DE2323193A1 - PYRAZOLIDINONE - Google Patents

Description

PATENT LAWYERS

DR.-ING. BY KREISLER DR.-ING SCHÖNWALD DR.-ING. TH. MEYER DR. FUES DIPL.-CHEM. ALKK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLOPSCK DIPL-ING. SELTING

5 COLOGNE 1, DEICHMANNHAUS

Cologne, April 27, 1973 AvK / Ax

EGG. du Pont de Nemours and Company, Wilmington, Delaware 19898 (U.S.A.).

Pyrazolidinones

The invention "relates to new pyrazolidinones attached to the ring nitrogen contain various oxygen-containing aliphatic hydrocarbon substituents. the new compounds are prepared by processes in which a selective ΐΓ-2-alkylation of a 3-pyrazolidinone, that at N-1 is a removable blocking group contains, is made.

It is known that 2-methyl-3-pyra £ olidinone is produced ■ can be formed by first forming the 1-benzoyl derivative, then alkylated with methyl sulfate and the benzoyl radical through Acid hydrolysis is removed (Born and Zubeck, Z.Chem. F>, 218 (1968)). The use of other protective devices that after other procedures are removed to 2-substituted It is not yet possible to form groups which have hydrolytically unstable functions, e.g. carbalkoxy groups has been described.

The invention relates to compounds of the formula

309847 / 1U9

Y
VcH ₂ (A) _1n (CH ₂

OH

Ά stands for CH = CH or C = C,

R is a hydrogen atom, alkali metal, amine salt, hydrocarbon or is a chlorinated hydrocarbon residue with up to 12 carbon atoms,

m has the value 0 or 1,

η is a number from 0 "to 6, ρ is a number from 0 Ms 6 and

Υ and Z are 0 or H ₂ with the proviso that in

Cases in which one of these radicals is 0, the other is a hydrogen atom.

Preference is given to compounds of the above structure in which m is 0 or 1, η is 5, P is 4 or 6 and A is a group of the formula .CH = CH.

The new compounds in which Y for 0 and Z for Hp are prepared by a) a 3-pyrazolidinone which contains a protective group at the 1-position, which can be removed under mild conditions, for example by hydrogenation, with a uJ-haloalkanoic acid ester or an alkenoic acid ester or an alkynoic acid ester, in which the halogen atom is preferably a bromine atom or an iodine atom is, reacts, b) the protective group is removed and c) the 1-position with a vinyl ketone or with an acetyle ™ nischen ketone alkylated and then carries out a reduction. By choosing the respondents or by further conversions will obtain the products according to the invention. ;

309847 / 1U8

The new compounds in which Z is O and Y is H ₂ are obtained by a) a vinyl ketone of the formula 0

CH ₂ = GHC (CH ₂ ) _p CH ₅

which is removable with a 3-pyrazolidinone, containing at the 1-position a protecting group under mild conditions, for example by hydrogenation, b) reacting the protective group is removed and c) the pyrazolidone with a 0 -Halogenalkansäure or acid derivative, for example the ester , of the formula p-XCH ₂ (A) _m (CHp) _n COOR, in which X is a chlorine atom, bromine atom or iodine atom and A, R, m and h have the meanings given above. By choice of reactants as well as simple conversions. related products are obtained which fall within the scope of the invention.

The new compounds are similar to the prostaglandins and their derivatives. In contrast to the natural prostaglandins of series E, F and A (which are difficult to synthesize because they contain several centers of asymmetry) contain the compounds according to the invention no more than a center of asymmetry. Instead of asymmetric ring carbon atoms, they contain two trivalent atoms Nitrogen atoms. Publications about nitrogen as a heteroatom in the ring of a prostaglandin-like Report structure, have not been found »

The new compounds according to the invention are identified with the pyrazolidinone ring as an essential feature but, for example, a compound according to Example 1 can be used as a prostanoic acid derivative, e.g. d, l-15-hydroxy-9-keto-8,12-diazaprostanoic acid, or as. denotes the prostaglandin d, l-tetrahydro-8,12-diazaprostaglandin A- will.

Specific embodiments of the invention are described in the following examples. In these examples

309847/1149 ■

all parts and percentages are based on weight, unless otherwise stated.

