CA1047503A - 3-pyrazolidinones and pyrazolidines - Google Patents

Abstract

ABSTRACT
3-Pyrazolidinones and pyrazolidines of the formula

Description

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 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

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

o CN~( CH2 ) 6C2_BU
N-~ -OCH20' 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 \=/

o ~(CH~)6C2C(CH3)3 NH + C02 + ~CH3 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, 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) -/\ ~ ( CH2 ) 6~otBu H2 n-C5Hll EtOH

-(CH2)6COtBu NaBH4 -C5 ~ 1 EtOH

~ ( CH2 ) 6C02tBu \~11n-C5Hll -(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.

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 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 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.

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

~, _ 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.

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. . ~ ' 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-(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 ~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.

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 O OH
ll l N ~ Zn N~ 8-OCH2CX3 X = Cl ( ~ or H ( O OH
~\ ~/\/
\~

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 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~
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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 '!
.... . .~ . .. . .. _ _ ., _ . ,~ _ . _ . _ .. ~ . _.. ~ . .. _ .. _ _ _ _ __~, _ _~, . _ _ _, , ~ , , 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 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~.

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 >

O OH

~C-~Na Il , 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.

~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.

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~047~Q3 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~
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~/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.

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

O OH
~ ~ B tCH ) C t .

O pH
N ~
N ~ . COt-Bu .
o 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~

_.

~(~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 - , .

- ~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.

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O
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` ~ / CO~tBU
N ~ /
OH

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 ', ' ' ' ' ' ' ' 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.

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~

: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.

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t~' ' ' ~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

-- .

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, ~ 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 . 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 ?~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.

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 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.

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~

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 ~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~

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 ~ , . .

1()47503 pH
~ N
- Nn C0~
N ~ CH2C02~a , ~ 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 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 O OH
2 3 ~ CN ~ ~ HC1/Et20 H2 N\~-- ( CH2 ) 2C02CH3 O OH
tl t \~N~ ( CH2 ) 2C2CH3 Cl Na2G3 O OH
O~~ HCl \~N~3 ( CH2 ) 2C02Na O OH

~ ( CH2 ) 2C02H
35a 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 .

.)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).

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 n t /\ W V~
\ ~ N ~ NaOH
H+ ~ ( 2)3 2 H3 >

O OH
n /\'--~

O OH ~ \~ ( CH2 ) 3co2Na ~\N ~/\ 38 ~_ ( CH2 ) 3C02H

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 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 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.

~g~7~3 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 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.

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~

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;

~ 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

( CH2 ) 2C02Na ~ ,~/
OX ~6 ~ 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.

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, A) N(3-oxo-n-octyl)pyrazole (47) and N(3-hydroxy-b-octyl)-p~razole (48~
O
~ N~ 11 ' ~ CH2=CHCC5Hll(n) EtOH

i~ ~'7~3 N
N

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 ~;

~ 3 CllH20N20 196.1575, meaæured 196.1573.
B) N-(6-carboethoxy-n-hexyl)-N'(3t-hydro~y-n-octyl)-razolium iodlde (49) (CH2)6C2 <~ ~ C02Et H

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

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 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 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.

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~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

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.

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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 ~ 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

~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.

.

~ 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 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

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 ~ ( CH2) nC2R

~(C~2)nC
XC~2 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.

.

~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).

æa ~ ~

~T
D C.~

P;c~ ~
O ~

~ ~
~ `
P: + P~
~; ~ ~; , O ~
\/ ~

5~3 P; ~

o~ ~ o= ~;~> o~ ~>
~' ~ ~ ~
~ O ~ ~ ~

o- ~ o= ~ - ~>

o ~ o, O O ~ ~

o~ <~,> - <">

o ~ o ~ '~ C~l C) n ~ p -o~ +P:

- \ -~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 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 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 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):

~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.

- - , 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.

~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 ~ ~ ~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 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 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

- 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:

., 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 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 ~.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:

~U \ Z~J
0=~ 1 0~ 0 V~

~1 N
0~ P~

~ 0 ~ V~ ~1 ¢^ ~ ~ ~
'C~ =

_~; g~ \Z-~
0-~ ¢1 ~ 0=~

~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 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 ~ 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.

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 ~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.

- ~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.

