Note: Descriptions are shown in the official language in which they were submitted.
5~3
BACKGROUND OF THæ INVENTION
Field of the Invention
This invention relates to pyrazolidinones and
pyrazolidines having ~n nuclear nitrogen different ali-
phatic substituents which generally have oxygen preæent
in each. The compounds are obtained by selective alkyla-
tion of the nltrogen atoms Or pyrazole or 3-pyrazolidinone.
They resemble pro~taglandins and their derivatives. The
natural prostaglandins of the E, F, and A series have
geveral centers o~ asymmetry and are dlfficult to synthe-
~ize. The compound~ o~ thc pre~ent invention, however,
have fewer centers o~ asymmetry in that they havc two tri-
valent nitrogen atom~ in the ring rather than two a~ymmetric
carbon atoms and therefore fewer i~omers are obtained.
Description of the Prior Art
It is known CDorn & Zubeck, Z. Chem. 6, 218
(1968)~ that 2-methyl-5-pyrazolidinone can be prepared
by ~irst ~orming the l-benzoyl derivativc, alkylating with
methyl sulfate and rcmcving the benzoyl group by acid
hydrolysis. Recently Dorn ana Dilcher LJournal ~ur prakt.
Chemie, 313, 229-335 (1971)~ reacted b~nzyl chloroformate
with 3-pyrazolidinone hydrochloride to give l-benzyl-
oxycarbonyl-3-pyrazolidinone. The latter was reacted
with formaldehyde and morpholine to give 2-morpholino-
m~thyl-l-benzyloxycarbonyl-3-pyrazolidinone. However, the
latter when ~ubJected to hydrog~nation (uith platinum oxide
catalyst) lost the morpholinomethyl group but not the
benzyloxycarboxyl group. No re~erence has been found
to a proætaglandin-likc structure with nitrogen a~ a
hetero atom in the ring.
- 2
d~75~;~
Description of the Invention
The invention is a compound havin~ the formula
y
N-cH2(A) (CH2) C02R wherein
N-CH2CHR~CR2CR~R5(CH2)pQ
~,OR
z
A is CH=CH, C-C, or C6H4,
R is H, alkali metal, amine salt, and alkyl and
cycloalkyl each o~ up to 12 carbons;
m is O or 1,
n i8 0 to 6;
p i8 0 to 6,
Y and Z are O or H2, with the proviso that where
one i~ 0, the other is H2;
Rl i H H ~
, C~ or C2 5,
R2 iæ H, C ~ , C2H5, CH=CH2 or C~CH;
R3 is H or alkanoyl of 2 to 4 carbon atom~;
: R i~ H, F, CH3 or C2H5;
R5 is H, F, CH3 or C2~53 and
Q is H, CH3, CF2CH3 or CF3;
with the provi~o that Rl, R4 and R5 are H when R2 is
other than H.
Pharmaceutically acceptable acid addition ~alts
of the compounds are also included within the scope of the
invention.
Preferred compounds are those uhere p is 3 to 5.
Within this group are those where Q iæ CH3, Rl, R3, R4
and R5 are each H, R2 i8 H or CH3, m = O and n iB 4 to 6.
Also within the group of preferred compounds are those
above, except that m - 1, A iB C6H4 and n ~ 0-4.
The new compounds wherein Y -0 and Z = H2 are
obtained b~ reacting (a) a 3-pyrazolidinone having on the
1-POBitiOn a blocking group that i8 removable under mild
conditions such as by hydrogenation, with an omega-halo-
carboxylate, i.e., an omega-haloalkanoic acid ester, an
omega-halo-alkynoic acid ester, or an omega-halo(methylene-
phenylene)alkanoic ester, wherein the halogen preferably iæ
bromine or iodine, (b) removing the blocking group, and
(c) alkylating the l-position with a vinyl ketone or with
an acetyle~ic kctone ~ollowed by reduction. By choice o~
reactants of further conversions, the products of this in-
vention are obtained.
The compounds wherein Z = 0 and Y = ~ are
obtained by reacting (a) a vinyl ketone,
o
CH2=C* -C-CR4R5-(CH2)pQ, or an acetylenic ketone
C~-CC-CR4R5(C ~)pQ, with a 3-pyrazolidinone having on the
l-po~ition a blocking group that i~ removable under mild
conditions such a~ by hydrogenation~ (b) removing the
blocking group, and (c) reacting the pyrazolidionone with
an omega-halocarboxylate as above.
The compound~ wherein both Y and Z are ~ are
obtained by reacting pyrazole with the above stated
omega-halocarboxylateæ or unsaturated ketones. No block-
ing group is needed since only one nitrogen atom of
pyrazole is alkylated under the conditions employed. For
example, pyrazole is reacted with an omega-halocarbo~ylate
in the presence of a strong baæe to give an N-alkylated
pyrazole. Reduction o~ the ring double bonds yields
-- 4 --
i ~7~
an N-alkylated pyrazolidine which iB then reacted
with an unsaturated ketone to alkylate the second nitrogen
atom in the ring. The order of reaction may be reversed
in that the pyrazole may be reacted fir~t with the un-
saturated ketone to give the N-alkylated pyrazole which
i~ then reacted with an omega-halocarboxylate to give the
N,N~-dialkylpyrazolium æalt, which i8 reduced to give an
N,N~-dialkylpyrazolidine.
me novel compounds Or this invention have been
named with the pyrazolid~ne ring as the important feature,
but a compound of Example 1, for instance, can be named as
a pro~tanoic acid derivative, e.g., d,l-15-hydroxy-9-
keto-8,12-diazapro~tanoic acid, or as a prostaglandln,
15(R,S)-tetrahydro-8,12-diaza prostaglandin Al.
SPECIFIC EMæODIMENTS OF THE INVENTIO~
In the following illustrative examples all
part~ and percentage~ are by weight unless otherwi~e
st~ted.
EXAMPI,E 1
7.~3~-Oxo-1'(3"-hydroxy-n-octyl)pyrazol~din-2~-y~ -
heptanoate~; ~so, z = ~, m=OJ n=5, R=tBu; H; Na;
Rl=R2=R3=R~=R~=H, Q=H, p=4
(a) l-Benzyloxycarbonyl-3-pyrazolidinone (1)
O ,0,
<~ NH2+Cl ~2C3 '112~ <~ N-C-OCH
0
A solution of 106 g (1 mole) of sodi.um carbonate
in 1 1 o~ water is cooled in an ice bath and stirred
with a paddle stirrer while 124 g (1 mole) of ~-pyrazoli-
dinone hydrochloride i8 added in portions. To the re~ult-
ing solution is added dropwise over a period of 2-3 hrs
with continued cooling and vigorou~ stirring 174 g (1.02
`~ -
7~3
mole Or benzylchlororormate. m e mixture is stirred ~ith-
out cooling rOr 2 hours, by which time it is neutral.
The 301id i8 collected by filtration and is tran~orred
to a 2 1 Erlenmeyer fla~k with 300 ml Or water. ~hen
800 ~1 of 5% NaOH solution is added to the slurry over
about 10 min. me mixture i8 stirred for 0.5 hr, by
which timR most of the solid dissolve~ lcaving some in-
~oluble oil. The aqueous maxture is filtered to re ve
the in~oluble oil. The clear ~iltrate is then coolod ~n
an lce bath while with vigorous stirring 100 cc of con-
centrated hydrochloric acid is added dropwisc. The white
~olid i8 collected by riltration, washed with water, and
dried at 75 under a high vacuum for 24 hrs. This gives
141 g (64%) Or l-benzyloxycarbonyl-3-pyrazolidinone
(3-oxopyrazolidine-1-carboxylic acid benzyl ester) (1) m.p.
98~98.5.
Anal. Calcd. for CllH12N203
N, 12.72; Found: C, 60.35; H, 5.64; N, 12.83, ~max (CHC13)~
2.94, 3.15, 3.28, 3.32, 5.85, 6.31, 6.67, 14.45; pmr
(CDC13, TMS): 441 (5, phenyl), 312 (2, s, benzylic), 240
(2, t, J = 8.5, CH2N), (2, t, J = 8.5, CH2CO) Hz at 60
MHz.
(b) l-Benzyloxycarbonyl-2(6~-tert-butoxycarbonyl-
hexyl)-3-pyrazolidinone (~
o
/~ I B2~ ( CE2 ) 6COtBU
N-~OCH2~ N82CO3, NaI, HMPA
0
o
CN~( CH2 ) 6C2_BU
N-~ -OCH20'
-- 6 --
5~
A m~xture oP 53 g (0.2 mole) oP tert-butyl 7-
brom~heptanoate 48 g (0.21 mole) o~ l-benzyloxycar~onyl-
3-pyrazolidinone, 50 g o~ sodium carbonate, and 2 g of
sodium iodide in 200 ml of dry hexamethylphosphoric
triaI~idc (HMPA) iB stirred at room temperature under
nitrogen ~or 6-7 days. The mixture is poured into 1 1.
of water, extracted with ether, and the ethe~ washed three
times with water, once w~th a llttle 5~ NaOH, and then
dried over Na2S04 and evaporated, giving 80.6 g (100%) of
crude product a~ an oil. The crude product (l-benzylo~y-
carbonyl-2(6~-tert-butoxycarbonylhexyl)-3-pyrazolid~none)
is used directly in the sub~equent hydrogenolysis step.
The corre~ponding ethyl ester slmilarly pre-
pared from ethyl 7-bromoheptanoate, is characterized as
follows. Evaporatlve distillation gives a colorless oil
at 175-180/0.028 m~ (84%). _ . Calcd. for C20H28N205:
C, 63.81; H, 7.503 N, 7.44; Found C, 63.78; H, 7.42;
N, 7.61; HR ma~s ~pec. calcd 376.1998, observed 376.2031;
~maX (CHC13): 3.31, 3.47, 5.8-5.9, 6.12 (weak), 6.29,
6.67 ~.
(c) 2(6'-tert-Butoxycarbonyl)hexyl-3-
razolidinone (3)
o
(C~2)6C02C(CH3)3
Pd/C
AcOH
~I \=/
2 0
o
~(CH~)6C2C(CH3)3
NH + C02 + ~CH3
-- 7 --
l~J4751~3
The tert-butyl cster ~ preferred to the ethyl
ester because the latter tends to form so~e polymeric
amide or lactam during high-temperature distillation.
A 500 cc hydrogenation bottle is loaded with
40 g (0.1 mole) of crude 1-benzyloxycarbonyl-2(6~-tert-
butoxycarbonyl)hexyl-3-pyrazolidinone, 100 ml o~ ethanol,
8.0 ml of glacial acetic acid, and 3.0 g of 5% palladium on
charcoal catalyst. The mixture is hydrogenated on a Parr
shaker apparatu~ for 1.75-2.0 hrs; the total pressure
drop in the bottle (isolated from the Parr tank) iB 45-55
psi. The bottle i8 vented cautiou~ly and the contents are
filtered through a M porosity funnel and concentrated in
~acuo to about 75 ml (temp. less than 40). The residual
liquid is poured into a ~eparatory funnel containing 13.0
ml of concd. HCL, 75 ml of H20, and 250 g of ice and ex-
tracted quickly with 150 ml and then 50 ~1 of other. The
ether i~ dlscarded. m e aqueous layer i8 quickly trans-
ferred to a 1 liter beaker in an ice bath, 200 ml of fresh
~ther i~ added, and 25 g of Na2C03 i~ added i~ a few por-
tion~ with stirring. The cold alkaline ~olution 1~ stirredfor 5 min. a~ter addition i8 completod and then transferred
to a separ~tory funnel. The ether layer i8 ~eparated and
~et aside. The aquoous layer i8 extracted again with two
l~O-ml portion~ Or ~resh ether and the combined ~ther
layers are dried over anhydrous Na2C03. The ether is
evaporated in vacuo (temp. le~8 than 35) to give 19 g of
yellow oil, crude 2(6l-tert-butoxycarbonyl hexyl-3-pyra-
zolidinone.
The crude ester is distilled from about 0.5 g
of MgO in a Kugelrohr (bulb to bulb) evaporative di~tilla-
tion apparatus at about 150-160/.004 nm giving a colorless
~ 7~3
liquid which i~ ~tored under nitrogen. The yield Or pure
ester i~ about 13 g (48%) Por the two steps, base on
tert butyl 7-bromoheptanoate.
Anal- Calcd- for C14H26~23 C~ 62-19; H~ 9-69;
N, 10.36. Found: C, 62.~0, H, 9.38; N, 10.49.
Liquld chromatography (ethanol-water) indlcates this
material to be 99.53% pure. Mass spectroscopy con~irm~
the assigned molecular compo~ition with m/e of M+ at 270;
ma~or fragment ions m~e 214 (M-56), m/e 196 (M-56-H2o)~
m~e 57 (t-Bu+). ~ mHx13: 2.95 (NH), 5.81, 5.95 (C0l8),
8.05, ~.68 ~. ~ith ~-chlorophenylisothiocyanate the amine
reacts to give a solid phenylthiourea derivatiVe ~n 96% yield,
two cryætallizations from ethanol gives white plates, mp
114-120.
Anal. Calcd. for C21H oClN30 S: ¢, 57.1; H,
3 3
6.88; N, 9.55; Cl, 8.o6, Found C, 57.14, H, 6.84, N, 9.42,
Cl, 8.39.
(d) 7 ~'-Oxo-ll(3ll-oxo-n-oct-l'!enyl)pyrazolidin-2
yl~-heptanoic acid t-butyl ester, trans (~
O O
/~ N-(CH2)6C2t 3U HC-C-C-C5Hll(n) ~,
~ NH EtOH
-(CH2)6C2tBU
n-C5H
4 0
l-Octyn-3-one can be prepared by addition of
acetylene to hexanal in the presence of potassium hydroxide
powder and glyme ~method Or H.A. Stanæbury, Jr., and
W.R. Proopg~ J. Org. Chem., 27, 279 (1962)~ to give amyl
et ~lyl carbinol, b.p. 80/13 mm, which is then oxidized
with Jones~ reagent to gi~e the 1-octyn-3-one, b.p. 66/15
mm fsee K. Bowden et al., J. Chem. Soc. ~ (1946).~ .
A solution of 2.704 g (10 mmoles) of amine 3
and 1.242 g (10 mmole8) of 1-octyn-3-one in about 75 ml of
dried ethanol ~R.H. Manske, J. Am. Chem. Soc. 53, 1106
(1931~ i8 heated at reflux temperature under a nitrogen
atmosphere for 1.5 hrs. The mixture is cooled, diluted to
100 ml in a volumetric flaækJ and a 1.0 ml aliquot removed
for ultraviolet ab~orption analyDis ().EtH 322 nm; 16,500;
when ordinary "absolute" ethanol i8 used ~ is about 12,000).
Evaporation of the ethanolic solution under re-
duced pre~sure gi~es a dark red-amber oil. Its 220 and 60
MHz pmr spectra (CDC13, TMS) are consistent with nearly
pure vinylogoue hydrazide and show two doublet vinyl pro-
tons at 7.54 and 5.37 ppm (J - 13 Hz); high resol. mass
spec. M+ m/e calcd. 394.2831, observed 394.2870, ~-max
( CHC13): 3.40, 3.49, 5.82, 5.92, 6.15 and 6.33 8 (vin~rlogou~
amide), 10.35 (trans double bond) ~.
Catalytic reduction o~ the enamino ketone can
be carried out without isolating it.
(e) 7~ Oxo-1' ( 3"-oxo-n-octyl)pyrazolidin-2'-yll-
heptano~c ac~d t-butyl ester (5) and 7~3'-Oxo-
11(3~-hydroxyoctyl)pyrazolidin-2~-yl1heptanoic
acid t-butyl ester (6)
-
-- 10 --
/\ ~ ( CH2 ) 6~otBu H2
n-C5Hll EtOH
4 0
-
(CH2)6COtBu NaBH4
-C5 ~ 1 EtOH
~ ( CH2 ) 6C02tBu
\~11n-C5Hll
6 OH
-
(e) (1) A solution of 2.70 g (10 millimoles) Or
the amine 3 and 1.24 g (10 mmoles) of o-octyn-3-one in 75 ml
of dry ethanol i8 heated at reflux temperature under a
nitrogen atmo~phero for 1~75 hrs and then cooled and trans-
ferred with 25 ml of dry ethanol into a hydrogenation bottle
with 1.0 g o~ 5% platinum on carbon. Reduction in a Parr
shaker with hydrogen i5 complete in about 25 ~in. After
2 hrs under hydrogen the ethanolic ~olution of 7 ~'-oxo-
l'-(3U-oxo-n-octyl)pyrazolidin-2~-y~ heptanoic acid t-butyl
ester (~ i~ filtered through M porosity sintered glas~ and
the light yellow ~iltrate cooled in ice and treated all at
once with 1.~ g of NaBH4. The ethanolic solution is stirred
~or 0.5 hr with cooling and then for 1 hr with no cooling.
~4 ~ ~3
It iB then coneentrated to about 30 cc in vacuo, poured
into 200 cc of ~0, and extracted with ether. The ether
is washed with water, dried, over Na2S04, and evaporated,
givin,g a yellow oil which according to thin layer ehroma-
tology (TLC) (2:1 benzene-acetone on silica gel) is about
60% of the hydroxyoctylpyrazolidin~ne of formula (~ (R~ -
o.38).
The pyrazolidinone alcohol was eharacterized
a3 follow~ using a æample from another, larger ~cale re-
aetion but having the same IR ~peetrum and Rf value.
Chromatography of 5 g of erude amine aleohol on 150 g of
basic III alumlna and elution with hexane-benzene, benzene,
and 1:1 ether-benzene gave in the latter eluate 2.41 g of
90% pure amino alcohol. One fraction which according to
TLC was clo~e to 100% pure was ~ubmitted for analy~is:
HRMS m/e of M+ ealed. for C22H42N204: 398.3144; observed
398.3146; ~ma~ (CHC13) 3350 (intramoleeular hydrogen
bonded OH), 2380 (~ NH+), 1720 (e~ter CO), 1675 (amide
CO ) cm~l .
(e) (2) Alternative Procedure - A solution of 10.8 g
of the amine 3 in 50 ml of dried ethanol with 6.o ~ of 1-
octyn-3-one i8 heated at roflux for 2 hrs., cooled to room
temp.~ and diluted to 100 ml. The dark red ~olution i~
hydrogenated in a Parr ~haker over 3.0 g of 5~ rhodium on
carbon at room temperature and at about 40 psi ~or 3 hrs.
Catalyst iæ removed by filtration through s~ntered glass
and to the yellow filtrate is added with stirring 3.5 g
of ~odium borohydride. After 3 hrs., the reaction mix-
ture is coneentrated in vacuo to about 25 cc, poured into
200 ec of water, and extracted three tlme~ wlth ether.
- 12 -
03
The ether is washed three times with water, wh~ch is dis-
carded. The ether is then washed twice with a total of
200 cc o~ ice-water containing 16 cc of concentrated hydroY
chloric acid, the aqueous extraction layer being run
directly into excess solid ~odium carbonate covered with
ether. Evaporation o~ the ether conta~ning the acid
extracted material gavo 2.07 g of the starting amine 3.