Example 1 a) 1-Benzyloxycarbonyl-3-pyrazolidinone

o ₀ o

OCCl ^

Na ₂ CO ₃ ,

A solution of 106 g (1 mol) of sodium carbonate in 1 l of water is cooled in an ice bath and stirred with a paddle stirrer, while 124 g (1 mol) of 3-pyrazolidinone hydrochloride are added in portions. 174 g (1.02 MqI) of benzyl chloroformate are added dropwise to the resulting solution in the course of 2 to 3 hours with constant cooling and vigorous stirring. The mixture is stirred for 2 hours without cooling, after which it is neutral. The solid is filtered off and transferred with 300 ml of water to a 2 liter Erlenmeyer flask. 800 ml of 5% NaOH solution are added to the slurry in about 10 minutes. The mixture is stirred for 30 minutes. By this time most of the pesticide is dissolved, but some insoluble oil remains. The aqueous mixture is filtered to remove the insoluble oil. The clear piltrate is then cooled in an ice bath, while 100 ml of concentrated hydrochloric acid are added dropwise with vigorous stirring. The white solid is filtered off, washed with water and ^{dried at 75 °} C. under high vacuum for 24 hours. Here, 141 g (64 ^) 1-benzyloxycarbonyl-3-pyrazolidinone (3-oxopyrazolidin-1-carboxylic acid benzyl ester) of melting point 98 to 98.5 ⁰ C obtained.

30 8.8 47/1149

"- 5 -

Elemental analysis: Calculated for C ₁ Λ Found:

C. 5 H N 59 , 99 5 , 49 12.72 60 , 35 , 64 12.83

: 2.94, 3.15, 3.28, 3.32, 5.85, 6.31, 6.67,

14.45
PMR (CDCl ₅ , TMS) ': 441 (5, phenyl), 312 (2, s, benzyl),

240 (2, t, J = 8.5, CH ₂ N), (2, t, J = 8.5, CH ₂ CO) at 60 MHz ₀

b) 1-Benzyloxycarbonyl-2 (6'-tert-butoxycarbonylhexyl) -3-pyrazolidinone

0 Br (CH ₂ J ₆ COiBu y \ ^ CH ₂ ) gCOgtBu

A mixture of 53 g (0.2 mol) of tert-butyl 7-bromoheptanoate, 48 g (0.21 mol) of i-benzyloxycarbonyl-3-pyrazolidinone, 50 g of sodium carbonate and 2 g of sodium iodide in 200 ml of dry hexamethylphosphoric acid triamide (HMPA ) is stirred for 6 to 7 days at room temperature under nitrogen. The mixture is poured into 1 l of water and extracted with ether. The ether is washed three times with water, once with a small amount of 5% NaOH solution, then _{dried over Na 2} SO, and evaporated, whereby 80.6 g ($ 100) raw product can be obtained as an oil. The crude product (1-benzyloxycarbonyl-2- (6 * -tert-butoxycarbonylhexyl) -3-pyrazolidinone) is used directly in the subsequent hydrogenolysis.

The corresponding ethyl ester prepared in the same way from ethyl 7-bromoheptanoate has the following characteristics. Distillation until complete evaporation gives 309847 / 1U8 at 175 to 180 ° C / 0.028 mm Hg

C. 23231 93 7, I. , 81 H 7, 44 63 , 78 7.50 61 63 7.42

a colorless oil

Elemental analysis;

Calculated for ^C 20 ^H 28 ^N 2 ° 5 ^:
Found:

HR mass spectrum: Calculated 376, 1998, observed 376.2031;

X _max (0HCl ₃ ): 3.31, 3.47, 5.8-5.9, 6.12 (weak), 6.29, 6.67 ya.

c) 2 ( ^; 6 ^t -tert _< , -butoxycarbonyl) hexyl-3-pyrazolidinone

f O

^ CH) COC (CH) Λ (CH ₂ ) ₆ C0 ₂

CO-CH-C ⁷

Ä ^Λ

The tert-butyl ester is preferred to the ethyl ester because the latter tends to form some polymeric amide or lactam during high temperature distillation.

In a 500 ml hydrogenation bottle, 40 g (0.1 mol) of crude 1-Be'nzyloxycarbonyl-2 (6'-tert -butoxycarbonyl) hexyl-3-pyrazolidinoti, 100 ml of ethanol, 8.0 ml of acetic acid and 3 , 0 g of 5% palladium carbon was added as a catalyst. The mixture is hydrogenated on a Parr shaker for 1.75 to 2.0 hours. The total pressure drop in the bottle (isolated from the Parr container) is 3.16 to 3.87 kg / cm.The bottle is carefully blown off and the contents are M-filtered through a funnel of porosity M and concentrated under reduced pressure to around 75 ml ( temperature below 4O ⁰ C). The liquid remaining as residue is poured into a separatory funnel _{containing 13.0 ml of concentrated HCl, 75 ml of H 2} O and 250 g of ice, and 309847/1149

quickly extracted with 150 ml and then 50 ml of ether.
The ether is discarded. The aqueous layer becomes
quickly transferred to a 1 l beaker in an ice bath. After adding 200 ml of fresh ether, 25 g of Na ₂ CO are added in a few portions with stirring. After the addition, the cold alkaline solution becomes 5 minutes
stirred and then transferred to a separatory funnel. The ether layer is separated and set aside. the
The aqueous layer is reapplied twice * with 100 ml each time
extracted from fresh ether. The combined ether layers are _{dried over anhydrous Na 2} CO. The ether
is evaporated under reduced pressure (temperature below 35 ° C.), 19 g of crude 2 (6 ^f -tert.-butoxycarbonyl) hexyl-3-pyrazolidinone being obtained as a yellow oil.