..~

.. ~ ..
. ~ ~ N
~' h o ~1 ~ o ~
P ~' V
~ I~ .
. ~ ~ `N ~ h~
~ X ~7 ~Q Xl~ u~
x :~, 'o ~ o I ~1 O h~
I
rt ~ S I ~ ,S: ~ ~I S C~
O l ~:: O l O ~ l ~ O l l O
a) X ~ ~ o u~
h O X
~) ,Q O aJ I ~ ~` I O ~ I ~ ~
O ~3 0 c~ ~CS rl r~l ~ rl ~-1 t~ ~ ~1 0 C,) P~ ~ ~I V ~ I S ~ c) 1 5~ I N cd ^
~ ~4 P~ I S ~1 0 +~ C~ ^ O ~, ~ O C~
C> O ~0 I ~ X I C~ X P, C~a: ¦ X h C~ G~l U~ ~~~ O O '~ J O ~r~ O ~-r~
' ~ I ~ O ~ I p~ O

O ~ O ~ C~ p, o ~ V ~:: IS ~

.

_ 163 - .

`
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~.

Claims (76)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound selected from the group consisting of (a) a compound of the formula wherein A is CH=CH, C?C, or C6H4;
R is E, alkali metal, amine salt, alkyl, or cyclo-alkyl each of up to 12 carbon atoms;
m is 0 or 1;
n is 0 to 6;
p is 0 to 6;
Y and Z are O or H2, with the proviso that where one is O, the other is H2;
R1 is H, CH3 or C2H5;
R2 is H, CH3, C2H5, CH=CH2, or C?CH;
R3 is H or alkanoyl of 2 to 4 carbon atoms;
R4 is H, F, CH3 or C2H5;
R5 is H, F, CH3 or C2H5; and Q is H, CH3, CF2CH3 or CF3; and with the provisio that R1, R4 and R5 are each H when R2 is other than H; and (b) a salt of (a) with a pharmaceutically acceptable acid, said process being selected from the group consisting of (A) a process for the preparation of a compound wherein Y=O, Z=H2 and R2=R3=H which comprises the sequential steps of (i) contacting a 3-pyrazolidinone of the formula wherein P is a blocking group with a substantially equimolar amount of an omega-halogenated car-boxylate of the formula XCH2(A)m(CH2)nCO2R
wherein X is chlorine, bromine or iodine, in the presence of a base and solvent at 0-150°C
to produce a compound of the formula (ii) removing the blocking group P from the product of step (i) under mild conditions such as by hydrogenation or hydrolysis at 0-50°C to produce a compound of the formula (iii) treating the product of step (ii) at 0-100°C, in the presence or absence of a solvent, with a substantially equimolar amount of an unsaturated ketone having a formula selected from the group consisting of (1) and (2) to produce a product having a formula selected from the group consisting of (3) and (4) , and (iv) reducing the keto side chains of the product of step (lii) to give an alcohol of the formula selected from the group (5) and (6) (B) a process for the preparation of a compound wherein Y=O, Z=H2, R3=H and R2 is other than H which comprises contacting a compound of the formula with a metal hydrocarbyl compound selected from the group consisting of Grignard reagents R2MgX and lithium alkyls R2Li to give the alcohol (C) a process for the preparation of a compound wherein Y=O, Z=H2 and R3 is other than H which comprises contacting a compound having a formula selectled from the group consisting of , and with an acylating compound selected from the group consisting of R3X and (R3)2O in which X is chlorine, bromine or iodine, and recovering a compound in which the OH group has been con-verted to -OR3.
(D) a process for the preparation of a compound wherein Z=O, Y=H2 and R2=R3=H which comprises the sequential steps of (i) contacting a 3-pyrazolidinone of the formula wherein P is a blocking group at 0-100°C with a substantially equimolar amount of an unsaturated ketone having a formula selected from the group consisting of (1) and (2) to produce a pro-duct having a formula selected from the group (3) and (4) , (ii) removing the blocking group P from the product of step (i) under mild conditions such as by hydrogenation or hydrolysis at 0-50°C to produce a product where the P group is replaced by H, (iii) contacting the product of step (ii) with a substantially equimolar amount of an omega-halogenated carboxylate of the formula XCH2(A)m(CH2)nCO2R
wherein X is chlorine, bromine or iodine, in the presence of a base and solvent at 0-150°C to produce a compound having a formula selected from the group (5) and (6) , (iv) reducing the keto side chains of the product of step (iii) to give an alcohol having a formula selected from the group (7) and (8) (E) a process for the preparation of a compound wherein Z=O, Y=H2, R3=H and R2 is other than hydrogen which comprises contacting a compound of the formula with a metal hydrocarbyl compound selected from the group consisting of Grignard reagent R2MgX and lithium alkyl R2Li to give the alcohol (F) a process for the preparation of a compound wherein Z=O, Y=H2 and R3 is other than hydrogen which comprises contacting a compound having a formula selected from the group consisting of , and with an acylating compound selected from the group consisting of R3X and (R3)2O in which X is chlorine, bromine or iodine, and recovering a compound in which the OH group has been converted to -OR3.