The orlginal ether layer remaining a~ter the extraction
with the 200 cc of aqueouæ acid is again extracted quickly
three times with a total of 16 cc of concentrated hydro-
chloric acid in 200 cc o~ ice water and then with saturated
sodlum carbonate solution. Evaporation o~ the ether gave
9.6 g of crude amino alcohol 6 essentially ~ree of amlne 3.
The amino alcohol iB much less readily extracted from the
ether pha~e perhap~ because the basic character of ~he
amino nitrogen i~ reduced by intramolecular hydrogen
bonding with the ~lydroxyl group, i.e.
o
~~ C02tBu
N ~
~o~
Chemical removal o~ the starting amine 3 is important
because it is s-parated only with diffic~lty ~rom the
amino alcohol 6 by colu~n chromatography. Starting amine 3
may orginate from a reveræe Mannich reaction during the
catal~tic hydrogcnation step (5-t ~ or from hydrogenoly-
siæ of ami~o alcohol 6 by exce~s æodium borohydride in the
ke~one reduction step.
;~/ C02tBU
o
N ~ C02tBu
~a~ ~ CH20 + CH3C-C5Hll
3 0
The 7.5 g of amino alcohol 6 can be further puri~ied by
chromatography o~ 230 g of basic, activlty-grade IV alum~na
by elution with bcnzene, cther, and ethyl acotate. The
latter ~olvent gave 3.4 g of pure amino alcohol 6 as a
thick oil; HRMS calcd. m/e o~ M ~or C22H42N204:398.3142;
ob~erved 398.3138, with virtually no 270 ion (amine);
TLC (3ilica gel, 2:1 acetone, benzene, iodine visualiza-
tion and ~ul~uric acid-charring visualization) ~howed the
pres~nce of onl~ one component.
(e) (3) Alternate route to 4 and 6
~N ~ C02tB
\~NH H2C=CHCOC5H
EtOH
n
~'~N ~ C02tBu
\~N ~
-
_ 14 -
7~
o
~~ C~2tBu
NaBH~4 <
~ ~ N
--7 \~ \~/V
OH
-
Amyl vinyl carbinol (b.p. 47/15 mm) can be
prepared by reaction Or amylmagnesium bromide with acro-
leln. me carbinol can be oxidized to amul vinyl ~etone
conveniently by the aqueous chromic acid/ether oxidation
method of H.C. Brown (J. Org. Chem. 36, 387 (1971); a 25%
excess of oxidant is ~mployed and the reaction is carried
out at 5-10. The ketone i~ fractionally distilled through
a ~pinning band column and boils at 64/16 mm. A p31y-
merization inhibitor, e.g. p-methoxybydroquinone, 0.2% by
wt., 1~ added to the distillate to prevent polymerization
during ~torage.
A ~olution of 10.8 g (40 mmolos) of amine 3 and
6.56 g (52 mmole~) of amyl vinyl ketone in 50 ml of dried
ethanol i~ ~tirred at room temperature for 4.25 hrs., by
which time thin layer chromatography on silica gel (2:1
aceto~e-benzene; iodine visualization) indicates the
presence of ketone 4 as a spot at Rf o.63 and less than
1% of the starting amine 3. To the well-stirred reaction
mixture i8 added 2.0 g of sodium borohydride; after 2.75
hrs an additional 1.0 g of sodium borohydride is added.
After a total reaction time of 3 hrs, the mixture is
poured into a separatory funnel containing 200 g of ice
water and some ether. After mlxlng, the ether layer is
drained o~ and the aqueou~ layer extracted once with
fresh ether. The combined ether layers are washed ~ith
water three times, dried over sodium sulfate, and
evaporated to give about 18 g o~ a yellow oil, which
- 15 -
13
according to thin layer chromatography i~ essent$ally
pure amino alcohol 6 mixed o~ly with a little amyl vinyl
carbinol. A solution of the amino alcohol in hexane is
applied to a chromatography column containing 500 g of
basic activity grade IV alumina and eluted with benzene,
ether, and ethyl acetate, in that order. Evaporation of
the ethyl acetate gives 8.7 g of pure amino alcohol 6
(55% yield based on amine 3).
(f) 7~3'-oxo-1~(3"-hydroxy-n-octyl)pyrazolidln-2'-
y~ heptanoic acid hydrochloride (7)
CO2tBu HCl
\ N
o
~\ ~~ C2H
N
H~Cl- '
OH
About 3.5 g of the ~mino alcohol 6 is
dissolved in 25 ml of chloroform and gaseous hydro-
gen chloride i9 bubbled into the solution for 5 min. The
mixture is allowed to stand at room temperature for 1 hr,
and thon a drop of water i~ added. An oil phase appears
immediately. The mixture is stirred for 1 hour and then
the chloroform is e~aporated, giving 4.0 g of the hydro-
chloride 7 as a tan glass, estimated to be about 90% pure.
- 16 -
This tan glass can be purified by being warmed
on a steam bath with 35 ml of 2N hydrochloric acid until
the temperature reaches 70, and then diluting the mixture
with 100 ml of distilled water, cooling, and extracting
with ether twice. The clear, colorless aqueous layer is
evaporated to dryness, giving 2.74 g of the above named
hydrochloride (~ as a colorless glass. Sllylation with
N-trimethylsilylimidazole in pyridine gives the bis-
trimethylsilyl derlvative (of the free amine). Analysisby high resolution mass spectroscopy: m/e MT calcd. for
C24H50N2o4si2 486-3~o6, found 486.3319.
(g) 7 ~'-Oxo-l~-(3"-hydroxy-n-octyl)pyrazolidin-2'-
yllheptanoic acid sodium ~alt (8)
N ~ C02H
NaHCO
~v~ ~ 3
H+Cl-~
OH
0 7
~, _
CO -NaT
N ~ 2
N
OH
A solution of 1.56 g of pure acid hydrochloride
7 i~ dissolved in 29.6 ml of 5% aqueous sodium bicar~onate
with gentle warming. The solution is cooled and filtered
to rem~ve a slight trace of flocculent material~ The
clear filtrate thuæ contains about 5% by weight of the
lV4'7S~
above~-named sodium salt (~ i~ a sodium bicarbonate
bu~fered aqueous solution.
Acidification of the sodium salt with 1 equi~a-
lent Or hydrochloric acid gives the carboxylic acid; use
of 2 equivalents Or acid gives the carboxylic acid amine
salt as described before. me sodium salt, the carboxylic
acld, and the carboxylic acid amine salts are substantially
equivalent pharmacologically.
In Example 1 when thc tert-butyl 7-bromo-
~0 heptanoate o~ part l(b) i8 substituted by a molar equivalentof the omega-halo ester or column A Or Table I thc product
obtained is the e~ter shown in column B. Substitution of
the ester o~ column B for an equivalcnt amount of l-benzyl-
oxycarbonyl-2(6~-tert-butoxycarbonyl)hexyl 3-pyrazolidi-
none (~ in Example l(c) gives the product shown in
column C. Reaction Or the product of column C with an alkyl
vinyl ketone Or column D as in Example l(e)(3) gives the
ketoalkylpyrazolidionone Or column E; reduction Or the
latter with sodium borohydride a~ in Example l(e)(3)
gives the amino alcohol o~ column ~. Treatment Or ths
amino alcohol Or column F with HCl gives the correspond-
ing carboxylic aci~ hydrochloride salt and treatment o~
the salt of column F with Na~C03 as in Example l(g) gives
the salt of column G.
- 18 -
lV~7~S)3
-
,1 ~
3 v~ ~I v~
v ~ o~
CU
o ~,
\ / ~ \ O~U
Z;~
m O_ <~ o- <~> o= <~
H t~ ,Q c~ ,~ ~ ~ bD
_ ~ C~
h ~ ~ CU
P; ~ O
~0 V ~q V
0 CU
O V
O V C~
,1 ~rl O ~
^ V V
C~ _ - V - _ V
b~ --~ V 1l
O ~N 5~N 5~N
H al 1
~i
O ~
V ~ p
- 1047~03
. ~ '
V~
s: ' " `'
- ~ ~.
V~ ~
C~l C~l .,
v~ ~ o~ ~ = ~ ~ =
C`J ~ V C~l V
O
V V o V C) V o
~ V ~ ~ . ~ ~
~ æ~
o~
r~
C~1
H ~
N
- ~ V
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_ 20 -- ,
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t~ ~ V
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_ 21 -
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- 22 - -
1047503
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-- 23 --
~047503
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25 --
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.
1047503
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~047503
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10475Q3
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-- 32 --
33
EXAMP~E 2
7r3~-Q~o~ (3~_ ~droxy-n-decyl)pyrazolldin-2~-y~ heptanoic
acid t-butyl ester, Acid, and Sodlum salt (9 a,b,c)
~-0, Z-H2, m~0, n-5, R=tBu; H3 Na; Rl2R2=R3-R4=R5-Q H p=6
O
N ~ C02tBu (-H, Na)
o
~ 9a~(~b~ 9c)
Following the procedure Or Example 1, heptyl
vinyl carbinol (b.p. 94/5 mm) can be prepared by reaction
o~ l-bromoheptane with acrolein. Oxidation o~ the car-
binol with Jones~ reagent give~ heptyl vinyl ketone tb.p.
90-92/10 mm). Treatmont of 5.4 g Or amine 3 with 3.5 g of
heptyl vinyl ketone in 75 ml Or ethanol at room tempera-
ture ror 18 _rs gives 7[3~-oxo-1~-(3~-oxo-n-docyl)pyrazoli-
din-2~-y~ heptanoi~ acid t-butyl cster. Reduction o~ this
k~tono with sodlum borohydride in e~hanol, followed by
chromatography on 450 g of basic IV alumina gives on
elution with ether 7~3~-oxo-1~-(3n-hydroxy-n-decyl)pyrazoli-
din-2t-ylJheptanoic acld t-butyl e~ter (9a). Troatment o~
this oster with cess hydrogen chloride in moist chloro-
~orm giveg the corrosponding acid 7 ~ '-o~o-1'-(3n-hydro~y-
n-decyl)pyrazolidln-2~-y ~ heptanolc acld (9b) which i~
converted to it~ sodium salt (9c) by treat~nt with one
or more equlvalents of ~odium hydroxide or sodium acid
phosphate. HRM~ m/e calcd. ~or silylatod H~l salt of tho
Carboxylic acid C26H54N24~12 514 3619; found 514-3651-
- 33-
EXAMPLE 3
(A) l-Benzyloxycarbony1-2(3~-oxo-n-octyl)-3-pyrazolidinone
(10),~ 1-benzyloxycarbonyl-2(3~-hydroxy-n-octyl)3-
yra~olidione tll), and 2-(3~-hydroxy-n-octyl)-3-
pyrazolidinone (12)
O O
CNH CH2=CHC-C5H11(n)
N-C ~CH2~
o
o o
t~ 11
N ~ NaBH4
C-OCH2~ EtOH
1~
O OH
,. ~
~ N ~
\~\ C-OCH20' P2/Pd
O 11 EtOH
. 'qH
/\
\~ _
1-Octen-3-ol i~ oxidized to amyl vinyl ketone
(AVK) by Jones~ CrO3 reagent in acetone. It boils at
64/16 mm and i~ stored with a traee o~ p methoxyphenol to
prevent polymerizat~on.
To a suspen~ion of 22 g (0.1 mnle) of benzyl-
oxgcarbonyl-3-pyrazolidinone in 75 ml of anhydrous ethanol
at 45 is added 13.0 g (1~.6 ml, 0.103 mole) o~ amyl vinyl
ketone and then 0.20 ml o~ 40% tetramethyl ammonium
- 34 -
~47~3
hydroxide (Triton-B) in meth~nol. The reaction mixture
is heated at reflux temperature for 1 hr, cooled, and 2
drop~ of glacial acetic acid are added. This ethanolic
~olution contains nearly pure 10. An aliquot which, after
isolation of product by successi~e treatment with water,
ether, and 5% NaHC03, shows by TLC a single component
(silica gel, 2:1 acetone-benzene development, Rf = o.63
by lodine ~isualization), ~ maX (neat) 1720 broad~
1500 cm 1, pmr (CDC13) 447 Hz (singlet, phenyl) 316
(sin4let, area 2, OC ~ ) etc. at 60 MHz; HRMS m/e calcd.
for ClgH~6N204 346~1889; measured 346.19333. The remain-
der of the ethanolic solution Or 10 is in an ice bath and
stirred while 1.6 g of sodium borohydride is added. me
reaction mixture is tirred with cooling for 0.5 hr then
with no cooling for 1 hr and poured into 300 ml of lce
water. ThiB aqueous mixture is extracted twice with two
1~0 ml portionæ of ethyl acetate, which in turn i9 Wa8hed
with 5% NaHC03, drled o~er sodium sulfate, and evaporated
to give 33 g (96%) of nearly pure 11; Rf = approx. 0.58,
2~ TLC under the same condltions described above for 10;
~ max (neat) 3400 cm 1 (0~); pmr agrees with expected;
HRMS m~e calcd. for ClgH28N204 348~2047~ found 348.2076.
with no 346 ion. A solution of 32 g of this oil in 75 ml
of ethanol with 10 ml of glacial acetic acid i9 th~n
hydrogenated in a Parr sh3ker over 3.0 g o~ 5% Pd on
carbon. A~ter the rapid hydrogen upta~e ceaseæ, the
ethanolic solution is filtered and the ~iltrate con-
centrated to about 40 ml under reduced pressure (temp.
le9æ than 40). m e reæidual liquid is poured into 150 ml
g~3
o~ ice water containing 10 ml of concentrated HCl and ex-
tracted ~wice with ether, which i~ di8carded. The cold
aqueous phase is then topped with about 100 ml of ethyl
acetate and basi~ied, with stirring, by adding Na2C03 to
pH 9. The ethyl acetate i8 drawn ofr, and the aqueous
pha8e i8 extracted twice again with a total of 250 ml o~
ethyl acetate. The combined ethyl acetate solutions are
dried over Na2S04 and evaporated in vacuo to gi~e 13.6 g
(69%) o~ nearly pure 12 a8 a slightly air-se~sitive,
light yellow oil. This oil is insoluble in ether. Pure 12
i8 isolated by a bulb to bulb di~tillation giving 12 g of
a thick, colorles~ or very light yellow oil at 130-140/
.017 mm.
Anal. Calcd. ~or cllH22N2o2: C, 61-65; H, 13-`07;
N, 13.07
Found: C, 66.69; H, 10.13;
N, 13.29
HRMS calcd. 214.1863, measured 214.17033 ~max (CHC13)
2.95, 3.09, 3.39, 3.49, 5.96 (C-0), 9.25 (CH0~) ~; R~ =
0.20 on sllica gel, 2:1 acetone-benzene, iodine visualiza-
tion.
A æolution o~ 12 in isopropanol reacts with
p-chlorophenyl isothiocyanate to give a p-chlorophenyl-
thiourea derivative, m.p. 104-197. This derivative is
identical (by mixed m.p. and IR) with the p-chlorophenyl-
thioureide o~ 4 obtained by the alternate synthesis
described in Part (B) below.
- 36 -
i7~3
(B) 1(~3,~ Trichloroetho~ycarbony1)-2-(3~-oxo-n-octyl)-
3 pyrazolidinone (14), l(~g,~ -Trichloroethoxycarbonyl~-2-
(3-hydroxy-n-octyl)-3-pyrazolidinone (15~, and an alternate
route to (12)
O O
n n
~\N CH2=CH-C -C5Hll ( )
~C-OC~2CC13
o
n n
/~N \ ~ aBH4
\ N EtOH
~/ \ C-OCH2CC13
o
14
O OH
ll l
N ~ Zn
N~ 8-OCH2CX3
X = Cl ( ~ or H (
O OH
~\ ~/\/
\~
12
A solution of 26.2 g (O~l mole) of 1(~ , p,~ -tri-
chloroethQxycarbonyl)-3-pyraæolidinone ( ~ in 75 ml of
ethanol is treated with 15.6 ml of amyl vinyl ketone and
- 37 -
lQ~75U3
tetra~ethyl ammonlum hydroYide and heated to reflux.
After 1 hr at re~lux, the react~on mixture is ~reated with
0~15 ml of ~lacial acetic acid, glving a solution of nearly
pu~e l(~ trichloroethoxycalbonyl)-2-(3-oxo-n-octyl)-3-
pyrazolldinGne (~4); TLC o~ an aliquot on silica gel,
1:1 acetone-benzene, R~ = 0.67 with visualization by
H2S04 charring. The alcoholic solution o~ 14 is cooled
and kept at 15-20~ while 3.0 g of sodium borohydride is
added. After 1 hr the reaction mixture is poured into
500 ml of ice water and extracted with ether. The ether
~ washed with wat~r and 5~ HCl, dried over sodium sul-
fate, and evaporated, giving 22.5 g of oil, a mixture of
5 and 16; ~.C Rf = 0.47 and 0.54 under the conditions
described for the TLC o~ 14; HEU5S: calcd. for C14H23N204C13
388.o724, measured 388.0725; calcd. for C~4H2~T~01~ 286,
~ound 286 (more inten~e). Treatment of 3.9 g o~ 15 and 16
with 4.0 g o~ zlnc dust in 20 ml of 90~ acetic acid for
-2 hrs at 25 glves 0.54 g (25~) of 12 as an o~ olated
by ~eans of its water-soluble hydrochloride and identified
as its derivative with p-chlorophenylisothiocyanate,
m.p. 106-110 (isopropanol).
Anal- Calcd- for C18H26N3S2Cl C~ 56-2; H~ 7-96;
N, 10.94.
~ound: C, 56.15; H9 7.18;
N, 11.10.
~ -Trichloroethyloxycarbonyl)-3-pyra-
zolidinone is prepared as described earlier.
(C) 7/~'-Oxo-2'(3"-hydroxy-n-octyl~Pyra%olidin-l'-yl7-
heptanolc acld ethy] ester (17) and it~ h~ydrochlorlde
~7a) Y-~J2 Z=Os- m=O n=5 R=Et ~l-R2=R3=R4=~5=H, Q=C~
, , 3
, ,
- 38 -
,
~047503
~ OH
< ,/ \/--` I(CX2)~;CO"Et
. . Na2C03
12
O OH
HCl
N ~ ~ C02Et
. ' ~ .
Il OH
N
H Cl-
_7a
. A mixture of 8.56 g (40 m~ole~) o~ pyrazolidi-
none 12, 12.5 ~ ethyl 7-iodoheptanoate (44 mmoles) and
10 g of anhydrous sodium carbonate in 75 ml of tetr~-
- methylenesulfone is stirred at room temperature in a
~toppered M ask for 7 days and then heated at 80-85
for 1.5 hours. m e reaction mixture is cooled,
poured into 500 ml Or 5% N~HC03 solution and ex-
tracted twice with e~her. me ether is washed with ~ater
three times and then dried thorou~hly over anhydrous
~odlum ~ulfate. me dry ether solutlon (3 mV is
filtered into a separatory funnel and excess dry gaseous
~ICl bubbled in, givlng ~n lnsoluble heavy oil, the
- 39 -
'!
