acids already esterified to the resin (e.g. Boc-Gly-Merrifield resin
catalog
number 04-12-2507, available from Calbiochem-Novabiochem Corp.).
N-protecting groups on the above-mentioned amino acids are well known;
they include t-butyloxycarbonyl (Boc} and 9-fluorenylmethoxycarbonyl (Fmoc);
most preferred is Boc. In the structures depicted herein, "Bl" is used to
indicate a N-
protecting group.
A subject invention process involves starting with a N-protected amino acid
ester of a solid-support resin:
R1
BINH
1
The N-protecting group is generally present on amino acid esters of resins
because it
is needed to properly esterify the amino acid onto the resin. The subject
process first
requires removing this N-protecting group; this can be accomplished using any

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known method. (If the N-protecting group is not present, this procedure can be
skipped.)
The resulting unprotected amino acid ester of a solid-support resin is reacted
with a sulfonyl chloride:
R2-S02C1
2
to provide:
O
_O
v
~R1
NH
I R
SQZ 2
3
This reaction is preferably carried out under basic conditions (e.g.
diisopropylethyl amine) in a halogenated solvent (e.g. dichloromethane).
In structures herein, R1 can be any moiety that provides stable intermediates
and final products for the subject processes. Preferred RI include hydrogen,
alkyl,
aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester. More
preferred
Rl are hydrogen and alkyl having from one to about four carbon atoms, the
alkyl
preferably being saturated, linear or branched, unsubstituted or substituted
with one
or more, preferably one, moiety selected from hydroxy, methoxy, ethoxy, thio,
methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino,
diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and
imidazo. Still more preferred RI are the side chains of the natural amino
acids.
In structures herein, R2 can be any moiety that provides stable intermediates
and final products for the subject processes. Preferred R2 include hydrogen,
alkyl,
aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester ; more
preferred
R2 are aryl and heterocycle.

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In structures herein, n is an integer from 0 to about 5, preferably from _0 to
about 3; more preferably n is 0 or 1, most preferably 0.
The next step of a subject invention involves a Mitsunobu reaction of 3 with
a N-protected amino alcohol:
BINH
BI
H
\ R3 H
m ~ _R
m
4 or 7
to provide:
O O
O \O
N \R1 \R1
/m / m
N\
BIHN \SO 2 BI-N S~2R2
2R
3 4
R
or $
Mitsunobu reactions are disclosed in a) Hughes, D., " The Mitsunobu
Reaction", J~anic Reactions, vol. 42, Paquette, L.A., ed.; 1992, John Wiley &
Sons, NY, pp. 335-656; b) Swayze, E. E., Tetrahedron Lett., vo1.38 (1997), p.
8643.
In structures, herein, R3 can be any moiety that provides stable intermediates
and final products for the subject processes. Preferred R3 include hydrogen,
alkyl,
aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl acyl, alkyl
or aryl
ester, alkyl or aryl sulfonyl. More preferred R3 are hydrogen and alkyl having
from
one to about four carbon atoms, the alkyl preferably being saturated, linear
or
branched, unsubstituted or substituted with one or more, preferably one,
moiety
selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy,

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carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo. Still more preferred
R3. are
the side chains of the natural amino acids.
In structures herein, R4 is an alkylene or heteroalkylene moiety. R4 has from
3 to about 10 carbon plus heteroatoms in the ring (incorporating R4),
preferably 3 or
4 carbon plus heteroatoms in the ring, more preferably 3 or 4 carbon atoms and
no
heteroatoms in the ring. (Of course, such ring has at least the one N depicted
in 8.)
Preferred R4 is saturated and unsubstituted or substituted with one moiety
selected
from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino,
methylamino,
ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl. Most
preferred
R4 is n-propylene.
In structures herein, m is an integer from 1 to 5, preferably from 1 to 3;
more
preferably m is 1 or 2, most preferably 1.
The next step of a subject invention process involves removing the N-
protecting group from 5 or 8 by any known method (similar to the analogous
procedure above).
The next step of a subject invention process involves cyclizing the product:
R 1 R1
.S~R2
g or 9
from the resin. This cyclizing/cleavage from resin reaction is carned out in
acidic
conditions in a mildly polar solvent at an elevated temperature.
Cleavage and cyclization is preferably achieved in a solution of acetic acid
in
2-butanol. The cleavage and cyclization reaction is not highly dependent on
the
amino acid or amino aldehyde used. The temperature required for maximum
cleavage and cyclization is typically from about 25 °C to about 70oC.
The subject invention processes are useful for making compounds
individually or in libraries of separate or mixtures of compounds. The
synthesis of