(G) a process for the preparation of a compound wherein Y=Z=H2 which comprises (i) treating pyrazole at 20-150°C with an equimolar amount of an unsaturated ketone having the formula to produce a mono N-alkylated pyrazole, (ii) reducing the keto group of the mono N-alkylated pyrazole, (iii) heating the sald N-alkylated pyrazole with a compound of the formula XCH2(A)m(CH2)nCO2R
wherein X is chlorine, bromine or iodine to give a pyrazolium salt, (iv) reducing the pyrazolium salt of (iii) to give the N,N'-disubstituted pyrazolidine, and (v) optionally acylating the hydroxyl group of the pyrazolidine from (iv) with an acylating compound selected from the group consisting of R3X and (R3)2O in which X is as stated above and recovering said compound.

2. The process of Claim 1 which is process (A).

3. The process of Claim 1 which is process (B).

4. The process of Claim 1 which is process (C).

5. The process of Claim 1 which is process (D).

6. The process of Claim 1 which is process (E).

7. The process of Claim 1 which is process (F).

8. The process of Claim 1 which is process (G).

9. A compound selected from the group consisting of (a) a compound of the formula of (a) of Claim 1 of record and (b) a salt of a compound of (a) with a pharmaceuti-cally acceptable acid, said compound having been prepared by the process of Claim 1.

10. The compound of Claim 9 in which Y=O, Z=H2 and R2=R3=H, said compound having been prepared by the process of Claim 2.

11. The compound of Claim 9 in which Y=O, Z=H2, R3=H
and R2 is other than H, said compound having been prepared by the process of Claim 3.

12. The compound of Claim 9 in which Y=O, Z=H2, and R3 is other than H, said compound having been prepared by the process of Claim 4.

13. The compound of Claim 9 in which Z=O, Y=H2 and R2=R3=H, said compound having been prepared by the process of Claim 5.

14. The compound of Claim 9 in which Z=O, Y=H2, R3=H
and R2 is other than H, said compound having been prepared by the process of Claim 6.

15. The compound of Claim 9 in which Z=O, Y=H2 and R3 is other than H, said compound having been prepared by the process of Claim 7.

16. The compound of Claim 9 in which Y=Z=H2, said compound having been prepared by the process of Claim 8.

17. The process of Claim 2 in which m=0, n=5, p=4, R=R1=R4=R5=Q=H.

18. The process of Claim 17 in which said process is followed by the step of forming the tertiary butyl ester of the compound so obtained.

19. The process of Claim 17 in which said process is followed by forming the sodium salt of the compound so obtained.

20. 7[3'-Oxo-1'-(3"-hydroxy-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=4, R=R1=R2=R3=R4=R5=Q=H, when prepared by the process of Claim 17.

21. The tertiary butyl ester of 7[3'-oxo-1'-(3"-hydroxy-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y-0, m=0, n=5, p=4, R=R1=R2=R3=R4=R5=Q=H, when prepared by the process of Claim 18.

22. Tho sodium salt of 7[3'-oxo-1'-(3"-hydroxy-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=4, R=R1=R2=R3=R4=R5=Q=H, when prepared by the process of Claim 19.

23. The process of Claim 3 in which m=0, n=5, p=3, R=R1=R4=R5=H, R2=CH3 and Q=CH3.

24. The process of Claim 23 in which said process is followed by the step of forming the tertiary butyl ester of the compound so obtained.

25. 7[3'-Oxo-1'-(3"-hydroxy-3"-methyl-n-octyl) pyra-zolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H, R2=CH3 and Q=CH3, when pre-pared by the process of Claim 23.