.... . .~ . .. . .. _ _ ., _ . ,~ _ . _ . _ .. ~ . _.. ~ . .. _ .. _ _ _ _ __~, _ _~, . _ _ _, , ~ , ,
1047503
hydrochlorlde o~ 7 ~ I-oxo-2'-(~'-hydroxy-n-octyl)pyrazolidin-
l~-yl7hep~anoic acid ethyl ester (17a). Arter 5 nin. the
supernatant ether layer is removed by decantation and
centrifuged to remove a small amount Or hydrochloride
- which is added back to the separatory funnel ~1ith the
~a~or portion of the hydrochloride. The hydrochlor~de is
washed with rresh ether and the ether removed by decanta-
tio~ and centrifuged as before. To the hydrochloride
in the separatory funnel is than added excess saturated
NaHC03 solution and about 250 ml of fresh ether. After
ag~tation, the ether layer is dra~n off, w~shed with 5%
~aHC03, dried over anhydrous sodium sulfate, and evaporated
giving 8.37 g (57~ yield) of nearly pure 17; l~C (silica
gel, 2:1 acetone-benzene, iodine visualization (Rf = 0.59;
~or another samnle prepared on a sm.aller scale ~ (neat)
3400 (OH) 172~ (C02Et), 1675 ~CON) cm~l, H~IS.
C cd- for C20H38N24: 370~2829~ measured 370.~824.
An alternate procedure ~or 17 is as ~ollows:
A mixture of 8.6 g (~0 mmoles), Or pyrazolidinone 12, 13 g
of ethyl 7-iodoheptanoate (46 mmoles), 10 g of sodium bi-
carbonate, and 75 ml of tetrametnyienesulfone is heated
wi~h stirring at 60+1 for 48 hours. The reaction
mixture is co~led, poured in 50Q ml of 5~ NaHC03
solution and extracted twice with ether. The ether is
washed with water three times, dried over anhydrous sodium
~ul~ate and filtered into a separa~ory funnel. Excess dry
HCl i9 bubbled in, giving an insoluble heavy oil, the
hydrochloride (17a) o~ ester 17. After 15 min. the super-
natant ether layer ls withdrawn with a syringe and the
oil partitioned between 200 ml of ether and excess
- 40 -
10475Q3
saturated Na~CO3 solution. The e~ther is dried over Na~SO4
and evnporated, ~lving 7.37 5 of ester 17~ ~ max 2.95, 3.40,
3.4g, 5,78, 5.9, 6.0~.
EXAMPLE 4
7/~'-Oxo-2'(3"-hydroxy-n-octyl)pyra~olidin-l'-yl7heptanoic
acid sodium salt ( lS~
, Z=O, m-O~ n=~, R=~a~ Rl--R2=R3=~4=~5=H Q=C~
.
O OH
,/~/~ ' .
C-OEt
l NaOH >
17
O OH
~C-~Na
Il ,
18
A solution of 4.69 (12.6 mmoles) ol ester 17
with 14.0 ml of l.ON aqueous sodium hydroxide in 75 ml of
ethanol is stirred at roo~ temperature under nitrogen for
4 days and then evaporated to dryness in vacuo. me residue
is taken up in 82 ml of O.l~ Na2~04 and the pH ad~usted to
about 8 with a few drops o~ 2N HCl, ~iving a solution of the
~odium salt 18 suitable for biological use.
When the amyl vinyl ketone ir~ Exa~ple 3tA) or
3~B) is substituted by an equivalent amoun~ of t~e alkyl
vlnyl ketone o~' Col. A of Table II (and after reduction
with ~aBH4 ana with hyaro~en over palladium), there is
obtained the mono substituted pyrazolidinone o~ Col. B.
- 41 -
~047SC~3
When the compound of~Col. B of Ta~le II is
reacted with an equivalent amount of the omega-halo
ester of Col. C. ~ ccording to the procedure of Example
3(C~7, or ~ith the halomethylphenylenealkanoic ester~ of
Col. C ~ccord~ng to Examples 12-177, the pyrazolidinyl
ester of Col. D is obtained. Oxidation of an ester of
Col. D with chromic acld in acetone, or preferably with
CrO3-pyridine co~plex ~n methylene chloride /~. Org. Chem.
35, 4000 (1970)7, gives the correspondi~ ketone. The
use of some of these ketones is described in Tables III
and lV - see items (f)-(i) and (n)-(q). ~reatment of tne
ester of Col. D with gaseous HCl gives the correspond~ng
hydrochloride. If an equivalent amount of an ester of
Col. D is substituted for 7 ~ ' oxo-2'(3"-hydroxy-n-octyl)-
p~razolidin-l'-yl7he~tanoic acid ethyl ester in Example 4
and an equivalent amount of a~ueous tetramethylammonium
hydroxide is substituted for the aqueous sodium hydroxide,
the amine salt of Col. E is obtained. Or, if an ester of
-Col. D i8 saponified ~lith an e~uivalent of a~ueous KO~,
the potassium salt of Col. F i8 obtained.
- 42 -
_
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:
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- 43 -
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v ~
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1047503
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-- 47
~0475Q3
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:}: V ~ V O V C~
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P~ l Vu~
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s ~ = ~0 e-
o ~ ~ ~
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a~ .
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1047503
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t~ V ~
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_ 49 -
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-- 50 --
~0475(~3
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., . . . . ..
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mU' ~
V V C`J CU . ~: N ~
C~ ~ O V O CU
~, ~ V ~ ~ V~ ~ ~ Vcu f ~
c> ~ m ~ m
F4 ~ h u~
'
O
i~5
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V~
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p~
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V V C~
. V '' V
O
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-- 51 -
~0-47S~3
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h ~ o ~= ~= <~ u
a) o
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0~ o ~ v ~v
W ~ V ~ ~ ~ h
p~N ~--~o C~J >-- ~ < CU ~CU >-
. --' <;`, V > V~ ~ ~ V~,~ h
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,
- 53 -
'!
~047~Q3
EXAMPLE 5
5~'-Oxo-2'(~'t-hydro~y-n-oct~vl)~vra~oli.~ -l'~y ~pentanoic
acld~eth~l ester (19~ and its h~ydrochloride salt (19~
Y-~l??_7_0 , m-O~ n=3, ~=~t Rl=R2-R3=R4=R4=H ~=CH p=3
'
^\ Br(Cc02)
. NH 2 3
12
.
O OH
-- ~
~ ~ C-OEt
Il . '
O
~ ~ , .
O OH
N ~
~/NI I ~02Et
Cl
` l9a
A mixture o~ 2.14 ~ (10 mmoles) of amlne 12,
3.0 g (14.4 mmoles) of ethyl 5-bromovalerate, 1.0 g of
. anhydr.ous sodium carbonate, and 20 ml of an`hydrous tetra-
methylenesulfone is heated ~ a steam bath for 16.5 hrs,
cooled, and poured into 150 ml of 5% NaHC03. Extraction
with ether, two portions each 100 ml, washing Or the ether w~th
~ater, drying, and addition of ~aseous HCl as descrlbed for thP
~ynthes~s of ester 17, gives the hydrochloride salt (.19a)
a~ a heavy oil. This oil is partitioned bet~1een exces~
~aturated MaHC03 and ether, givin~ in the latter phase
_ 51~ _
~047503
after drying l.4 g Or ester 19; sinsle component by TLC
(~llica gel, 2 1 acetone-benzenè, ~odine vlsualization)
Rr = '5; ~max (neat) 2-95 (O~I), 3.40, 3.49, 5.75 (es-~er),
5.95 (CON); HRMS calcd. for Cl8C3l N204, 342.2250, measured
342.2547.
EXA IPLE 6
4/~t-Oxo-2'(3"-hydroxy-n-octyl)pyrazolidin~ y].7butyric
~cid~ ethyl ester (?) and itS h~ydrochlorlde salt
~=H2, z-o, m=O, n=2, R=Et, Rl=R2=R3=R4_R5=H, Q~CH3, p=3
O
10 ~ Br ( cH2) 3co2~ t
l2 Na2C3
OH
~ '
\~ C02Et
__
me above named ester (20)and its hydrochloride
salt are prepared from 4.28 of amine ?~ 7. g o~ ethyl
4-bromobutyrate, 0.5 g of sodium iodide, 40 ml of tetra-
methylenesultone, and 4 g of anhydrous sodium carbonateat 60 for 4 days, ~iving l.90 g of ester 20 (2$,~); ~MS
calcd. for Cl7H32N204 328.2360, measured 328.2370.
Xh~IPLE 7
7/~'-Oxo-2~(3~ -hydrox~r-n-oct~y].~yrazolidin-l'-yl7heptano1 c
~;~_ tert-butyl ester (21) and its hydrochloride ~alt
2~ Z , m=O~ n=5, R=tBu~ Rl=R2-R3=R4=R5=H Q CiI
- 55 -
1047S03
O OH
~ ~ B tCH ) C t
12
.
O pH
N ~
N ~ . COt-Bu
.
o
21
A mixture of 2.14 g OI- amine ~2.9 g of tert-
butyl-7-bromoheptanoate, 25 ml of tetramethylenesulfone,
2.0 g Or sodiv.m carbonate and 0.5 g of sodium iodide is
~tirred ln a stoppered flas~ at room temperature for 9
days. The resultinO ester 21~ and the hydrochloride salt,
are isolated as in the example ~iven above (ror 20); TLC
~f the ester on silica gel (2:1 acetone benzene) indicated
a single component Rf = O.6, H~U~ ~/e of M~ calcd. for
C2 ~42I~204 398.3142, measured 398.3142 ~ max (CHC1
2.93, 5.81, 5.95, 7.17, 7.30, 8.68~.
EXQl~IPLE 8
7/~'-Oxo-1'-(3"-hydroxy 3"-~ethyl-n-octyl)~yrazolidin-
2!-yl7heptanoiG acid, t-bu~yl ester (22~
Y-O,-Z=H2, m=O, n=5, R=t~u, Rl=R3=R4-R5=H, R2=CH3, Q=CH3,
-
P=3
N
/~\/ C02tBu
\/~
0~
22
_.
~(~47503
- A mixture o~ 1.3~ g (ll mmoles) of amyl vinyl
ketone and 2.70 g (lO mmoles) of 2(6'-tert-butoxycarbonyl)-
hexyl-3-pyrazolidinone is stirred at room temperature for
18 hours, ~iving 7 ~ '-oxo-1'(3"-oxo-n-octyl)pyr~zolidin-2'-
yl7heptanoic acid-t-butyl ester (5). m is oil is dissolved
ln 75 ml of dry ether and the solution cooled in an ice
bath while lO ml of 1.6 molar methyl lithium in ether is
added with stirring. The ice bath is removed after 15 min.
anq the reaction mixture is stirred at room temperature
overni$ht. The reaction mixture is then poured into lO~
aqueous ~mmonium chloride and extracted with ether twice.
The ether is washed with 5~ aqueous NaHC03 twice, dried,
and evaporated, giving 3.92 g or oil. Chromatography of
the oil on llO g of basic activity grade IV alumina,
eluting with ether and ether-ethyl acetate mixtures gives
in the 1:1 ether-ethyl acetate eluate about 0.9 ~ of an
oil that is crystallized from petroleum ether to give
7 ~ '-oxo-1'-(3"-hydroxy-3l'-methyl-n-octyl~pyrazolidin-2'-
yl7heptanoic acid t-butyl ester (22), m.p. 41-42; H~U~
~alcd- ~or C~3H44N204 412.32~9; measured 412.3305.
~ The t-butyl ester is converted to the corres-
pondin~ carboxylic acid alkali metal salt by refluxing
wltn 1 equivalent of alKali metal hydroxi~e in a solvent
suc~ as ethanol.
If, instead of 7 ~ '-oxo-1'-(3~-oxo-n-octyl)-
pyrazolidin-2-yl7heptanoic acid t-butyl ester, tne ketones
o~ col. A, o~ Table III, prepared as described in
Examples l and 3 are treated with mcthyllithiu~, the
methyl tertiary carbinols of Col. B ~re o~tained. ~Jhen
the ketones ~f Col. A are not tert-butyl esters, but
- , .
- 57 -
- ~0475()3
rather less.hindered esters such as methyl or ethyl
ester~ t~o ~ethyl tertiary carbinols of Col. B are ob-
tained in better yields by ~sing Grignard reagents such
~8 methylmagnesium bromide and some~hat lower reaction
temperatures, e.g., 0~. lf for methyllithium, ethyl-
llthium or ethylmagnesium bromide are substituted in
the reactions with the ketones of Col. A, the ethyl
terti-ry carblnols o~ Col. C are obtained.
., ,
.' ,'''' .
- 58 - .
.
i04~5~3
',............... .
, X el,
. X DN oN
~ e ~ x
~o ~ ~ V V ~
H ¦ . - , .
~1 ~
~ ~0 O
H H H H
~ ~' ~I
,~
. - ., . h~
'. ¢
~ a~ a) Q)
O ~ ~
~ C~ ,Q O 'CS ,
. ' ' '
_ 59_
1~47so3
t
V ~=
l ~i n ~ o Q
~o ~o ~j=o
~u~
_60 -
. 10~75(~3
., .,. '' , ..
~ ~ ~ ~ â~ ` ~ ~ X~
~ ~X
~o . o ~ o ~ V
U ~ ~ ~ ~î
~_ .
H . . . _ .
. ~ ' ~0 ' t~ t~
N ' ~ H H H
-
¢ ~ a
V ~ _ ~
.
-- 61 -
.~
~0475~3 - `
, ;, , .
O C~ ^N ~
~î ~m , ~
V V ~ ~ ~o
o ~ ~ ô
t~
. ~ U'~
¢ ~ ~=0 <~:= ~=0
~ ' ~
-- 62 -
10475Q3 -
,; :,. . ' ' ' '' '.
. . ' '.
~ ~ .
V
o C~l
' ~w
~, ~
~ o
V ~ .
. .
Hl .
~,N
C~ V
.~ ~ ' ' ' , . '
,¢ ~ ''
O ~
' . ~ .
'
. . ,
- 63 -
` 1~47S03
. EX~MPI,~ 9
oxo-l'(3"-hydr~xy-3"-meth~yl-n-d~cyl)~yr~Jolidin-
2'-yl7he~tanolc acid t-butyl ester (21~)
-
Y=O, Z=H2, m=O, n=5, R=tBu, Rl=R3=R4=R5=H, R2-CH3, Q=CH3 and
.
O
N /r\ ~ 2- CH2=C~COC7Hl~(n) >
H
^~/^\/\v/CO tBU
23 0
` ~ / CO~tBU
N ~ /
OH
24
A solution or 3.39 g (22 ~oles) of heptyl vlnyl
ketone and 5.4 g (20 mmoles) o~ 2(6'-tert-butoxycarbonyl)-
hexyl-3-pyrazol~dinone in 50 ml of dry ethylene~lycol dimethyl
ether is stirred at room temperature ~or 2 1/2 days, ~iving
a solution of 7/~'-oxo-1(3'1-oxo-_-decyl)pyrazolidin-2'-yl7-
heptanoic acid tert-butyl ester (23). To thls uith cooling
at about -30~ is added methyl lithium in ether (about 40
mmoles) and then the reaction mixture allowed to warm to
- 64 -
', ' ' ' ' ' ' '
7~g~3
room temperatt~e and i8 stirred for 2.5 hrs. The reaction
mixture is proces~ed similarly to the procedure used
~or 22, glving 6.7 g o~ crude 24 which is purified by
chromatography on 180 g of basic, activity grade IV
alumina. HRMS C25H48N204: 440.3611; measured
44o.3633.
EXAMPLE 10
7r3l-oxo-1~(3~'-ethynyl-3~-hydroxy-n-octyl)pyrazolidin-
2'-yl~heptanoic acid t-butyl ester (25)
Y=O, g-H~, m=O, n~5, R3t-Bu, Rl=R3~R4~R5-H, R2=-C-CH,
Q=C~ , ~=3
o
C02tBu
N ~ LiC-CH-EDA
o
n
~\ N/\~\/ C02tBu
,~
OH
To a solution of 5 mmoles of 7[3~-oxo-1~(3"-
oxo-n-octyl)pyrazolin-2~-yl~heptanoic acid t-butyl
ester (5) in 25 ml of dry ethyleneglycol dimethyl ether
saturated with acetylene is added o.60 g o~ lithium
acetylide ethylenediamine complex. The mixture is stirred
with ice cooling ~or 20 min. and then kept at room tempera-
tt~e for 2.5 days. The mixture is then heated at reflt~temperatt~e for 2 hrs. If thin layer chromatography indi-
cates the presence of unchanged 5, about 10 cc o~
- 65 -
:lU47503
dimethylsul~oxide and 0.60 ~ more lithiu~ acetylide EDA
i8 added and the mix~ure stlrred for another 18 hrs at
room temperature before po,urin~ it into water ana extract-
~ng wlth ether. Evaporation o~ the ether gives 1.6 g of
crude 25; ~MS ca1culated for C24~22N24 42~-3144;
measured ll22.3127.
If, for 7 ~ '-oxo-1'-3"-oxo-n-octyl)pyrazolin-
?'-y ~heptanoic acid t=butyl ester the ketones of Col. A
o~ Table IV are substituted in Example 1~, the acetylenic
tertiary,carbinols of Col. B are obtained. Su~stitution
of one equivalent of vinyl lithium for the lithium
acetylide ethylene diamine co~plex and acetylene used in
Example 10, gives on reaction with the ketones o~ Col. A,
" the correspondin~ vinyl tertiary carbinols of Col. C.
With use of vinyl lithium, lower reaction ter.peratures,
~or example 0, af~ord better yields o~ the vinyl tertiary
carbinols, especially when the ketones of Col. A are not
tertiary butyl esters but rather less hlndered esters such
as methyl or ethyl esters. Hydrolysis o~ the esters of
Cols. B and,C ~ith alkali metal hydroxides as in ~xample 8
gives the correspondin~ al~ali metal salts. Acid~fication
o~ these salts with one equivalent o~ mineral acid gives
the corresponding carboxylic acids.
- 66
q
~047503 - .
'. .. , . . - ~,
V V
~) N ' C~l
VN ~ VN
V ~: V ~ C~l V C`J
(O V oN V~ :r: `~ mV
N C~ ~N ~
V ~ V~ ~ ~: V UV ~V ~ 11~
V V`-- V ~ - ' ~ V', O
111 llt ~ ~ llt 111 \ ~ V ~J ~ O
V V~ V ~ O ~N ~ IN
~ 0=1~ ~ ~ 'V
O~ ~ _~ ~
V
. , ` .
~ . ~ ~ - ~ F~
~t O _i
V V V ' V
H H H
~1 ~ ~ a
~t ~ ~ ~
.~
. Q~
o o o o
~ $
v
- 67 -
1047503
."' '. . . . .