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9
libraries of compounds of structure 6 and/or 9 can readily be carried out
using a
multiple cell procedure, e.g., 96 plate format (e.g., Robbins Block), where
different
compounds having different combinations of R1, R2 and R3 or R4 can be made in
each cell simultaneously. Also, libraries of mixtures of compounds of
structure 6
and/or 9 can be made by reacting reagents which are mixtures rather than
single
compounds. Both types of libraries are useful for rapid screening of numerous
compounds for pharmacological and other activities.
An exemplary process of the subject invention is depicted in the following
scheme:
O R~ 1. TFA, DCM ~O 'R'
NHBoc 2. R -S02C1 NH
10 S02R2
11
HNBoc
1. PI~ P H O
R
R O
12
2. DIAD N~S02R2
3
BocHN R
13
O
R~
1. TFA, DCM HN
R3~N\
2. 2M AcOH/2-BuOH S02R2
14
A Boc-amino acid attached via an ester link to Merrifield resin 10 is used
as starting material. The amino group is deprotected and sulfonamide 11 is
formed. The resin is washed with dilute acetic acid in order to remove any
residual amine. Mitsunobu reaction with Boc-proctected amino alcohol 12 leads
to
alkylated product 13. To ensure the completion of this process, alkylation is

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repeated once more. Finally, the Boc group is removed and 2-oxopiperazine 14
is
cleaved from the resin (2M AcOH in 2-BuOH).
The following examples of the synthesis of 2-oxopiperazines using Boc-
prolinol and Boc-alaninol are typical.
Boc-Ala-Merrifield resin ester ( 1.070 g, 0.74 mmol, 0.69 mmol/g,
NovaBiochem) is rinsed several times with dichloromethane (DCM). It is then
treated with trifluoroacetic acid (95%; TFA/H20) for 1 h at room temperature.
The resin is washed with DCM several times, then with 5% diisopropylethylamine
(DIPEA} in DCM, and again with DCM. The suspended resin (DCM ca. 5 mL) is
treated with DIPEA (645 mg, 869 ~L, 5 mmol) and 4-methoxybenzenesulfonyl
chloride (762 mg, 3.7 mmol, 5 eq) and vigorously shaken for 16 h, filtered and
washed (DCM, methanol and again DCM several times, acetic acid (1% in DCM),
DCM several times, and finally methanol) and dried under vacuum for 20 h at
room temperature to give resin ester 15 ( 1.121 g, new loading, 0.61 mmol/g):
O
.,,~,
H
15
Resin ester 15 (200 mg, 0.122 mmol, 0.61 mmol/g) is rinsed several times
with tetrahydrofuran (THF). Triphenylphosphine (Ph3P) (0.37 mmol, 97 mg, 3
eq) and (S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (N-Boc-L-prolinol}
(0.37 mmol, 75 mg, 3 eq) are dissolved in THF (ca. 4 mL) and added to the
reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.37 mmol, 75 mg, 73
~,L, 3 eq). The reaction mixture is vigorously shaken for 8 h and filtered.
The
resin is washed several times with THF. Then the alkylation procedure is
repeated
one more time.
The crude resin product from the previous step is rinsed several times with
DCM and then treated with trifluoroacetic acid (95%; TFA/H20) for 1 h at room

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temperature. The resin is washed with DCM and methanol and finally suspended
in 2M AcOH/2-BuOH and vigorously shaken at 50°C for 15 h and filtered.
The
resin is washed a few more times with DCM and methanol; filtrates are
collected
and evaporated. The oily residue is co-evaporated with chloroform (in order to
remove traces of acetic acid and butanol) to give a purified product of 16:
O
''','~''''' ~ O
'' N
N\
O~ ~O
16
Compound 17 is prepared using a similar process. Resin ester 15 (300 mg,
0.183 mmol, 0.61 mmol/g) is rinsed several times with tetrahydrofuran (THF).
Triphenylphosphine (Ph3P) (0.56 mmol, 148 mg, 3 eq), N-Boc-L-alaninol (0.56
mmol, 113 mg, 3 eq) are dissolved in THF (ca. 9 mL) and added to the reactor,
followed by diisopropyl azodicarboxylate (DIAD) (0.56 mmol, 113 mg, 110 pL, 3
eq). The reaction mixture is vigorously shaken for 8 h and filtered. The resin
is
washed several times with THF. The alkylation procedure is repeated one more
time.
The crude resin product from the previous step is rinsed several times with
DCM and then treated with trifluoroacetic acid (95%; TFA/H20} for 1 h at room
temperature. The resin is washed with DCM and methanol and finally suspended
in 2M AcOH/2-BuOH and vigorously shaken at 70°C for 48 h and filtered.
The
resin is washed a few more times with DCM and methanol; filtrates are
collected
and evaporated. The oily residue is co-evaporated with chloroform (in order to
remove traces of acetic acid and butanol) to give a purified product of 17:

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O '',
.....~~~ ~ O
HN
o,~ N~S
,.
O/ ~O
17
While particular embodiments of the subject invention have been
described, it will be obvious to those skilled in the arts that various
changes and
modifications of the subject invention can be made without departing from the
spirit and scope of the invention. It is intended to cover, in the appended
claims,
all such modifications that are within the scope of this invention.