26. The tertiary butyl ester of 7 [3'-oxo-1'-(3"-hydroxy-3"-methyl-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H, R2=CH3 and Q=CH3, when prepared by the process of Claim 24.

27. The process of Claim 3 in which m=0, n=5, p=3, R=R1=R4=R5=H, R3=C?CH and Q=CH3.

28. The process of Claim 27 in which said process is followed by the step of forming the tertiary butyl ester of the compound so obtained.

29. 7[3'-Oxo-1'-(3"-ethynyl-3"-hydroxy-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H, R3=C?CH and Q=CH3, when prepared by the process of Claim 27.

30. The tertiary butyl ester of 7[3'-oxo-1'-(3"-ethynyl-3"-hydroxy-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H, R3=C?CH and Q=CH3, when prepared by the process of Claim 28.

31. The process of Claim 2 in which m=0, n=5, p=3, R=R1=R4=R5=H and Q=CF3.

32. The process of Claim 31 in which said process is followed by the step of forming the tertiary butyl ester of the compound so obtained.

33. The process of Claim 31 in which said process is followed by forming the sodium salt of the compound so obtained.

34. 7[3'-Oxo-1'-(3"-hydroxy-8"-8"-8"-trifluoro-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CF3, when prepared by the process of Claim 31.

35. The tertiary butyl ester of 7[3'-oxo-1'-(3"-hydroxy-8"-8"-8"-trifluoro-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CF3, when prepared by the process of Claim 32.

36. The hydrochloride salt of 7[3'-oxo-1'-(3"-hydroxy-8"-8"-8"-trifluoro-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CF3, when prepared by the process of Claim 31.

37. The sodium salt of 7[3'-oxo-1'-(3"-hydroxy-8"-8"-8"-trifluoro-n-octyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=3, R=R1=R4=R5=H
and Q=CF3, when prepared by the process of Claim 33.

38. The process of Claim 5 in which m=0, n=5, p=3, R=R1=R4=R5=H and Q=CH3.

39. The process of claim 38 in which said process is followed by the step of forming the tertiary butyl ester of the compound so obtained.

40. 7 [3'-Oxo-2'(3"-hydroxy-n-octyl) pyrazolidin-1'-yl] heptanoic acid, the compound of Claim 9 in which Z=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 38.

41. The tertiary butyl ester of 7[3'-oxo-2'(3"-hydroxy-n-octyl) pyrazolidin-1'-yl] heptanoic acid, the compound of Claim 9 in which Z=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 39.

42. The hydrochloride salt of 7[3'-oxo-2'(3"-hydroxy-n-octyl) pyrazolidin-1'-yl] heptanoic acid, the compound of Claim 9 in which Z=0, m=0, n=5, p=3, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 38.

43. The process of Claim 2 in which m=0, n=5, p=6, R=R1=R4=R5=Q=H.

44. 7[3'-Oxo-1'-(3"-hydroxyl-n-decyl) pyrazolidin -2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=6, R=R1=R4=R5=Q=H, when prepared by the process of Claim 43.

45. The process of Claim 3 in which m=0, n=5, p=5, R=R1=R4=R5=H, R2=CH3 and Q=CH3.

46. 7[3'-Oxo-1'(3"-hydroxy-3"-methyl-n-decyl) pyrazolidin-2'-yl] heptanoic acid, the compound of Claim 9 in which Y=0, m=0, n=5, p=5, R=R1=R4=R5=H, R2=CH3 and Q=CH3, when prepared by the process of Claim 45.

47. The process of Claim 5 in which m=0, n=2, p=3, R=R1=R4=R5=H and Q=CH3.

48. 4[3'-Oxo-2'-(3"-hydroxy-n-octyl) pyrazolidin-1'-yl]
butyric acid, the compound of Claim 9 in which Z=0, m=0, n=2, p=3, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 47.

49. The process of Claim 5 in which m=1, n=0, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3.

50. p-[[3-Oxo-2-(3'-hydroxyl-n-octyl) pyrazolidin -1-yl] methyl] benzoic acid, the compound of Claim 9 in which Z=0, m=1, n=0, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 49.

51. The process of Claim 5 in which m=n=1, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3.

52. p-[[3-Oxo-2(3'-hydroxy-n-octyl) pyrazolidin-1-yl] methyl] phenylacetic acid, the compound of Claim 9 in which Z=0, m=n=1, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by hhe process of Claim 51.