S ~ ~ > _ ~ ~
~ --S'i ~0 ~ O ~
~ , .
. .
,
~ > ' æN ~ ,N ~ ~<
~` e ~ Y ~ ~
~-0 ~-0
O ~ ~ ~
~ q~
- 6~ -
- 1047503
,..,',-. '. .' , , ",- t~
~u ~ ~ r ~ ......... N N Gr~: V N C`J C\J
~ ~ ~ V ' V ~
V ~ V ~ ~W ~> X
~ -oil ~= ol~V ,,~ ,,
C~
. ~3 ~ ~y~ V D ~
V ~ . H` H H
~ ~r
~1 \æ-æ ~ ~ ,,
' ' ~
..
1047SQ3
~, . ~1 o
CU C~
V g ~ .
V ~) ~ ~) ~ ~N
C!J ~ N V CU V V
V V V _` V ~` ~:
J ~ N C`.l 1 V
. . ;~ J V V V V P~ ~ r
~_ 11 `--V ~.7 ~ O V V~o ~0
\z ~> ~\ S C~\ S
~d O ~
V E3 S:: o p~
rl "
O
~1 ~ o~
E~ v oN ~
~ ~ v ~ ~u
~ ~ v ~ v ~
N V C~J I
S ~\ S
. ¢ -0 <~ e-- S~;_
O
V ' ~3 ~ O p~
70 -
. 1047503
. "'. '.' . , -
. ~
V
.
C~
N ~,J I
. . ~
.. \>
V ~ ' , ,'
. ~ V ~ , ~) .
.
.
''.'- .''..
riN ~ .
O ~
V~ ' . .
\
~C , <~
t~' ' '
- 71 -
~0475()3
X~5PLE 11
7 ~ 1-Oxo-1'(3"-h~droxy-~",8",8"-trifluoro-n-octyl)-
~ _ . . . . . . _ . . ...._ . . .
pyrazolldin-2'-yl7heptanoic acid, t-butyl ester (27)
Y=O, Z=H2, m=O, n=5, R=t-Bu, H, Na, Rl=R2=~3-R4=R5=H,
. . ,
Q-CF3, P=3
- Q O
~ ~ 2_ CH2=C~C(c~2)4c~3
>
V NH
O
~ I~/^\~'\v~\~/ C02tBU
<\~NV~CF3
O
26
-- .
NaB~ O
- >
~l /\/ /C02tBu
\/NV\.,/ ~F3
~H
2'7 - '
~ A solution of 5.~ g (20 mmoles) of 2~6'-ter~-
butoxycarbonyl)hexyl-3-pyrazolidinone an~ 4.5 g (25 m~oles)
of 1~1,1-trifluoropent-5-yl vinyl ketone in 75 m~ of
ethanol is stirred at room temperature overni~ht and then
the solution of ketone 26 cooled in ice Rnd treated wit~
1.6 g o~ sodiu~ borohydrlde. The ice is allo~ed to slo~lly
melt. ~he reaction mixtu-re is stlrred at room temperature
~or about 6 hrs. The mixture is poured into ~ater,
- 72 -
~ 0475(~3
extracted with ether, and th~ ether evaporated to ~ive ar~
oil that i9 applied to 240 g of basic activity ~rade IV
alumina. Elution wlth benzene and then ether gives in the
latter 4,65 g of 7 ~ '-oxo-1'(3"-hydroxy-8",8",8"-trifluoro- .
n-octyl3heptanoic acld t-butyl ester (.27); ~r- -4
(silica gel, 2:1 acetone-benzene); H~S calcd. for
C22H39F3N204 452.2860, measured 452.2835.
.(~) 7 ~-o~o-1'(3"-h~dro~-8",8".~8"-trifluoro-n-
octyl)7hept~noic acid h~drochloride (25) and
_odium salt (?9)
o
~ N ~ C2-BU HCl
N ~ 3
- OH
~,
~ C02H
N\~/ ~ CF3
.~. OH
. Cl
28
. Q
T/\ ~02Na
. . ~ N ~ y CF3
- OH
Into a mixture of 3.91 g of t-butyl ester 27,
0,25 ml of water, and about 50 rnl of chloro~orm ~s bubbled
gaseou~ hydrogcn chloride for about 30 minutes. After
about 10 minute~ the mixture becomcs cloudy and hydro-
chlorlde 28 appears as an oily pha~e. A~ter tne addition
~ 73 ~,
i~ 4 YS~
of HCl is completed, the mixture is stirred for an
additional 2 hrs and then evaporated in a rotating
evaporator, giving 4.37 g Or 28 as a colorleæs glass;
HRMS (of disilyl derivative of 28 prepared in pyridine)
lcd C24H47F304N2Si2 540.3004; mea~ured 540;2988.
Treatment of 16 with water and enough Na3P04
to give a solution having pH = 8 gives an aqueous solution
of the sodium salt ( ~ buffered with phosphate.
~ The l,l,l-trlfluoropent-~-yl vinyl ketone
used in the preparation o~ 2~ is prepared as rollows:
Br(CH2)4C2H ~ Br(CH2)4CF3
Mg > BrMg(cH2)4cF3 CH2=CHCHO
CH2-CH-CH-(CH2)4CF3 ~ CH2=CH~C~(CX2)4CF3
OH o
A 1 1. autoclave containing 100 g (0.55 mole)
of 5-bromovaleric acid, 40 g (2.0 mole) of hydrogen
fluorlde~ 180 g (1.65 mole) o~ sulfur tetrafluoride, and
200 ml o~ methylene chloride is agitated for 20 hrs at
28-29. The autoclave i8 vented and its content~ poured
into 1 1. of ice water. The aqueou~ mixture is extracted
with ~ethylene chloride, whichin turn i8 washed with
water twice and then with exce~s NaHC03, solution, The
washed solution i~ dried over M~S04, ~iltered, and dis-
tilled to give l,l,l-trifluoro-5-brompentane, 71 g
(63~ boLnng at 68-70/66 mm; ~ maX 1130, 1210, 1250,
1285 cm 1; Anal. Calcd. ~or C5H8BrF3: C, 29.3; H, 3.93;
F, 27.8; Found, C~ 29.79, H, 3.98, F, 28.3
1,1,1-Trifluoro-5-brompentane is con~erted
- 74 -
?~t~3
~o the Grignard reagent by reaction with magnesium in
ether. To this reagent is then added dropwise with stir-
ring an ether ~olution o~ acrolein, keeping the tempera-
ture of the reaction at 10-15 by external cooling. The
reaction mixture is heated at re~lux for 1 hr, cooled,
and poured into 10% aq. NH4Cl. Extraction with ether and
distillatlon give tri~luoropentyl vinyl carbinol, bp
78-79/6 mm, n 25 1.3910.
Oxidation o~ the abo~e carbinol with chromlc
L) acid in acetone gives the ketone b.p. 56/3 mm, n 25
1.3900, HEMS calcd for C8HllF30 180.0761, meaæured 180.0770;
maX 3.27, 3.37, 3.44, 5.92, 6.15, 8.9, 10.13, 10.37 ~.
~-Methoxyphenol (3% by wt.) iæ added to the distilled
ketone to inhibit it polymerization.
EXAMPLE 12
p-~ ~ -Oxo-2(3~-h~droxy-n-octyl)pyrazolidin-l-yl~methyl~ -
benzoic acid, methyl ester (30), the methyl e~ter hydro-
chloride and the æodium salt ~30a)
~ H~, Z~O, A=p-C6H)~, mrl, n=O, R=Me, Na, Rl-R2=R30R4=R5~,
2~ Q-CH~, p=3
O OH
~- ~
~ N/ ~ BrCH2 ~ C02Me
N
Na2C2
~MS
OH
~\C~I2~ C02Me
3
- 75 -
S03
0 O~I
- ~ N
\ CH2 -~:02Na - ' '
, 30a
.
p-Bromoethylbenzoyl bromide is converted to
p-bromomethylbenzoic acid methyl ester by refluxing in
methanol; pmr (CDC13) 230 Hz (C02CH3)~ 265 Hz (CH2Br)
at 60 ~z.
A ~olution o~ 4.3 g (20 mmoles) of 2-(3'-hydrox~-
n-octyl)-3-pyrazolidinone (see 12 of E~ample 3) and 6.6 g
(29 ~moles) o~ ~-bromomethylbenzoic acid methyl ester in
25 ml of~ dry tetramethylenesulfone ~ith 5.0 g of anhydrous
sodium carbonate and 0.2 g of sodium iodide is stirred at
ro~m temperature ~or 4 dayæ and then heated on a steam bath
for 1.5 hrs. ~he mlxture is cooled, poured into 150 ml of
,5% NaHC03, and extracted with ether (2 x 100 ml). The
ether is ~ashed ~ith water (3 x 50 ml), dried o~er anhy-
drous Na2S04, and filtered into a separatory funnel.
Addition of` excess gaseous hydrogen chloride causes the
separation or tne hydrochloride as an oil ~rom which the
~upernatant ether layer is remov~d by decantation. m e
oil is washed ~lith fresh ether which,is removed by decan-
ta~ion giving the hydrochloride o~ ester 30. This oil is
partitioned between excess satura~ed sodiu~ bicarbonate
~olution and ether, giving on evaporatlon Or the Na2S04-
dried ether layer 5.93 g (~20 f~ ester 30; single component
by TLC (sili~a gel, 2:1 acetone-benzene; iodine visuali-
zation) Rf ~ 58; ~ a (neat); 2.93 (O~I), 3.38, 3.40,
- 76 ~
3.~g, 5.79, 5.95, 6.19, 6.32, 7.82, 9.0, 9.78 ~; HRMS
calcd for a2QH30N204~ 362.2226, measured 362.2212.
Saponi~ication of ester 30 wit.h one equivalent
of l.ON sodium hydroxide in ethanol give8 a æolution of
sodlum salt 30a.
EXAMPLE 13
P -r t3-oxo -2(3~-hydroxy-n-octyl~p~razolidin-l_y~ methyl~ -
~enylacetic acid~ methyl ester (31) and the ester
hydrochloride Y=~, Z=O, A=p-C6H4, m~n=l, R=Me,
Rl=R2 R3=~4=R5_H, Q=CH , 3
~ P='
O OH
ICH2~ CH2C02C~I3
-
o OH
~I t
N
N ~ C ~ C02C~
31
Phenylacetic acid is chloromethylated to give
a mixture of ortho-, meta-, and para-(chloromethyl)-
phenylacetic acids. Several recrystallizations ~rom CC14
gives pure p-(chloromethyl)phenylacetic acid, m.p. 154-156
~M. N. Bogdanov, J. Gen. Chem. USSR (Engl. trans.) 1670
(1958)~ . Treat~ent of this acid with methanol in the pre-
sence of dry HCl at room temperature overnight gives the
p-(chloromethyl)phenylacetic acid methyl ester as colorless
liquid. This in turn is treated with sodium iodide ~n
- 77 -
1047S03
~cetone to glve the solid p-(iodomethyl)phenylncetic acid
methyl ester. This is u~ed immcdiately in the rollowin~ re -
action.
A mixture Or 4.07 g (19 mmoles) of amine 12
5.8 g (20 mmoles) ol ~ iodomethyl)phenylacetic acid methyl
ester, 5.5 ~ o~ anhydrous sodium carbonate, and 50 ml o~
tetramethylenesulfone is stirred at room temperature in
the dark for 2 days a~ld then heated on ~he steam ba~h
for 2 hrs. The mixture is cooled, poured lnto 2~0 ml
of 5% Na~C03 and extracted witIl three 125 ml-portions of
ether. The ether is t~ashed three ~imes ~ith ~ater, dried
over anhydrous sodium sulfate, and filtered into a
~eparatorX funnel. H~dro~en chloride ~2S iS bubbled into
the ether until no ~nore insoluble oil separates. After
the oil ~e~tles ou~, the super~atant ether layer is
~r~ P~ ~ith a syr~nger ~he remainin~ oil (the hy~ro-
chloride) is then partitioned bet~leen excess 5~ sodium
bicarbonate and ether. The ether phase is dried over
~odium sulrate and evaporated in vacuo, giving 5.23 g
(71%) o~ tne ester 31 as a li~ht yellow oil, pure by TLC
(~ilica ~el, 2:1 acetone-benzen~, R~ 0.65, iodine visuali-
zation. The oil could be ob~ained colorless by eluting it
~rom a column OI- basic alumina (Activity grade ~) with
3 1 benzene-ethylacetate; HRI~ calcd. ~or C21H32r~204
376.2270, measured 376.2315; ~ max (neat) 2-90~ 5-72~ 5.95,
6.58, 7.27, 8.66~
- XAMPLE 14
p~r-oxo-2 (3l-h~ldroxy-n-octyl)~yra7~olid~-ne-l-~yl7~ th
~henyl acetic acid (32a) and the sodium salt (32)
3 Y~12, Z-0~ A=p-C6H4~ m=n=l, R=H, Na, Rl=R2=R3=R -R5=H,
.
Q=CH3, p~3
~ , . .
- 78 -
1()47503
pH
~ N
- Nn C0~
N ~ CH2C02~a
32
,
~ C~2C2H
3?a
A ~Dlution of 5.53 g (14.7 mmoles) of ester
31 in 60 ml of methanol is cooled in ice and treated with
a solution of 1.56 g (14.7 mmoles) of Na2C03 in 55 ml of
- water. The mixture is stirred with cooling for 2.5 hrs
and then at room temperature overnight. Then 100 ml of
water is added and the solutlon extracted with two 100 ml
portions of methylene chloride, WhiCh iS then discarded.
The aqueous phase, containing the sodium salt 32 is t~en
carefully acidified ~lth dilute HCl just to the point
where tne last drop causes the ~lly precipitate or 32a to
start redissolving (pH about 6). The oil is extracted
into 200 ml or methylene chloride. (Additlon of a ~e~
more drops o~ dilute HCl to tne clear aqueous layer re~ain-
ing gives no cl~udiness or oily precip~ate ir the acidi-
fication is carried out properly.).The methylene chloride
layer is dried over Na2S04 an~ evaporated, giving 4.51 g
(80 ~f the acid 32a as a llght yello~ glass after drying
under a hi~h vacuum at 5; ~ max (neat) 2.9-3.2 broad~
3.4, 3.5, 3.7-4.1 broad, 5.8, 6.0-6.1, 6.58 sh a~ 6.62,
6.85, 7.05, 13.6, 15.0 ~; H~ calcd. for C20H30~204:
362,2204, measured 362.2204; for the bis-trimethylsilyl
derivative calcd. 506.2994~ mensured 506.3028.
~ 79 -.
5~3
EXAMPLE 15
f~ - [ P -t r3 -Oxo -? ( 3 ' -h~rdro~-n-octyl ) Pyrazolidin--1 -yl~ meth~
phenyl~propionic acid (35a), its methyl ester (33), the
e~te:r hydrochloride ( 34) a2~d the sodium salt ( 35)
Y~ Z=O, A=p-C6H,I, m=l, n=2, R=CH3, Na, H, Rl=R2--R3=R4-
R5---H, Q=CH3 ,~
O OH
., ~
BrCH2 4~ ( CH2) 2C02CH3
12
O OH
2 3 ~ CN ~ ~ HC1/Et20
H2 N\~-- ( CH2 ) 2C02CH3
33
O OH
tl t
\~N~ ( CH2 ) 2C2CH3
Cl
34
Na2G3 O OH
O~~ HCl
\~N~3 ( CH2 ) 2C02Na
O OH
~ ( CH2 ) 2C02H
35a
-- 80 -
1~47S(;~3
~ -Phenylpropionic acid (150 g, 1.0 mole) is
bromomethy]ated by passin~ HBr ~AS into a mixture of t~e
acid, parnformaldehyde (40~), and 48% aqueous HBr (2Q0 ml)
~t 50-55 for 3.5 hrs. This gives a mixture o~ ortho,
meta, and ~ bromomethylp~lenylpropionic ac~ds from wAich
the para isomer can be isolated by recrystallization ~ron~
CC14. The ~(p-bromomethylp~enyl)propionic acid obtained
(100 g, 41%) melts at 133-316.
Anal. Calcd. ~or ClOHllBrO2: C 49 4 H, 4-55;
Found: C, 49.67; H, 4.78;
Br, 33.05.
The bromoacid (50 g) is converted to the methyl
-e~ter in methanol (300 ml) and methyl orth~formate (20 ml)
with ~nhydrous HBr as the catalyst, giving ~-(p-bro.~o-
~ethylphenyl) propionic acid methyl ester (42.5 g) m.p.
38-42 (hexane); it contains about 20% ~-(p-methoxymethyl-
phenyl)propionic acid methyl ester, according to pmr
~pectroscopy.
h mixture o~ 10.7 g (50 ~moles) o~ pyrazolidi-
none 12, 16 g o~ the ~(p-bromomethylphenyl)propionic acid
~ethyl ester, 10 g of sodium carbonate~ and 100 ml of
tetramethylene sulfone is stirred at room temperature for
8 days and then heated in a steam bath for 4 hrs. The
~ixture is cooled, poured into 500 ml of water and ex-
tracted with ether. The hydrochloride 31~ and the free
ester 33 (1~.3 g, 73%) are isolated by a procedure
analogous to that used to prepare e~ter 30 and its hydro-
chloride.
Hydrolysls of ester 33 wi~h sodium carbonate
.
81 - -
.)3
in ethanol-water gives the water-soluble sodium salt 35.
An aqueoUs solution o~ salt 35 acidified to pH 6 and
extracted with methylene chloride gives acid 35a; ~ maX
2.45, 3.40, 2.48, 3.s-4.0, 5.80. 6.oo, 6.60 11~ HRMS calcd.
~or C21H32N204 376.2360, measured 376.2336; silylation
gives an intense 520 m~e ion (376 ~ 2 ~MS).
EXAMPLE 16
P[ ~ -Oxo-2~3~-hydroxy-~octyl)pyrazolidin-l_y~ _
methyl~ -phenyl¦but~ric acid methyl ester (36), its
hydrochloride salt (37), sodium salt t38), and acid (39)
Y=H~, Z=O, A=p-C6H4, m~l, R=H, CH3 Na, R --R =R3=R4=R5=H,
Q=CH~ p=3, n=3
~ BrCH2~( CH2 ) 3C2cH3
NH
o , OH
~ ~ N ~ (CH2)3c2
O OH 36
n t
/\ W V~
\ ~ N ~ NaOH
H+ ~ ( 2)3 2 H3 >
37
- 82 -
O OH
n
/\'--~
O OH ~ \~ ( CH2 ) 3co2Na
~\N ~/\ 38
~_ ( CH2 ) 3C02H
39
4-Phenylbutyric acid (150 g) is ~romomethylated
in 200 ml of 48% HBr with 36 g paraformaldehyde and gaseous
HBr ~or 3.5 hrs at 60-65, and then without addition of
B r for 1.5 hrs at 70-75, glving a mixture of ortho,
ta, and ~ isomers from which pure 4-(p-bromomethyl-
phenyl)butyric acid, m.p. 137-138 ls isolated by re-
crystallization from CC14. Trcatment of the acid ln
ether-tetrahydrofuran with dia~ometh~ glves the mothyl
~0 ester of 4-(~-bromomethylphenyl)butyric acid as a liquid.
Reaction of this compound with pyrazolidinone 12
gives the methyl ester 36 from which it~ hydrochloride
salt ( ~ the sodium salt, ( ~ and the rree acid 39
are readily obtained by the general procedures given in
Example 14. For the acid 39 HRMS calcd. ~or C22~ 4N204
390.2517; measured 390.2528.
EXAMP~E 17
~L P~ ~3-Oxo-2(3~-hydroxy-n-octyl~pyrazolidin-1-y~ -
meth~ phenyl~butyric acid isopropyl ester (40) and its
drochloride salt (~1~
2 Z=~ A=p-C6H)I, m-l, n=3, R=i-Pr, Rl--R2=R3=R4-R5=H,
Q C~3, p 3
- 83 -
o OH
<~ CH2 ) 3C02CH( CH3 ) 2
NH N~HC03
O OH
.~ ~
/\1 --/
\./N~ ~ (CH2)3C02CH(C~3)
n
HCl > ~\N~
N ~ (C ~ )3C02CH(CH3)2
~I
Cl
41
4-(p-Bromomethylphenyl)butyric acid i8 con-
verted to its lsopropyl ester in isopropanol containing
anhydrous HBr. The reaction is carried out over 4A
molecular sieve at room temperature for 2 days. This
ester 1~ a collorless liquid.
Amine 12 (2.14 g) i8 allowed to react with 3.9 g
of thi~ ester in 25 ml of tetramethylenesulfone over
8.0 g of anhydrous ~odium bicarbonate for 3 days at 50.
Processing the reaction mixture by a procedure analogous
to that used in Example 1~ gives the e~ter 40 and its
hydrochloride 41. HRMS calcd. for C25H40N204 (ester
m/e 432.2986, found 432.3045.
- 84 -
~g~7~3
EXAMPLE 18
rl~ phenyl propionates (45) ~nd (46)
meth~
E~ , trichloroethoxycarbonyl)-3-oxo-
pyra~olidin-2-yl~ methylJphenylpropionic acid isopropyl
ester (42)
N-H BrCH2 ~ (CH2)2co2cH(cH3)~
HMPA, Na~C0
C-OCH2CCl3 3
0 l3
~-- ( CH2 ) 2C02CH( CH3 ) 2
\ C-OCH2CC13
42
A mixture Or 26.2 g Or l( ~ trichloroethoxy-
carbonyl)-3-pyrazolidinone 13, 16 g of ~ -(p-bromomethyl-
phenyl) propionic acid lsopropyl ester in lO0 ml of dry
hexam~thylphosphoric triam~de and 20 g of anhydrous sodium
bicarbonate is stirred at room temperature for l9 day~ and
then poured into 500 ml of water. The aqueous m1Yture is
extracted twice with ether and the ether e,Ytract is in turn
wa~hed with water, 5% NaHC03, and finally with 5% HCl.
Evaporation Or the ether give~ 22.7 g of crude product.
- 85 -
m is i8 crystallized from about 100 ml o~ cyclohexane, giv-
ing ~-~p ~ '-trichloroethoxycarbonyl)-pyrazolidin-2-
y~ m~thy~ -phenylpropionic acid isopropyl ester ( ~ m.p.
91-92 ~ ~max CHC13, 3.36, 5.83, 6.20, 6.60, 12.23 ~.
Anal. Calcd. ~or C19~23N205C13: C, 48.99; H, 4.98;
N, 6.02; Cl, 22.84
Found: C, 48.99; H, 5.07
N~ 6.15; Cl~ 22.92
(B)~-r p(3-oxopyrazolidin-2-yl)methyl~phenylpropionic
acid isopropyl ester (43)
42 Zn ~ ~ t (CH2)2C02CH(cH3)2
N~
43
To a solution of 7.0 g of 42 in 50 ml of methanol
is added 4 g o~ 20 mRsh zinc granules that had previously
been purified by waæhing with nitric acid-8ulfuric acid.
The mixture is heated at gentle reflux, where upon a vigourous
evolution o~ carb~n diozide takes place. When the reaction
subsides the mixture is heated at re~lux for an additional
0.75 hr. me reaction mixture iB then cooled and filtered,
and the filtrate i8 concentrated to about 20 ml in vacuo.
The concentrate i~ then mlxed with water and NaHC03 i~ added
to pH 8. Extraction with ethyl acetate gives in the organic
layer 4.1 g of 43 as an oil.
Alternatively 43 can be treated with zinc dust in
83% acetic acid at 0-5 for 1 hr. By processing the reac-
tion mixture by a procedure analogous to the procedure
described above, colorless 43 i8 obtained in about 40% yield;
- 86 -
~ 7 ~ ~ 3
HRMS calcd. ~or C16 ~ 2N203 290.1629; measured m~e. o~
290.]~630.
Treatment of 0.545 g of 43 in 3.0 ml of i~opropyl
alcohol with 0.32 g of p-chlorophenyliso~hiocyanate gives
0.75 g (87~) of the thioureide; m.p. after recrystallization
from isopropanol 117-118, lmaX 3-3~ 3-37, 5.81, 6.30, 6.62
~h, 6.67, 12.09 ~.
Anal. Calcd. for C23X26ClN303S: C, 60.05; H, 5-70;
N, 9.14
Found: C, 60.40~ H, 5.51;
N, 9.11
( c~ ~ - [P-L L 3-oxo-l(3l-hydroxy-n-octyl)pyrazolidin-2
y~ methyl~-pheny ~ propionic acid isopropyl ester (45),
and sodium ~alt ~6)
Y~O, Z=E2, A=P.C6H~, m=l, n~2, p=3, Rzi-Pr; Na;
Rl=R2=R3=R4-R5=E- Q-CH3_
CH2 ~ ( CH2 ) 2C02CH( CH3 ) 2
43 CH2'CXCOCsHll(n)
EtOH ~ ~ N
44 o
NaBE4 ~ N/ H2 ~ (CH2)2C02CH(cH3)2
EtOH ~ N
OH 45
( CH2 ) 2C02Na
~ ,~/
OX ~6
- 87 -
~ 0 3
To a solution of 3.02 g of 43 in 25 ml ethanol is
added 1.44 g of amyl vinyl ketone and the resulting solution
is stirred at room temperature for about 16 hr~. This gives
a solution of ketone 44 which is then cooled in ice and
treated with 0.8 g of sodium borohydride. The reaction mix-
ture is stirred in the cold for 1 hr and at room temperature
~or 2 hrs, and then poured into 200 ml of water. Extraction
with ether and e~aporation of the ether gives an oil that
according to th~n layer chromatography on silica gel con-
taing ester 45 and some amine 43. This oil is redissolved
in ether and washed with 0.5N HC1 four times, which removes
most of the amine 43 and leaves most o~ 45 in the ether.
Evaporation of the ether gives crude 45 which i8 ~urther
purified by elution from basic alumina of acti~ity grade IV
with 2:1 (vol/vol) benzene-ether. By th~n layer chromato-
graphy on silica gel (2:1 acetone-benzene) the oil 45 is
shown to be pure (Rf = 0.72), HRMS Calcd. for C24H38N402
418.2829; measured 418.2823, ~ x 34~ 1750, 1675, 1512,
116OJ 820 cm~l.
Saponi~ication of an ethanolic solution oP 45 with
one equivalent of l.~N sodium hydroxide at room temperature
~or several days gives the sodi~m salt 46.
EXAMPLE 19
N-(6-Carboethoxy-n-hexyl)-N'-(3~-hydroxy-n-octyl)pyrazolidine(50)
YZ--H~, m=O, n=5, R=Et, Na, H, Rl=R2=R3-R4=R5--H, Q=CH3,
P-3
A) N(3-oxo-n-octyl)pyrazole (47) and N(3-hydroxy-b-octyl)-
p~razole (48~
O
~ N~ 11
' ~ CH2=CHCC5Hll(n) EtOH
- 88 -
i~ ~'7~3
N
N
47
NaBH
EtOH
H
4~
A solution of 17.0 g (0.25 mole) ~ pyrazole
and 38.0 g (0.30 mole) of amyl vinyl ~etone in 250 ml of
ethanol i8 heated at reflux temperature for 5 hrs and then
cooled in ice, giving a solution of N-(3-oxo-n-octyl)
pyrazole ( ~ . To thi~ ~tirred solution kept at 20-25 by
external cooling is then added in portlons 8.0 g of sodlum
borohydride. When the addition is complete the reaction
mixture i8 allowed to stir for 2 hr~ at 25 and then con-
centrated in ~acuo to ~bout 150 ml, poured into 600 ml of
water, and extracted with ether. me ether is washed with
three 200 ml portion~ of 5% aqueous HCl and the combined
HCl layers aro backwashed with fre~h ether. me HCl solu-
tion is then ba~ified with excess Na2C03 to pH 9 and ex-
tracted with ether whl~h, after drying (Na2S04) and
evaporation, gives 30 g (61%) of a colorless liquid.
According to pmr spectroscopy this is nearly pure ~(3-
hydroxy-n-octyl)p~razole ( ~ : (C~C13, ~MS) 449 (d, 1,
J = 2, CHN), 445 (d, 1, J = 2, C~N) 373 (t, 1, J - 2,
C=CH-C) 259 (t, 2, J = 7, C ~ N), 210 (m, 1, OH) ~z at
60 MHz~ Di~tillation of this liquid gives a small fore-
~hot of pyrazole and then 26.5 g of pure 48, bp 95-100/.005
Torr; ~ maX (neat) 2.98, 3.42, 3.49, 6.60, 7.27, 9.18 ~;
- 89 -
~ 3
CllH20N20 196.1575, meaæured 196.1573.
B) N-(6-carboethoxy-n-hexyl)-N'(3t-hydro~y-n-octyl)-
razolium iodlde (49)
(CH2)6C2
48
<~ ~ C02Et
H
49
Tetramethylene sulfone or N,~-dlmethylformamide
can be used as solvents for thi~ reactlon, but acetonitrile
gives a better yield than N,N-dimethylformamide and an
easier workup than tetramethylene sulfone.
A solution of 5.88 g (30 mmoles) Or pyrazole
alcohol 48 and 10.0 g (35 mmoles) of ethyl 7-lodoheptanoate
~n 18 ml of dry acetonitrile iB heated in a sealed, evacuated
glass tube at 135 ror 20 hrs. The lig~t yellow reaction
mixture is evaporated in acue (50) to remove acetonitrile,
giving crude pyrazolium salt 49, which by pmr ~pectroscopy,
contains little or no unchanged 48. The crude product is
mixed with 15 ml Or 5% aq. ~aHC03 and 75 ml Or ether in a
separatory funnel and the lower (3rd phase) drawn Orr.
This heavy oil is dis~olved in 100 ml of ethy]. acetate
~0 and washed with a few ml o~ water containing a few crystals
o~ Na2S203 to remove iodine. me clear, colorless ethyl
acetate solution is dried o~er anhydrous Na2S04 and
evaporated in acuo, giving 10.8 g (75%) of the pyrazolium
salt 49. TLC (silica gel, acetone) indicates a single
- 9 -
~`f-~ 7S~3
polar component. me pmr spectrum is quite characteristic:
(CDC13, TMS) 516 (tror two overlapping doublets~ 2, J =
2.5, CH-N), 404 (t, 1, J = 2.5, ..CH - , 285 (m, 4, NCH2),
240 (q, 2, J = 7, OCH2), 73 (t, 3, J = 7 OCH2CH3)~Z at
60 MHz.
C) N-(6-carboetho~y-n-hexyl)-N t _ ( 3~-hydroxy-n-octyl)-
~_azolidine (50)
CO Et
2 NaBH4
OH
49
N ~ C02Et
\~
H
A æolution of 5.8 g (12 mmoles) of the pyrazollum
salt 49 in 100 ml of anhydrous ethyleneglycol dimethyl ether
iæ stirred wlth 0.8 g (21 mmoleæ) of analytical grade
sodium borohydride at room temperature for 16 hrs under
nltrogen. The mixture is evaporated to dryness at 30
in vacuo, c ~ iously mixed with 100 ml of 2.5% aq. HCl,
and mixed with ether in a separatory funnel. me ether
layer is carefully separated and the aqueous layer together
with the oily (third) phase baæified with exce~s Na2C03 to
pH 9. Extraction wlth two 100 ml portion~ o~ ether and
evaporation of the dried ether layer gives 2.5 g o~ oil
that was applied to benzene to a column of 90 g of basic,
activity grade IV alumina. Elution with benzene and then
- 91 -
1~475U3
with 25:7.5 ether-benzene giYes 1.56 g of a colorless
.-mobile liquid, the pyrazolidine 50; ~ (neat) 3400
(OH), 1725 (C02Et) cm~l; one component by TLC (silica
. gel, 2:1 acetone-benzene, iodine visualization) Rf =
0.54; H~l~ calcula~ed for C20H40N203 356.3037, measured
356.3040.
. Better ylelds of the pyrazolidine 50 can be
obtalned by addition of acid to the reduction mixture.
m e ~avorable e~ect of acid is believe~ due to protona-
tion and subsequent reduction o~ a pyrazoline intermediate
(5l), e.g.
~ R H- ~ R ~r'
.. ~_ ~ R
~here R and R are the side chains o~pyrazolium salt 49
and pyrazolidine 50. Apparently in the absence of a
~u~ficient proton source the pyrazolldine 51 i8 a ma~or
product o~ the reductlon ~nd it can be easi.ly oxidized by
air during the ~orkup to ~ive the or~inal pyrazolium salt.
An example of the improved reduction procedure follo~s
- 92
1~475l~3
~ solution o~ l4.4 g (30 mn1oles) of pyrazolium
salt 4~ ~n lOO ml o~ anhydrou~ ethyleneglycol dlmethyl
ether is stirred t~ith l.25 g (33 mmoles) o~ pure sodium
borohydride at room temperature in a stoppered flask for
64 hrs. Glaci~l acetic acid (9.2 ml, 160 mmoles) is then
added ~lo~lly with st~rring and then l.3P g Or sodium boro-
hydride added in portions with cooling in a water bath
over about 5 minutes. ~fter lO min. an additional l.30 g
o~ sodiu1n borohydride ~s added~ The additions are
accompanied by some foaming. A~ter t~o hours another
1.30 g or sodium borohydride is added and then the reac-
tion mixture stirred for one day at room temperature under
nitrogen. The reaction mixture ~s evaporated in vacuo a~
then treated cautiously with 90 ml of 30~ ace~ic followed
by 70 ml of 2,5% HCl and enough additional water to make a
total volume or about 20U ml. Concentrated ~Cl is then
added to pH = l or 2, and the whole extracted twice t:ith
ether. The e~her layer is evaporated and the resulting mix-
ture of acetic ac~d and product treated with excess 5%
Na2C03 and extracted with ether. The ether extract is
washed with 5~ aqueous NaHC03, dried and evaporated, to
give 8.51 g ~79~) of pyrazolidine 50 as a colorless oil;
~ (as abovc) 0.50; H~ calcd ~or C20H40N 03: 355.3037,
- measur~d 356.305~.
D) N(6-CarboY~y-n-he~yl)N'-(3'-h~droY~y-n-oct
~razolidlne sodium salt (52)
aO.I
~I
- . ~;0
~ 93 -
lQ47~iU3
~\/\/\
~H
.
: Pyrazolidine 50 10.0 ~ (28 ~molcs) in 50 ml of
ethanol and 14 ml of 2.0N sodium hydroxide ls heated at
reflux temperature for 4 hrs., allo~ed to stand ov'ernight,
and then evaporated to dryness at 60 in vacuo~ The resi-
due is taken up in a '~ittle water, extracted t~lice ~ith
ether, and then the aqueous phase evaporated to dryness
~t 60 in vacuo to give sodium salt 52 as a colorles~
powder.
Aci~ification of 52 with one or two equivalènts
of mineral acid HX gives,respectively,the correspondin~
carboxylic acid (53~ and the corresponding carboxylic acid
t54;
~ ~ C0 H
\~
- , .
~ C~)2H
.. ' ' \/~
,
If a ketone from Col. A o~ Table V is substituted
~or amyl vinyl ketone in the ~bove Exa~ le (P~rt A) there
i~ obtained the keto alkyl pyrazole of Col. B instead of
~(3'-oxo-n-octyl)pyrazole. Reduction of the keto alkyl
pyrazole Or Col. B with NaBH4 yield~ the
_ 94 -
i,
lQ47~Q3
hydroxyalkyl pyrazole of Col. C. Substitution of the
hydroxya'kyl pyrazole o~ Col. C for N-(3-oxo-n-octyl)-
pyrazole and substitution o~' the omega-haloalkanoic acid
ester or Col. D for ethyl 7-iodoheptanoate in Part B pro-
vides ~he pyrazolium salt of Col. E. Substitution o~ the
. pyrazolium salt of Col. E for~he pyrazoliu~ salt of
Part C, in the first or second (i~proved) procedure gives
the N,N'-disubstituted pyrazolidine or Col. F. Saponi*i-
cation of the ester Or Col. F with NaOH (or the hydroxide
of any other physiological acceptable alkali metal) as in
- Part D gives the corresponding metal salt; in the case
of l~aOH thls salt being the salt of Col. G.
If the ketoalkyl pyrazole of Col. B is treated
with the corresponding organometallic reagent of Col. H
by a procedure s~alogous to the procedure used in
Examples 8-10, the correspondin~ tertiary carbinol pyra-
zole o~ Col. I is obtained. Alkylation of the pyrazole
of Col. I with the corresponding ome~a-haloalkanoic acid
ester o~ Col. D as in Part B of the above Example affords
the pyrazolium salt which can be reduced with NaBH~ as
in (A) and then saponified to the carboxylate salt of
Col. J by treatment with one èqulvalent of NaOH.
- 95 - ,
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- 10475U3
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- 97 -
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- 100 -
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- 101 - ~
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- 103
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- 104
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.. ..
~ N o
. C`J V r , ~ ~N
~ ~ P' " '~
O ^ ^ ^ ' '
O
. C~
a
~ V H
~i . V V ~ VN ~ V~
V C~l ~C V V~ V W
~ V V, V
- V~ rS~ N_~
t~ +~ +~ +\_
v
_ 105 --
lQ47SQ3
. m~
,
. ~ ~) N p
~ m ~ --N mN ~N
~ . ~ ~ ~ ~ m ~ m (~ , m
~::
V b~
P l ~ ~ C~ ~
DN~
- 10~ -
~0475~3 --
,, . . ;
,., . ... . .
..
, P
C~l V o ~ V
o
V ts~ N :~ O
~!J VN ~ V v .
::~ o ~
V
~ s ~
t~ ~ . ~
~7
~? O N V
O
V C`J {~I ~ O
.P
C~ ~ ~ ~
.