53. The process of Claim 5 in which m=n=1, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3.

54. p-[3-Oxo-2(3'-hydroxy-n-octyl) pyrazolidin -1-yl] methyl phenyl acetic acid, the compound of Claim 9 in which m=n=1, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when pre-pared by the process of Claim 53.

55. The process of Claim 2 in which m=1, n=2, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3.

56. .beta.-[p-[[3-Oxo-1(3'-hydroxy-n-octyl) pyrazolidin -2-yl]methyl]phenyl] propionic acid, the compound of Claim 9 in which y=0, m=1, n=2, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 55.

57. The process of Claim 5 where m=0, n=3, p=3, R=R1=R4=R5=H and Q=CH3.

58. 5[3'-Oxo-2'-(3"-hydroxy-n-octyl) pyrazolidin -1'yl]pentanoic acid, the compound of Claim 9 in which Z=0, m=0, n=3, p=3, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 57.

59. The process of Claim 5 in which m=1, n=2, p=3, A=p-C6H4, R=R1=R4=R5=H and Q-CH3.

60. .beta.-[p-[[3-Oxo-2(3'-hydroxy-n-octyl) pyrazolidin -1-yl]methyl]phenyl]propionic acid, the compound of Claim 9 in which Z=0, m=1, n=2, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 59.

61. The process of Claim 5 in which m=1, n=3, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3

62. ?-[p-[[3-Oxo-2(3'-hydroxy-n-octyl) pyrazolidin -1-yl]methyl]phenyl]butyric acid, the compound of Claim 9 in which Z=0, m=1, n=3, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 61.

63. The process of Claim 5 in which m=1, n=3, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3.

64. ?-[p-[[3-Oxo-2-(3'-hydroxy-n-octyl) pyrazolidin -1-yl] methyl] phenyl] butyric acid, the compound of Claim 9 in which Z=0, m=1, n=3, p=3, A=p-C6H4, R=R1=R4=R5=H and Q=CH3, when prepared by the process of Claim 63.

65. The process of Claim 8 where m=0, n=4, p=3, R=R1=R2=R3=R4=R5=H and Q=CH3.

66. N-(6-Carboxy-n-hexyl)-N'-(3'-hydroxy-n-octyl) pyrazolidine, the compound of Claim 9 in which Y=Z=H2, m=0, n=4, p=3, R=R1=R2=R3=R4=R5=H and Q=CH3, when prepared by the process of Claim 65.

67. The process of Claim 8 in which m-0, n=5, p=3, R,R1=R2=R3=R4=R5=H and Q=CF3.

68. N-(6-Carboxy-n-hexyl)-N'-(3'-hydroxy-8',8'.8'-trifluoro-n-octyl) pyrazolidine, the compound of Claim 9 in which Y=Z=H2, m=0, n=5, p=3, R=R1=R2=R3=R4=R5=H and Q=CF3, when prepared by the process of Claim 67.

69. The process of Claim 2 in which said process is followed by the step of forming a derivative of the compound so obtained, said derivative being selectsd from the group consisting of an ester and the sodium salt.

70. The process of Claim 3 in which said process is followed by the step of forming a derivative of the compound so obtained, said derivative being selected from the group consisting of an ester and the sodium salt.

71. The process of Claim 5 in which said process is followed by the step of forming a derivative of the compound so obtained, said derivative being selected from the group consisting of an ester and the sodium salt.

72. The process of Claim 8 in which said process is followed by the step of forming a derivative of the compound so obtained, said derivative being selected from the group consisting of an ester and the sodium salt.

73. A derivative of a compound of Claim 9 having Y=O, Z=H2 and R2=R3=H, said derivative being selected from the group consisting of an ester and the sodium salt, when prepared by the process of Claim 69.

74. A derivative of a compound of Claim 9 having Y=O, Z=H2, R3=H and R2 is other than H, said derivative being selected from the group conæisting of an ester and the sodium salt, when prepared by the process of Claim 70.

75. A derivative of a compound of Claim 9 having Z=O, Y=H2 and R2=R3=H, said derivative being selected from the group consisting of an ester and the sodium salt, when prepared by the process of Claim 71.

76. A derivative of a compound of Claim 9 having Y=Z=H2, said derivative being selected from the group consisting of an ester and the sodium salt, when prepared by the process of Claim 72.