,
- 107
.~
~047S03
~J ~ D
0~ C~ ~ C~ ~
~ ~ o ' ~O
,~ V ~, ' O ~ '
t~ .
._
~~ m
o v~, v~
~ ~_ ~ ~ V
~ p~u V~ ~ Cc~ ,
~ O ~ ~
4 ~ e ~ ~-
V c o P~
. , .
- 108 -
.. .. . . ..... . . . . . ... . . . ..
~047S03 --
.. .. . ' , '
-.
Ocu ~ m~
C~
. ~ U~ ~ V O
C~
p:: ~ T li:4 v P~
~C`J C~ ~ o _,
m ~ o
\>_ O ~ U p: \
~ Z-- Z ~--Z
o ~
g UCJ~ h ~q
~ .
P
~ . H H
i~ . H
. , ~
C~
O ~
V ~ . ~ :r
~) I' I v '~
m
V N C~J O p~
~ - v o v v v
~ V~ ~\ m ~ ~' P ~
. ~ ~
O
- 109
.. . . . . . .. . ~ .. ..
~.Q475Q3
m~ ~ 3
~ u ~ .o , c) , ~ ,,
E;l ' .
, ' ~ o~
~ ~ ) o t , ~ t ~ .
V ~ ~ ,,, ~
.
-- 110 -- ,
~47503
., .~ ' '"'' .
N
.,' ~ ba ,~ ,
- ~1 ~ . . .
~ ' ~ c~ ~ O ~>
. ~47503
.,, ., .'
, . . -
~ . . . .
. ~
~ o ~ ~ ~ ,_
~ C~ ~ ~
.
C) .
~ , Oa
V~ V~ ~ ~ ~ V
~C~ C~
. s~ m'~
o ~ ~ _~ ~
- ~
.
- 112 - .
1(~475(;?3
. ,, .. .
., ~ ' Z
~ ' ~v :~
. :~ . . V
~o ~ ,_ _~
o V ~ s: o ~
P
V ~ o ~
CU O V N
~ U ' ~ O
C~ ~ ^ ~ V
, CU CU '~ V
I V
N --- ~) CU V
O V I er
~ _ ~_ ~ V ' , ~
~U ~ b~
o ,~
V ~ ~ . o ~. .
- 113 - .
.~
; . 1~47S(~3
. , . .
. . V~
~ ~ V ?
F~ V t5' h U~ V t~
~V
~1 ~ .
V~ -
V V ~ C~l
O r o 1:
~ V ~ V V
V
V V ~) . ~
~_
v ~ v ~
e~ ~ o
e;-- <~ ' ~,> H ~>
, o ~ _~ ~ O --~
V Cs~ h lq V ~
, .
.
~ . . .- ~
~'347~03 --
.
.
~i ~ ~
~ ^ V
- N ~ C V ~ V ::C
V V ~ v ~ V
~ ) m~-- v v~
"
O
V
a)
.,~
,~ .
C)
~i ~ ~ ~
~N N ~ ~ V
. V~
~> ' ' ~> <~;~
- O ~
~r
'
~475~3
. , -, ,
, . ~. '` `. .
. ~ .
. o
~ ~ ~ V
. V o~v V ~ ~v
U~ ~ V 1, `_
V
~ V <~ ~V~ ~ o
o . ~ o
o
æl . ..
~ o~O ~ .
C~
C~
:~ ~o
<~ æ~ ~
V ^ .S~ o
- - 116 -
- 1~47503
n~
.. . N ~N
r~ I é
. Z~
.
.
.
o
. ~1 . . ..
N N
H
- 117 -
. .
~7S~3
Alternatively many of the pyrazolidines of this
invention can be made by reduction of the corresponding 3-
pyrRzolidinones. The reagent of choice for effectlng thi~
reduction is diborane.
CH2(A)m(cH2)nco2R ~ CH2(A)m(CH2)nc02R
N ~ (CH2)pO THF ~ ~ (CH2)pQ
(A)m(cH2)nco2R BH ~CH2(A)m(cH2)nc02R
N ~ 2)p ~ ~ (CH2)pQ
OR 3
EXAMPLE 20
N(6-~arboxy-n-hexyl)N'-(3'-hydroxy-8',8',8'-trifluoro-n-
octyl)~yrazolidine hydrochlor~de (55) Y = Z = H~, m = O,
o 5 R Rl = R2 = R3 = R4 = R5 = H, Q = CF3- P ~ 3
C02tBu 1) BH3/Th~
N CF 2) HCl ~>
N ~ ~ ~ 3
~/~\/ C02H
N+ ~ ~ CF3
Cl OH
To a ~olution of 0.226 g of 7 ~'-oxo-1'(3"-
hydroxy-8",8",8"-trifluoro-n-octyll7heptanoic acid t-
butyl ester (Example 11) in 5 ml of dry tetrahydrofuran
i~ added 1.5 ml of lM diborane in tetrahydrofuran. me
reactlon mixture is refluxed for 1 hr, cooled, and 1.0 ml
of 2.0M aqueous RCl is added. me resulting mixture i~
- ~18 -
104~503
reflu~cd for 1 hr and then stirred at room temperature
overniOht. Evaporation oI the mixture to dryness under
a vacuum gives a solid. Extraction o~ the solid with
-ethanol an~ evaporation of the clear ethanolic solution
gives a colorless oil which is mainly the desired car-
boxylic acid 55. H~U~ on thesilylnted pl'OdUCt in pyridine
~hows a parent ion with m/e 526.3208; calcd ~or the disilyl
derivative C2yH49F303N2Si2 5263331-
~hen a carbinol of Col. A o~ the follo~ing
Ta~le VIis treated with an excess o~ the correspondin~
alkanoic anhydride of Col. B, the ester of Col. C is
obtained. When the carbinol is a secondary alcohol the
react~on is conveniently carried out in pyridine at room
temperature for 12-24 hrs. ~Jhen ~e c~rbinol is a ter-
tiary alcohol a mixture o~ the tertinry alcohol and al-
kanoic anhydride in benzene is treated with a 2-molar e~-
cess o~ 4-di~ethylaminop~ridine at room temperature until
thin l~yer chromato~raphy indicates that the esterifica-
tion is complete. In both processes the excess alkanoic
anhydrlde is decomposed by stirring the re~ction mi~ture
with 50~ aqueous pyridine and then tne ester ~sisolated
by conventional means such as extraction and column
chromatography.
- 119 -
. ~475Q3
oc~ ' o
cu ' v~ o
c, m~ t ~
~ ~ ' .
. ~1 ..
" ~ t
~ z ~ z-- z ~; ~
o Q~ V V ~ ~
0 . .o O ~
- 120 -
- 1047503
,; ............. , ' ' ,
cu
. o~ cu
~'0 ~N -o`
~¦ V o ~ N
~) ~) ^ <~J ~
~ ' ~ V
e ~
- :
- 121 -
1'~47503
. . -` .
., . . . . .
, o ~ V
.
r, ~ ~ c~
~U V~ V~ V P~ V
_, _ V ~--
v~ ~ v- o ~ !~ ) v= o
V r: ~ V~ O ~ ~>~ Yc~ ~o
V \ > V\ ~
~. ~o, <~>,, ~ ,
O Q~ ~ ,
CU CU V
C~ ~ V ~ V 5~
V V ~ --' ~J N V ~ ¢~ ~ V V V
_ C~ V V V . l C ~ 1 11 ~ V= O
I ~ m ~} ~}~~ ~d
v o , o~> o ~o
o ~ ~ ~ ~
v c .o o
.
- 122 -
.
1(~47503
The-new compounds ~herein Y-0, Z-H2 and
R'=~3=H are obtained by
(~) contactin~ a 3-pyrazolidinone of the formula
. ~ NH wherein P is a
~ N-P
-. . . .blocking group with
a æubstantially equimolar amount of an
-halogennted carboxylate o~ the formula
XCH2(A)m(CH2)nC02R
wherein X is chlorine, bromine or iodine, in
~he presence or a base and solvent, to produce
a compound of the formula
aN~CH2(A)m(C~2)nc02R~
:?
(B~ removin~ the blocking group P from the product of
step (A) under mild conditions such as hydro~enation
or by hydrolysis with a molar equivalent or base,
e.~., an alkali metal hydroxide, to produce a co~-
pound of the formula
O
~N-CH2(A)m( C~)nC2
. ~ Il~
(C) contacting the product of step (B) with a sub
stantially equimolar amoun~ of an unsaturated
. ~etone having a formula selected from the group
. consisting of 0
- . (1) CH2-C~l-C~CR4R5(CII~)pQ and
(2~ C~I-C-C-CR4~5(CH2)pQ to produce
a product having a formula elected :~rom the ~roup
conslsting Or
- 123 ~
o
CH2 ( A ) rll ( C~I2 ) nC-02R
\~ - CI12- CHRl - C CR4R~ ( CH2 ) Q and
.. . . .
(4~ ~
N-cH2(A)m(cH2)nco2R
\~N-cH=cH-c-cRL~R5(cH2)
, . o
. (D)(a) reducing the keto group o~ the product Or
step (C)(3) to give the corresponding alcohol
of the formula
-CH2(A)m(C~)"co2R.,,
N~CH2C~IRl-CH-CP~4R5(CH2)pQ or
OH .
(b) reducing the keto group and the con~ugated
ethylenic group of the product Or step (C)(4)
. to give the correspond~ng alcohol o~ the
formula
(6)
~ N-CH2(A)m(C~2)nc02R
- ~ ~-cH2cH2~cH-cR4R5(cH2)pQ
OH
wherein the values for R, Rl, R4, R5, A, m,
n, p and Q are as stated above.
To produce a compound in ~lhich Y=~, Z=H~, Rl=R3-R4=
R --H, and R2 is other than h~drogen, the ketone compound
O
2(A)m(C~I2)nC02R
-CI~2-CH~l-C-CR4R5(CII2)pQ
- 1~4 -
1~'475Q3
i~ react~ with a me~l nydroc~rbyl con~p~und such as a
Gri~nard rea~ent R~X, or an alkyl lithium cor.lpound, R2Li
- to.~ive the alcohol
. O
~N-c~I2(A)m(cH2)nco2R
\~N-CH-CHRl-CR2C~4~5(CH2)pQ. ' '
OH
To prod~ce a compound in which Y=O, Z-H2 and
R3 is ot~ r than hydrogen~ a hydroxy compound ~;elected
fro~ the group
O
/I~N-cH2(A)m(cH2)nco2~
N-CH2CHRl-CH-C~4R5(CH2)pQ,
OH
N-C~2(A)m(cH2)c02p~
` . ~ N-CH2CH2-CH-CR4R5(CH2)pQ, and
0
~ N-cx2(A)m(c~2)nco ~
\~ N-CH2-CHRl-CR2-CR4R~- (CH2)pQ
OH
- is reacted ~itn an acylatin~ compound havin~ the ~ormula
R3X or (R3)20 in which R3 is an alkanoyl group of 2 to 4.
carbon atoms and X is chlor~ne bromine or iodine. The OH
group is thus eonverted to the e&ter group oR3.
m e compounds ~herein Z=O, Y=~I2 and R2-R3=H
are obtained by e~entially the ~rne reac~ ons except that
the ~equence of steps (B) and (D) a~ove are reversed;
- 125 - ~
`~Q47503
that is, a 3-pyrazolidinone oP step (A) abov~ is reacted
wi.~h an unsaturated ket~ne of ~tep (D), removin~ the
bl.ocl;ing ~roup and then reacting with omega-halogenat~d
carboxylnte o~ step (B).
. The above compounds where R2 is other than
~ydrogen are obtained by reacting the corresponding ketone
compounds ~ith a metal hydrocarbyl compound as sho~n with
the compounds where Y=0 and Z-H2.
. Likewise, the above compounds ~Jhere R3 is
other thall hydro~en are obtained by reactin~ the corres-
pondin~ hydroxy compound ~ith an acylating a~ent, in the
same fashion as those compounds where Y=0 and Z--H~.
A compound wherein Y-Z=H2 is obtained by the pro-
ces~ which comprises
(A) treating pyrazole at 20-150C. with an equimolar
amount o~ an unsaturated ketone having ~ne Iormu
CH2-CRl-C-CR ~5(CH2)pQ
O
to produce a mono N-alkylated pyrazole of the
formula
~ N
~ N -CH2-CRl-C-CX ~ 5(CH2)pQ
(B) reducing the keto group o~ the product of step (A),
(Cj heatin~ the product of step (B) with a compound
o* the formula
XCH2(~)m(CH2)nC2R
wherein X i~ chlorine, bromine or iodine to ~ive
a pyrazolium salt of the formula
N -CH2(A)m(CH2)"co2R X~
N-CH2-CH~lCHCR4~5(CH2)pQ
OH
- 126
~475Q3
(D) reducin~ ~he pyra~olium salt Or step (C) to ~ive
an N,N'-disubst~tute~ pyrazolidine, and
(.~) o~tionally ncylating the OH group of the product
of step (D) with an acylatin~ agent selected from
the group consistlng o~ R3X ~n~ (~3)20 as ~tated ~bove
Compounds Or the formula
N _ CH2(A)m(Cll2)nc02R
--CH2CHRlCR~CR4R5(CH2)pQ,
0~ , .
~herein R2 is other than H are obtained by reacting the N-
alkylated pyrazole of step A with a metal hydrocarbylsu~h as
.O a ~rignard reagent or an alkyl lithium in place of step B
~olloued by heating the reactlon product as in step C with
a h~locarboxylate followed by step D and optionally acylation
as in E.
Compounds of the formulas
7- CH2(~ 3 m(CH2)nC2R and
I~H
N-C~2CX~lCR2CR4R5(CH2) P
NH oR3
~herein the values for ~ ~ A, ~, R , R2, R3, R4, R5, m,
n~ p and Q are as previously stated, are valuable inter-
mediates to the end products of the invention.
The halocarboxylates have the generic s~ructure
- XCH2(~)mtC~2) CO2X wherein ~ is a chlorine, bromine or
iodine and A, m, n and ~ have the values prevlously
~ted.
.
- 127 -
~ 3
Some of these e~ters are commercially available,
other~ can be made from the corresponding omega-bromo
acidls and the appropriate alcohol u~ing conventional methods
for esterification (see ~or example C. Buehler, D. Pearson,
Surv~ey of Organic Synthesis, Wiley-Interscience~ N.Y.
1970, Chap. 14).
n XCH2(CH2)nC02R
O methyl iodoacetate
1 ethyl ~ -bromopropionate
2 t-butyl 4-bromopropionate
2 t-butyl 4-chloropropionate
2 ~-chlorobenzyl 4-bromobutyrate
3 methyl 5-bromobutyrate
3 n-octyl-5-bromovalerate
3 i~o-octyl-5-chlorovalerate
4 isopropyl 6-bromohexanoate
4 valeryl 6-bromohexanoate
4 tert-butyl 6-bromohexanoate
ethyl 7-bromoheptanoate
t-butyl 7-iodoheptanoate
cyclopentyl 7-bromoheptanoate
cyclohexyl 7-bro hoptanoate
3-phenylpropyl 7-bromoheptanoate
n-dodecyl 7-bromoheptanoate
6 t-butyl-8-bromooctanoate
The iodo esters are made by Finkelstein-halide inter-
chan~e (~uehler and Pearson, ibid., page 339) (NaI in
acetone~ with the corresponding bromo ester or~ the bromo
- 128 -
7503
esters c~n be used directly for tlie preparation Or t~le
2-alkanoa~e derivatives in the presenc~ Or sodi~m iodide,
which ~enerates the more reactive iodo ester in situ.
~e bro-mo esters also alkylate 1 of ~ample 1 in the
absence o~ sodium iodide, but more slo~lly. Dimethylsul-
foxide can be used as the solvent, but hexamethylphosphoric
tr~amide (~ )is preferred when there i~ a protective
~roup present that is to be removed by hydro~enolysis in
. the next step.
The acids XCH2(C6H4)(CH2)nC02H are prepared
by chloromethylation or bromomethylation of the
-arylalkanoic acids.
~ (CH2? CO ~I HX, CH
.
XCH2~ ( C~H2) nC2H +
~3 ( CH2) nC02~I
CH2X
CH2X
Mixtures of the o, m, and p-isomers are produced by
these reactions /~. N. Nazarov et al., ~ull. Acad. Sci.
USSR, Div. Chem. Sci. 103 (1957~7 and the preferred
~-~somers are readily isolated by fractional crystalliza-
tion. From the mother liquors of such crystallizations
the corresponding ortho and meta isomers can be isolate~
by column chromatography or, ln the case Or their methyl
- 12g _
~47S03
ester deriv~ives, by preparative ~as chromatosraphy.
Chloromethylation is best carried out itl the
pre~ence o~ zinc chloride (see G. A. Olah and W. S.
Toly~yese in Olah, Friedel-Crafts and nelated Reactions,
~ol. I~ part 2~ Chapter XXI, Interscience, l964). The
benzyl chlorides are readily converted to the correspond-
ing benzyl lodides by the action o~ NaI in acetone.
Althou~h bromomethylation is reported to ~ve
less satis~actory yields than chloromethylation (Organic
Re~ctions, Vol. I, Chap. 3, p. 72, Wiley and Sons, N.Y.
1942), in the case of the ~-phenylalkanoic acids, bromo
methylation has been found more convenient. m e benzyl
bromides obtained are better N-alkylating agents than the
Gorresponding benzyl chlorides, and ~hey need no~ be con-
verted to the correspondina relatively unstable benzyl
iodides before reaction ~ith amines o~ type 4. Better
yields of bromomethylation products are obtained ~hen the
reactions are carried out ln the absence of added zinc
salts.
The w- halomethyl alkanoic acids can be con-
verted to ~heir allcyl esters for example by reaction ~ith
diazoalkanes in ether or by Fischer (acid catalyzed) es-
~erification ~ith alcohols
~( CH2) nC02~ ~N2 !~-
XCH2
XCH2 ~ ( CH2) nC2R
~(C~2)nC
XC~2
- 130
lQ475(~3
XC112~(C~2)nC2~ .
In the latter c~se yields are increased by using an
excess of the alcohol and a drying agent~ e.g., 3~ or
4A ~olecular sieves, can be used. t-Butyl esters can be
. made from reaction o~` the acids ~lith ~sobutylene in the
presence of sul~uric acid.
Carboxylic containin~ moieties wherein A is
C-C and CH=CH (i~e., m=l) are obtainable as follows.
By using ho~olo~s o~ the kno~n acetylenic ester methyl 7-
iodoheptynoate XCH2~_C(CH2)nC02CH3, X - I, n = 3, R = CH3)
erdinandi and Just, Can. J. Che~. 49, 1070 (1971)7 the
2-substituted pyrazolidinone ace~ylenic and ethylenic
analogs can be prepared. Starting with an ester o~ ~he first
column belol~l gives by the analogous sequence o~ reactions
a corresponding acety]enic ester of the second column
below, where the halogen is either bromo or iodo depend-
ing on whether the metal halide is LiBr or ~aI.
.
Ester Acetylenic ester
.
20n--l ethyl ethyl 5-halopent-3-ynoate
bromoacetate
n=2 ethyl 3- propyl 6-halohex-4-ynoate
bromopropionate
n=3 ethyl 4- methyl 7-halohept-5-ynoate
bromobutyrace
For the synthesis o~ ethyl4-halobut-2-ynoate,
~he case ~lhere n is 0, the following synthetic sequence
can be used, ~tarting with ethyl propiolate.
- 131 -
.
~Q475Q3
~C--C- C02Et C~20 .
H~2
~IOCH2-C-C-C02Et CH3so?
CH3S020CH2C-c- C2
acetone
XCH2C-C- CO 2Et
Acetylenic halosubstituted esters o~ the above
.general structure are used to prepare the acetylenic and
ethylenic analo~s (the latter by re~uction over Ni2B or
the Lin~lar catalyst) by the followin~ sequences of reac-
tions (P is ~ protective group).
- 132 -
æa
~ ~
~T
D C.~
P;c~ ~
O ~
~ ~
~ `
P: + P~
~; ~ ~; ,
O ~
\/ ~
- 133 -
5~3
P; ~
o~ ~ o= ~;~> o~ ~>
~' ~ ~ ~
~ O ~ ~ ~
o- ~ o= ~ - ~>
- 134 -
o ~ o,
O O ~ ~
o~ <~,> - <">
o ~ o
~ '~ C~l C)
n ~ p -
o~ +P:
- 135 -
- \ -
~g~
Lindlar catalyst [H. Lindlar, Helv. Chim. Acta
35, 446 (1952)~ is palladium on calcium carbonate which
has been deactivated by addition of lead acetate and
quinc\line. mi8 catalyst is inacti~e toward hydrogena-
tion of olefins and the hydrogenation of acetylenes over
this material practically stops after absorption Or one
mole of hydrogen. Palladium on barium sul~ate with
synthetlc quinoline is a slmilar catalyst but it ~8
somewhat superior in reproducibility and ease of prepara-
tion ~D. J. Cram and N. L. Allinger, J. Am. Chem. Soc.78, 2518 (1956)~ ~ Both catalysts give olefins of the cis
configuration. Alternatively nickel borlde catalyst
(Ni2B), especially that designated ~-2 CH. C. Brown and
C. A. Brown, JACS 85, 1005 (1963 ~ can be u~ed to effect
catalytic reduction of the acetylenic compounds to cis
olefins. The other reactions indicated above are carried
out analogously to those describcd for the preparations
gi~en earlier.
The cis-ethylenic analogs represented in the scheme
above can also be made by a ~eries of reactions analogous to
those described ln Example 1 using the cis allylic
~-halo ester~ XC~ CH=CH(C ~ )nC02R rather than the saturated
~r-haloalkanoate ester XCH2(C ~ )nC02R. For example, reaction
of pyrazolidinone hydrochloride with ~ -trichloroethyl-
chloroformate give~ "~,~ -trichloroethyloxycarbonyl)-
3-pyrazolidinone (m.p. 151-152) as described earlier.
Treatment of the compound with ethyl 7-bromo-5-heptenoate
(German Offenlegunschri~t 2121361) in the presence of ~odium
carbonate in hexamethylpho~phoric triamide by a procedure
~ 136 -
1tl ~7~3
analogou~ to that described in Example lb, gives 1~
trichloroethyloxycarbonyl)-2(6'-etho~ycarbonyl-2t-hexenyl)-
3-pyrazolidinone as an oil.
O O
<~, C02Etzn ~--\ C02Et
H-C-OCH2CC13 ~ NH
o
me protective group i8 smoothlg removed by treatlng a
solution of this oil in 90% acetic acid with powdered zinc
~t room temperature for 3 hours and then lsolating the
2(6'-ethoxycarbonyl-2-hexenyl)-3-pyrazolidinone through its
water-soluble hydrochloride salt as described in Example lc.
The ~ree P~tne 18 obtained by careful di~tillation under
high vacuum as described in Example 1c.
This amine can then be treated with one equivalent
of l-octyn~3-one in ethanol as de~cribed in Example ld to
give 7 ~ 3'-oxo-1'(3"-oxooct-1"-enyl)pyrazolidin-2'-g ~hept-5-
en-l-oic acid ethyl ester a~ an orange-amber oil.
o
~ N ~ HC-CC0C5811(n)
NH
~/\ C02Et
C5Hll (n )
o
The correspondlng ,mono-unsaturated ketone is
obtained by treating the amine wlth amyl vinyl ketone in
ethanol as descrlbed ln Example Ie-3, glving 7 ~ '-oxo-1'(3n-
oxooctyl)pyrazolidin-2-y ~ ept-5-en-1-oic acid ethyl ester,
a Yi8CoU~ oll which i~ colorless when pure. This oil i8
- 137 -
5~3
reduced by sodium borohydride in ethanol as described ln
Exa~ple le-3, to give alcohol 7~'-oxo~ (3"-hydro~yoctyl)-
pyrazolidln-2'-yl7hept-5-en-1-oic acid ethyl ester.
<~ C02Et H2CSCECC5Hll(n)
O
C N C02Et
N ~ C5Hll(n)
o
NaBH4 ~ N ~ C02Et
\~ C5Hll (n )
OH
~ hl~ e~ter can be converted quantltatively to the
correspondlng sodlum salt of the acid, i.e., 7 ~'-oxo-1'(3~_
hydro~yoctyl)pyrazolidln-2'-y ~ ept-5-en-1-olc acld, sodlum
salt, by treatlng its solutlon in methanol with exactly one
equivalent of 1.0 N sodium hydroxide. Evaporation of the
reactlon to dryness arter standing at room temperature for
several days (under nitrogen) gives the pure sodium salt.
~ ~ C2Et
/ C5Hll(n)
OH
<~ ~02~a+
N ~ C5Hll(n)
OH
~he 3-oxy-aliphatic chain moiety that i8 present
~n the novel pyrazolidones and pyrazolidine~ Or this in-
ventlon are derlved from reaction of a vinyl or acetylenic
ketone with a pyrazolidone or pyrazole having hydrogen on a
- 138 -
1~?4'~ 3
nuclear nitrogen to give a 3-oxo compound. If an acetylenic
ketone i~ used, catalytic reduction Or the latter compounds
over Pd/C or pre~erably Rh/C affords the corre~ponding sat-
urat;ed ketones. Alternatively reduction can be carried out
by using one equivalent of lithium aluminum hydride in
tetrahydrofuran or ether, or by other aluminum hydride~,
for example, by ~odium bis(2-methoxyetho~y)aluminum hydride
in benzene or ether. Preferential reduction of the double
bond instead of the keto group, by catalytic reduction or
lithium aluminum hydride reduction, is typical Or many
"vinylogous amides" (Martin, J. Org. Chem., 31, 943(1966),
WalXer ibid 27, 4227 (1962)).
When N-alkylation i8 effected by acetylenic
ketones of the ~ormula
O
Hc-c-c-cR4R5(cH2)pQ
the resulting pyrazole or pyrazolidone has the group
o
~ -CH=CH-C-CR4R5(CH2)pQ
which upon subsequent reduction of the ethylenic double
bond gi~es the group
o
~N-CH2CH2~CR4R5(CH2)pQ
where~n H has replaced R' of the generic formula.
Suitable acetylenic ketones that can be used ln-
clude those of the above ~ormula wherein R4 and R5 are H
and Q is CH3, e.g.,
p = O ethyl ethynyl ketone
p = 1 ethynyl propyl ketone
p = 2 ethynyl butyl ketone
- 139 -
t~3
p = 3 amyl ethynyl ketone
p - 4 hexgl ethynyl ketone
p = 5 heptyl ethynyl ketone
p = 6 octyl ethyngl ketone
The reduction of the ~ double bond i~ avolded
when vinyl ketones are used in place o~ acetylenic ketones.
Vinyl ketones are generally pre~erred ror the reactlon.
m e~e have the structure
o
H2CzCR'C-CR4R5(CH2)pQ
and include, when Rl = R4 = R5 z H and Q = ~ and CH3,
p = O methyl vingl ketone (Q = H)
p = O ethyl vingl ketone (Q = CH3)
p = 1 propyl vlnyl ketone
p = 2 butyl vinyl ketone
p = 3 a~yl vingl ketone
p = 4 hexyl vinyl ketone
p z 5 heptyl vinyl ketone
p z 6 octyl vinyl ketone
The rirst two ketones are commercially available; the others
are readily prepared by oxidation (e.g., by a Jones'
reagent) Or the corresponding vinyl alkyl carbinols, e.g.,
a~ described above for the preparation Or amyl vinyl ketone
and heptyl vlnyl ketone.
Vlnyl ketones of the preceding ~ormula where Rl is
H, CH3, or ethyl, R4 is H, CH3, or ethyl, R5 is H, CH3, or
ethyl; p i8 o6; and Q i8 CH33 CF2CH3, CF3 are prepared by
a sequence Or reactions represented by the rollowing
equation~, where X is halogen (Cl, Br, or I):
- 140 -
~9
R4 R4 Rl
~C(CH2)pQ + Mg ~ XMgC(CH2) Q CH2=C-CHO
Rl R4 Rl R4
+ ~ I
CH2s=C-CH-C-(CH2)pQ CrO3~ H ~ CH2=C-C-C-(CH2)pQ
OH R5 o R5
Thu~ the Grignard reagent derived from the halo compound
XCR4 (R5)(CH2)pQ is treated with an unsaturated aldehyde
CH2=C(Rl)CHO to give a carbinol that on oxidatlon gives
the vinyl ketone. The starting halo compound~ are either
kno~n or avallable by conventlonal synthetlc method~.
Some typical syntheses Or XCR4 (R5)(CH2)pQ are:
Br(CH2)7CF3 - from reaction of Br (CH2)7C02H and
SF4. (See Example 11).
gr(c~3)2(cH2)5cH3 - from reaction of HBr with
2-methyl 2-heptanol.
I(CH2)6CF3 - from reaction of I(CH2)6C02H and SF4.
(See Example 11).
ClC (CH3)2(CH2)3 CF3 from reaction of the Grignard
reagent derived from CF3 (CH2)3 Br with acetone ~ollowed by
reaction of the resulting tertiary carbinol with HCl.
ICH(CH2)(CH2)2CF2CH3 - from the reaction or 4-
chloro-2-butanone with SF4 to give 2,2-difluoro-4-chloro-
butanone, followed by reactlon of the Grlgnard reagent of
the latter with acetaldehyde and con~ersion of the result-
ing secondary alcohol to the mesylate; treatment of the
mesylate with sodium iodide in acetone gi~es the difluoro-
alkyl iodide.
grCH(C~3)(CH2)3CH3 - ~rom the action of carbon
tetrabromide and triphenylpho~phine on 2-pentanol.
ClC(C2H5)2CH2CH3 - from the action of HCl on tri-
ethylcarbinol.
- 141 -
- - ,
SU3
Conversion of halo compounds such as these to the
Grignard reagents by reaction ~ith magnesium in ether or
tetrahydrofuran, or alternatively to the aIkyl lithium
derivatives, followed by reaction o~ the organometallic
derivative with the ole~inic aldehydes acrolein, methacrolein,
or ethacroleln ~-ethyl-2-propenal (column A ~ gives vlnyl
carbinols whlch are readily oxidized by chromic acld to give
the correspondine vlnyl ketones, of which the following
(column B) are typical.
- 142 -
~7S~J3 ~y~
V
~ C~l
V~ V
~ C~l
l -- V N V ~
I V~ V ~ ~ V ~ ~
~ V C~ V
~ ~ ~ V ~ V~ ~
_~ ~ _~ _ ~ _ _ _ ~ Y
V V C~ V C)
~J ~J C'J N CU N CU Nl N
~ ~ ~ V~ V ~
H
~ ¢1 ~ ~ ~ 0 ~ ~ 0 ~ ~ ~
1~1 h ~rl h O ~rl 0 0 h ~ rl
~: y ~ t~ h O h ~ c~ 0 ~D
Et w ~1 ~ ? 0 ~1 ~I
5: 0 ~ w 0 ~5 w s:: O O
h S ~ ~ h h
~ 0 ~ a) 0 ~ 0 ~ ~ ~
V ~
~_ ~ ~ N ^ V
:~ ~ v v v ~n ~ v ~
V C~l CU ~ C~l ~ V -- -- --
~ t~ V -- C~
o ~ ~ ~ ~ ~ ~ ~ ~ ~ P~
V C~ -- N ~ V C`J
p: V VC~ VC~ ~ V ~ V
O V ~ V ~ ~
~1 `-- V V V V V -- ~ V
w h h h-- rt -- h V h ~1
P: m m P: H V H m H m v
- 143 -
~ ~ ~7 S~3
The vlnyl ketones CH2=CRlCoCR4(R5)(CH2)pQ where
R4 and R5 include fluorine are prepared by two alternate
methods; by reaction o~ the appropriate ~luoroacyl chloride
with ethylene followed by dehydrochlorination (method 1) or
by reaction o~ the appropriate ~luoroaldehyde with vinyl
lithium followed by oxidation of the resultlng carbinol to
the ketone (method 2).
Method 1
Q(CR2)pCR5FCOCl ~ X(cl~2)pcR5FcocH2cH
base, or ~ Q(CH2)pCR5FCC~=C~2
spontaneous
whore R5 1~ H, CH3, or ethyl
me synthesis Or alkgl vinyl ketones by this kind
of process is well known to take place in the presence of
aluminum chloride, stannic chloride, or zlnc chloride. The
-chloroketone addition product readily loses HCl either
~pontaneou~ly or on mild alkaline treatment /Zatch et al.,
J. Chem. Soc. 278 (1948); Colonge and Mostafavi, Bull. Soc.
Chim. France, 6 (5), 341 (1939)7. me fluoroacids from which
the acylchlorides are prepared are either reported in the
literature or easily prepared by methods analogous to those
de~cribed ~or the synthesis o~ closely-related rluoroaclds.
Several general methods for preparing ~-~luoroacids are known
. L. M. Patte~on, et al., Can. J. Chom., ~ , 1700 (1965);
E. Elkirk et al., Compt. Rend. Ser C, 262 (9), 763 (1966);
E. Elkirk, Bull. Soc. Chim. France, 2254 (1964 y. These acld~
are in turn ~moothly converted to the corresponding scyl
chloride~ (for u~e in the Friedel-Crafts addition to ethylene)
1~47SM3
b~ the action of well-known reagents ~uch as SOC12 or PC15
(see for example, Buehler and Pearson, "Survey or Organic
Syntheses", Wiley-Inter~cience, 1970, Chap. 15).
~ Difluoropropionic acid and ~, ~-difluorobutyrlc
acid are examples o~ known ~,d -di~luoroaIkanoic acids. The
d,~ -difluoro alkanolc aclds can be made from reaction of
sul~ur tetrafluoride with the appropriate ~-ketoalkanoic acid
or the ester. I~ the reaction is carried out under mild con-
ditlons, e.g., at about 10~ in CH2C12 solvent in the presence
o~ HF catalyst, the keto group o~ the ~-ketoalkanoic acid is
converted to a gem-difluoro group ~hile the carboxylic acid
group, and to a le~ser extent the ester group, i~ converted
to an acyl ~luoride group. Hydrolysis of the ~,~ -difluoroacyl
rluoride and/or the ~ di~luoroaIkanoic ester, gives the
,~ -difluoroalkanoic acid.
Uslng method 1 the acids o~ column A are converted
through their acid chlorides to the vinyl ketones of column
B.
_ 1. A Col. B
la-C5HllCF2C02H n-C5HllCF2COCH=cH2
n~C4HgC~(CH3?C2H n-C4HgCF(cH3)cocH~cH2
3( 2)3 2 CF3(cH2)3cHEcocH=c~2
CH3CF2CH2CHFC02H CH3cF2cH2cHFcocH=cH2
C2H5CF2C02H C2H5CF2COCH=cH2
Method 2
mi~ ~ynthe8iB 0~ fluoroalkgl vinyl ketones can be
repre~ented by the follo~ing equations:
5CHo CH--CH2 Q(CH2)pCER5CHCH--CH2
OH
CrO3 ,> Q (CH2 )pCFR5CCH=CH2
o
145 -
t~33
The ~tarting ~luoroaldehydes Q(CH2)pCFR5CHo can be made by
- convlentional methods of organic synthesis. For example,
reduction Or fluoroaIkanolc acids with LiAIH4 with NaAlE
(OCH2CH20CH3)2 provides the aldehydes (or their hydrates).
Other methods for making ~-fluoroaldehydee are known (e.g.
J. Cantacuzine and D. Ricard, Bull. Soc. Chim. France,
1967(5), 1507; F. L. M. Pattison, loc, cit.), and in some
ca~es the~e methods are more convenlent than reductlon of the
fluoroalkanoic acids.
Using the vlnyl lithium method of method 2 the
aldehydes of coll~mn A are converted in two steps to the vinyl
ketones o~ column B.
Col. A Col. B
n~C6H13CHFCH C6H13CHFCcH=cH2
CE3CH2CF(Et)CHO CH3CH2CF(Et)nCCH=CE2
o
CF3(CH2)4CH CF3(CH2)4,c,cH=cH2
o
The 3-hydroxyaliphatic molety Or the N,N-substituted
pyrazolidine or pyrazol~done is obtained after reactlon of
the monosub~tltuted pyrazole or pyrazolidone with the vinyl
ketone
CH2=CRl-C-CR4R5(CH2)pQ
o
to give the grouping
-CH2-CHRl-2-CR4R5(CH2)pQ
o
attached to nuclear nitrogen. m e carbonyl of the latter can
be reduced to hydroxyl or reacted with a 1 to 2 carbon metal
- 146 -
1~47S(~3
hydrocarbyl to form the
GH C~lCR2C~41'5(CH ) Q -
OH -
group. The hydroxyl can then be acylated ~s set out ~bove
with lower alkanoyl h~lides or anhydrides to ~ive the
CH2-CHRlCR2CR4R5(CH2)pQ
1R3
- moiety~ e.g., with ac~tic9 proplonic~ or n-butyric anhydr~d~s
or acid chlorldes. The reaction is most conveniently carr~ed
out in warm pyridine.
A removable protective group (P), also called
"blocking group" is generally employed in the synthesis
sequence to direct the bonding of a second group to the less
reactive nuclear nitrogen. Particularly useful is the
benzyloxycarbonyl group~ This group of the 2-alkanoate
derivatives can be removed conveniently by hydrogenation in
a solvent such as ethanol over palladium on carbon catalyst
under mild conditions. Alternately the benzyloxycarbonyl
group can be removed by treatment with hydrogen bromide in
glacial acetic acid, but this is less convenient because the
ester grouping of the molecule is hydrolyzed under these con-
ditions. Other protective groups of the klnds well known in
- peptide chemistry can be used for the conversion of pyrazoli-
dinone hydrochloride to 2-carbalko~yal~yl-3-pyrazolidinones.
For example, reaction o~ 3-pyrazolidinone with ~ -tri-
chloroethyl chloroformate (~Jindholz and Johnston, Tet. Letters,
2555 (1~67) under Schotten-Baumann conditions givcs 1~
trichloroethyloxycarbonyl)-3-pyrazolid~none, as follows:
- 147 -
.,
o o
~ ClCOC~2CC13 ~
N~+Cl- H 0 ~ ~ -C-O-CH2CC13
3-Pyrazolidinone hydrochloride, 49.6 g (0.4 mole)
in 400 ml o~ water is stlrred in a crea~ed round bottomed
flask while 42.4 g (0.4 mole) of sodium carbonate i~ added
in portlons. To the resulting solutlon cooled wlth an
ice bath and stirred vigorou~ly with a paddle stirrer i~
added 86.4 g (408 mole) of ~, ~,~ -trichloroethylchloroform-
ate dropwise over 0.5 hr. The reaction mixture i8 stlrred
overnight without cool1ng and the soltd is collected by
flltrat~on. me white ~olid i8 washed thoroughly wlth
water and then with ether-hexane (1:1 v/v) to give after
drying 94 g (90%) of 1-(~ trichloroethgloxycarbongl)-
3-pyrazolidinone; crystallization rrom chloroform (about
350 ml) give~ about 84 g o~ pure material. Another sample
prepared ~lmilarly had mp 151-152.
Anal. Calcd. for C8H7C13N203: C, 27.55; H, 2.70;
N, 10.70; Found C, 27.34; H, 2.64; N, 10.90; ~ma~ (CHC13):
2.95 ~harp (NH) and 5.8 ~ (C=0).
Treatment o~ this co~pound with XCH2(CH2)nC02R gives
the ester. The protective group i8 removed by the action of
zir.c in acetic acid or in hot methanol to give the pyrazoli-
dinone as shown by the equation
O O
N CH2(cH2)nco ~ ~ N C~ (CH2)nC2R
\~NC-OCH2Ccl3 ~/
lQ47503
Another protective ~roup is p-nitrobcnzoyl. ~liS group
cnn bé removed b~ saponification w~th one equivalent of
base. R. Boissanas (Advances in Org. Chem. 3, 175 (1963))
and Fieser and Fieser (Reagents for Organic Synthesis~
Wiley-Interscience, N.Y., ~ols~ I and IIIO describe
a number of other N-protectin~ groups, many of which can
be used for the above conversion.
Removal Or the protective group (P) is accomplishe~
under mild conditions, that is, conditions which remove
the (P) group but do not ~ause other parts of the ~olecule
~o undergo undesirable changes. These conditions include
hydrolysis, hydrogenation, or the use of zinc in acetic acid
~r methanoi at O to 50C. or higher.
The ~ollo~ng scherr.es ~urther illustr~te the
manufacture of both isomcric confi~urations of the
asymmetrical pyrazolidinones of this invention. In these
"P" represents a "Protective Group" and the other variables
are as defined previously with R generally being lower alkyl
or cycloalkyl. The Rl, R2, R3, R4R5 and Q groups preferably
are hydrogen and so specified in these equations.
_ 149 _
7S~3
m~
~ l l O
I ~ ,1 v
. ~1 ~ ^ C
o= ~ $- o ~ o~
v ~ v '~
e I
~ ~ ~ ~C
o~ O ~
o~cl V ~1 o~vl
~1
- 150 -
03
OH
/~\(CH2)1 7CH3
+~cH2 (A)m(cH2)nco2R
E~ F
OH
~ (CH2 ) 1 7CH2
~CH2(A)m(CH2)nc02 M
G
OH
l~ CH2 ) 1-7CH3
~ CH2(A)m(CH2)nC02H
G_~ H
\
OH
~N/\~ (CH2 ) 1-7CH3
N~ CH2(A),~,(CH2)nC02H
H+X
OH
H R~ N /~ ~ (CH2)1-7CH3
3 ,~ \ N _ , +
\,/ ~CH2(A)m(CH2)nC02 NHR 3
- 151 -
~.0475(~3
The preparation o~ the isomeric 3-pyrazolidinones
hav~ne a carboxyllc acid ~ro~p on the 2-position is further
lllustrated~as follo~s. Il~lt represents a "Protective Group"
and the other variables are as defined previously.
.
- 152 - .
lg,.~7~ 3
o~ ~ ~ :~
v p:
~ v --~
:~
~ ~ c~l v
v ~ p:~ -
~: V ~ O
'l:
V 11 5N
~U \ Z~J
0=~ 1 0~ 0
V~
~1 N
0~ P~
~ 0 ~ V~ ~1
¢^ ~ ~ ~
'C~ =
_~; g~ \Z-~
0-~ ¢1 ~ 0=~
- 153 -
~4~SQ3
CH2(A)m(CH2)nc02R
\~+~ (CH2)l-7cH3
OH P
O ~ CH2(A)m(CH2)nC02
\ MOH ~ N
(CH2 ) 1_~CH3
OH Q
,CH2 (A)m(CH2)nC02H
t---- ;~ c
\~/ (CH2)l-7cH3
Q ~ OH R
~ CH2(A)m(CH2)nC02H
\ 2HX ~
~ > ~
H+ ~ ~CH2~1-7CH3
OH
S
R3'N ~ CH2(A)m(CH2)nC02 NHR3
R _ ~ ~ N
(CH2 ) 1-7CH3
OH
Compounds A are made by reactlon of 3-pyra-
zol~dinone hgdroehloride with the appropriate protecting
group reagent e.g. of the kinds well kn~wn in peptide chem-
i~try. The u~e in the ~ynthetic ~equence and the exact
- 154 -
method for removal of the protectlre group (P) will
depend on the nature of PJ but in general groups which can
be removed by reduction or m$1d alkaline hydrolysis are
removed after reaction with the ~haloalkanoate,
XCH2(A)m(CH2)nC02R, or Michael addition of the vinyl
ketone CH2=CRlCOCR ~ 5(CH2)pQ, e.g., CH2=CHCO(CH2)2 6CH3
and reduction of the ketone side chain.
m e choice of protective group P wlll depend
somewhat on the nature of the side chains attached
ln lntermedlates B or L. For example, when the group A
is phenylene, the slde chain Or L has a benzylic-nitrogen
bond that is susceptible to hydrogenolysis. In this case
it ls advantageous to use a protectlve group such as
~ trichloroethoxycarbonyl which can be removed by
reagents that do not cleave the benzylic function, e.g.,
zinc in methanol (cf. Ex. 18). Other nitrogen-protective
groups P that can be used and cleaved, for example, by
treatment with acids, include tertlary butyloxycarbonyl,
tert$ary amyloxycarbonyl, triphenylmethyl ("trityl"),
2~ tritylsulfenyl, ~-toluenesul~onyl, 2~ toluenesulfonyl)-
ethoxycarbonyl, and ~-nitrocarbobenzoxy. The most
generally u~eful protectlve groups are, however, the
"carbobenzoxy" or benzyloxycarbony~ group.
Michael addition of A and M to the alkyl vinyl
ketones can be carried out in alcohol or a nonprotic solvent
such as ether u3ing a catalytic amount of a base such as
hydroxide ion or tertlary amine.
- 155 _
-
1 ~ ~ 7 ~
Reduction of the ketones B and N i8 carried out
wlth a reducing agent ~uch as a boron or alum¢num hydride
that doea not cleare off the protective group before
reducing the keto group. Sodium borohydride i8 preferred
for this purpo~e. If, however, the reduction o~ B 1~
carried out with hydrogen over a rhodium catalyst, for
example, hydrogenoly~is of the protective group occurs in
competition with reductlon of the carbonyl group and reduc-
tive cycloalkglation occurs to give
o
\ ~ N - ~
(CH2)pcH3
Amine D, obtained after removal of the protectlve
group from C, 18 then N-aIkylated with the appropriate
halogen compound XCH2(A)m(CH2)nC02R, where X is chloro,
bromo, or iodoJ and R is as previously derined but
preferably is an alkyl group of 1-12 carbon atoms.
AIkglation of D proceed~ alowly at room tempera-
ture, although elevated temperaturea (50-125U) are pre-
~erred~ The alkylation can be run in ethanol, but the
preferred solvent is tetramethylenesulfone. The pre~ence
o~ a base, such a3 NaHC03 or Na2C03, increases the yield
of alkglation product E.
Alkylation product E conveniently 3eparated
from by-products, e.g., unchanged halo e~ter or olefinic
ester resulting from dehydrohalogenation of the halo
ester, by precipitating it from ether a~ the hydrochloride
- 156 -
~ 7 ~3
salt. E can be rege~nerated by treatment with aqueous
NaHC03 and be converted to a new salt F, e.g., by treat-
ment with maleic acid or perchlorlc acid, or it can be
hydrolyzed to a carboxylate salt G with one equivalent
o~ an alkali metal hydroxide. G can in turn be converted
to the free acid H (inner salt) by neutralization to pH 6
in an aqueous system, or on ~urther acidlfication it can
be converted to J, the HX salt of the carbo~ylic acid.
If R i8 tert-butyl, E can be converted to the corre~pond-
ing acid or hydrohalide salts of the acid by treatment with
one or more equivalents of strone acld HX in water or
chloroform. Amlne salts can be prepared by reaction of
the aclds H with pharmaceutically acceptable amines.
By using homologs of the acetylenic ester
methgl 7-iodohept-5-ynoate XCH2C_(CH2~C02CH3; X = I, n =
3, R = CH3) @erdlnandi and 7ust, loc ~ the l-substituted
pyrazolldlnone acetylenic and ethylenic analogs can be pre-
pared. ~he preparation oi these esters where n i8 1-3 is
given previou~ly.
N-Alkylation of the amines "D" by XCH2(A)m-
(CH2)nC02R to give E can be carried out in the absence
oi solvents, or ln solvents such as ethanol~ dimethyl-
formamide, or hexamethylphosphoric triamide. However,
ior thi~ purpose tetramethylenesulfone gives good re-
sults particularly at room temperature or at ~lightlg ele-
vated temperatures, e.g., 50-110, and in the presence of
proton acceptor~ such as NaHC03 or Na2C03. Compounds D and
E are conveniently purified by precipltation irom ether as
their hydrochloride salts. m e iree amines E and 0 are re-
generated by treatment with aqueous base, e.g., NaHC03.
- 157 -
Saponlfication of the ester~ E and D is carried out in the
pre~ence of one equivalent Or aqueous base MOH, where M
i8 generally an alkalt metal, to gSive the carbox~late salts
G ~d Q which in turn can be converted to acid (inner salt)
H or R, or the acld hydrohalide J and S by treatment with
one or two equivalent~ or a halogen acid, HX. In addition
to the HCl salt~ other pharmaceutically acceptable acid
addition salts such as the ~ulfate~ phoæphate, acetate,
citrate, tartrate, etc. can be prepared by using
the appropriate acid. Treatment of H and R wlth a
pharmaceutically acceptable amine such as tris(hydroxy-
methyl)aminomethane or triethanolamine gives the amine
salts K and T.
m e N,N'-disubstituted pyrazolidines de~cribed
are made by the ~ollowing sequence of reactions.
' ~ CH2=C - C-C-(CH2)PQ ~ ~ Rl R4
NH Rl o R5 ~ (CH2)pQ
o
N Rl R4
~ N ~ (CH2)pQ
R MgX ~
(CH2)pQ
OH
-
t~3
$ N R ~ XCH2(A)m(CH2)nC2R
R CH3CN,
OH
(R = H or C~3, C2H5,
CH=CH, or C_CH)
N~ m 4 n 2 NaBH4 ~ N~ 2 m 2 n 2
( 2)p ~ ~ (CH2)pQ
OH
alkanol CH2(A)m(CH2)nC02R
chlorlde ~ N Rl R4
pyridine ~ N ~ (CH2)pQ
The compound~ of this invention are sur~actants
(emulsifying agents or deterg~nts) in acidic, neutral, or
basic aqueou~ system~ by virtue of their polar carboxylic
and amine runctionalitles combined with lypophilic hydro-
carbon chains. In dilute acid, the ~ne function rorms a
water soluble ~alt, permitting dissolutlon of even the ester
form of these compounds. me alkali metal or amine salts Or
the carboxylic acids are compati~le with and soluble in weakly
basic aqueous solutions. me carboxylic acids themselve~ are
essentially neutral because they exist as inner salts with
the amine portlon of the molecule and these inner salts are
slightl~ soluble in water under condltions of neutral pH.
Compouna 8 of part (g) of Example 1, i.e., the
sodium salt o~ 7/~'-oxo-1'-(3"-hydroxy-n_actylpyrazolidin-2'-
y ~ eptanoic acid (also named as the sodium salt if 8,12-
diaza-9-keto-15(~) hydroxyprostanoic acid) has prostaglandin-
like activlty. For example, stimulation o~ rat ileum (smoothmuscle) occurred when the concentration of the compound was
above about 50 micrograms per ml of perfusion bath with
~ 7 ~3
rhythmic pulses Or contraction each 2-3 seconds. Acetyl-
choline (10 ~ ) induces strong contractlon which ri e~ to a
maximum tension in 2-3 seconds and maintains that tension
for one to ~everal second~ before relaxing. When the above
described pyrazolidinone derivative is employed with acetyl-
chollne, the tension falls to half the peak value ~nd remains
there for a long period. m is effect has been reported for
prostaglandins P OE , and PGF2a by Horton, British Journal of
Pharmacology 24, 472 (1956). me smooth muscle stimulation
by prostaglandins is also discussed by J. E. Pike, et al.,
in "Prostaglandins", Nobel Symposium No. 2, S. Bergstrom
and B. Samuelsson, ed., Interscience, STockholm, 1967,
p. 161. The stimulation of smooth mu~cle by this diaza-
pro8tanoic acid i8 not inhibited by compounds which block
receptors rOr neurotransmitters when such compounds are used
at concentrations which are su~ficient to block neurotrans-
mitters. At much higher concentrations, however, some of
the neurotran~mitter blockers will block the effects Or the
diazaprostanoic acid.
Compounds 9c and 29 have smooth muscle stimulat-
ing properties s~mllar to those of compound 8, although 9c
i~ more potent than 8.
Lowering of blood pre~ure is also typical of
prostaglandins, especially the prostaglandins of the E
series (Pike, loc cit) and A serie~ (J. Lee, et al., in
Ann. N.Y. Acad. Sciences, Vol. 180, Ramwell and Shaw,
N. Y. Acad. Sciences, 1971, 218). When compound 8
is admini~tered by intravenous in~ection to anesthetized
DOCA ~desoxycor~icosterone acetate treated) hypertensive
rats, the ED30 i8 0.2 mg/kg., where ED30 is the dosage
- 160 -
~75U3
neces8ary to lower blood pressure in a group of rat~ by
the mesh value of 30 mm of mercury.
Some of the esters are prostaglandln antagonists
in in vitro tests employing ~trlps of rat uterus. For
example, a concentration of 80 ~g/ml of ethyl ester 17
causes a 50% inhibition of the contraction caused by a test
dose of a natural pro~taglandin, either PGEl or PGE2. The
test dose of the natural prostaglandin is adJusted to the
concentration required to give about 75% maximum stimula-
tion of the smooth muscle. Under similar conditions the
corresponding t-butyl ester 21 causes 50% inhibition at
40 ~g/ml. Generally the compounds having a phenglene group
(A~C6H4) are prostaglandin antagonlsts. The methyl ester
30 causes 50% lnhlbition at 50 ~g/ml and eqter 31 requires
60 ~g/ml. Methyl ester 33 and the corre~ponding acid 35a
cause 50% inhibltion at concentrations of 25 ~g/ml. The
methyl ester hgdrochloride 37 causes 50% inhibitlon at 15
~g/ml. and the acid ~ at 75-80 ~g/ml. Ester 40 causes 50%
lnhibition of the rat fundus muscle at about 80 ~g/ml.
The metal salts and amine salts of these car-
boxyl~c acids have biological properties very simllar to
those of the corresponding acids.
Pro~taglandins appear to be involved in inflamma-
tion, fever and pain processes. A~perin, for example,
apparently exerts its favorable drug effects on such proces-
ses by vlrtue of its ability to inhibit the ~ynthesis of
prostaglandins in vivo. Prostaglandin antagonistic
activities are thererore recognized as being of potential
value as anti-infla~matory agents or antipyretics or anal-
ge~ics or for the treatment of so~e forms of diarrhea or
shock.
- 161 -
- ~t~475Q3
-Some of the ~sters and acids Or ~his invention
inhibit or prevent experimentally-induced ulcers in rats.
Th~ acids, their metal or amine salts and their
hydrohalide salts, have Qther prostaglandin-lik~ properties.
Salt ~ at 25~u~/ml has smooth muscle stimulating activity
in vitro on rat uterus; at lower concentrations it sensitizes
the muscle to~-ard the stimulatin~ effects of prostaglandin
El. Salt 52 lnhibits ep~nephrine-induced lipolysis in
rat fat cells.
Prostaglandin-like compounds are well recoOnized
~or their pharmacological value, e.g., as nasal dec~nges-
tants, bronchodilators, abortifaclents, labor inducers, anti-
hypertensives, etc. For example, the compounds sho~ potential
Yalue as bronchodilators. Guinea pi~s were placed in a closed
chamber ~hich had been sprayed for 60 seconds ~ith a 0.2%
~2 mg/ml) histamine diphosphate solution. At the onset of
respiratory distress a~ convulsions the animal was removed
- from the chamber and the time recorded æs the control time.
Only animals ~Jith a control prostration time in the range of
32-110 seconds ~ere used in the test. After a 4 hour
-;~ recovery period the animals ~ere exposed in a second cha~ber
to test compounds for 2 minutes and allowed an additional 1
minute in the chamber before being exposed a~ain to the
histan;ine aerosol in the first chamber~ The onset of res-
- pirator~ distress and convulsions o.n second exposure to
histamine ~as recorded as the test time "Protection" was
~alculated as the test time divided by control time. The
data are presented in Table VIII.
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_ 163 - .
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5~3
The relatlonship of prostaglandin-like or antago-
nist properties can be dependent on concentration, e.g.,
salt 7 in the rat uterus has prostaglandin antagonist
actlvity at 50 ~g/ml but at concentrations greater than
75 ~/ml mimics the action Or prostaglandin E2. Usually
the acids and salts Or the compounds of this invention are
prostaglandin mimics while the esters are prostaglandin
antagonists.
The compounds of this invention can be ~ormulated
lnto the usual pharmaceutical dosage forms for administra-
tion to humans and animals by any of the kncwn routes, e.g.,
nasal, oral, parenteral, anal or topical application. The
compound3 can also be iormulated in polymeric matrices for
sustained release. Particularly use~ul are W odegradable
polymer matrices, such as homopolymers of lactic acid or
glycolic acid, mi~ture~ thereof, or their copolymers. These
drug-polgmer compositions can be inJected as small particles
in suspension, implanted as pellets, or sprayed on skin or
lesions as films. The active component is then released
~lowly and the polymer~ are degraded to physiologically
normal substance~.
- 164 -