The crude ester is made from about 0.5 g of MgO in a Kugelrohr evaporative distillation apparatus (ball to ball)
distilled about 150 to 160 ° C / 0.004 mm Hg, with a
colorless liquid is obtained which is kept under nitrogen. The yield of pure ester is about 13 g ($ 48) for the two stages, based on tert-butyl 7-bromoheptanoate.

Elemental analysis; Calculated for C ^ H ^ NgO ,: Found:

Liquid chromatography (ethanol-water) shows that this material has a purity of $ 99.53. the
Mass spectroscopy confirms the assigned molecular composition with m / e of M at 270; Main fragments m / e 214 (M-56), m / e 196 (M-56-H ₂ 0), m / e 57 (t-Bu ⁺ )

C. 9 H 1 0 N 62 , 19th 9 , 69 1 0 , 36 62 , 40 , 38 , 49

* max ^CHC1 3 ^{: 2 '95 (NH)> 5} ' ⁸¹ ' ⁵ ' ^{95 (C0} >' ⁸ ' ⁰⁵ '
The amine reacts with p-chlorophenyl isothiocyanate to form a solid phenylurea derivative in 96% yield. By two crystallizations from ethanol, white platelets of melting point 114- bi3 120 ⁰ C are obtained.

309847/1149

Elemental analysis t jC HN £ 1

Calculated for C ₂₁ H ₅₀ ClN ₅ O ₅ S: 57.1 6.88 9.55 8.06 Found: 57.14 6.84 9.42 8.59

d) 7/5 ¹ -oxo-1

terto-butyl heptanoate, trans

ϊ. ο

Il
Ν - (CH ₂ ) ₆ C0 ₂ tBu HC = CCC ₅ H ₁

EtOH O

1-0ctin-3-one can be prepared as follows: Acetylene is added to hexanal in the presence of potassium hydroxide powder and glyme (method by HA "Stansbury Jr., and WR Proops, ■ J.Org.Chem. 27, 279 (1962)). ); amylethinylcarbinol with a boiling point of 80 ° C / 13 mm Hg is obtained, which is then oxidized with Jones reagent, whereby 1-octin-3-one with a boiling point of 66 ° C / 15 mm Hg is obtained (see KoBowden and Collaborator, J. Chem. Soc «, ^ ⁰ / (1946)).

A solution of 2.704 g (10 mmol) of the amine 4 prepared in accordance with section (c) and 1.242 g (10 mmol) of 1-octin-3-one in about 75 ml of dry ethanol (RHManske, J. Am. Chemo S0C. 55, 1106 (1931)) is kept at the reflux temperature under nitrogen for 1.5 hours. The mixture is cooled and diluted to 100 ml in a volumetric flask. A 1.Ό ml aliquot is removed for UV analysis. ( Kz ^ T 322 nm; 16500; when using more common "absolute" ethanol, £ has a value of about 12000.)

3 0 9 8 4 7/1149

A dark red-amber-colored oil is obtained by evaporating the ethanol solution under reduced pressure. Its PMR spectra at 220 and 60 MHz (CDCl, TMS) correspond to almost pure vinylogous hydrazide and show two doublet vinyl protons at 7.54 and 5.37 ppm (J. = 13Hz); High resolution mass spectrum: M m / e calculated 394.2831, observed 394.2870; ^ m _3x (CHCl ₃ ): 3.40, 3.49, 5.82, 5.92, 6.15 and 6.33 s (vinylogous amide), 10.35 (trans double bond) au

The catalytic reduction of the enaminoketone can be carried out without isolating it.

3098A7 / 1U9

-1ο-

Ce) 7 ^ 3'-Oxo-1 * P'OxooctylJpyrazolidin ^ '- yl / tert-butyl heptanoate and 7 ^ 3'-Oxo-1 · (3 "-hydroxyoctyl) -pyrazolidin-2'-yl7heptanoic acid tert-fautyl ester

\ Α / γ ^η

EtOH

EtOH

a- ^c 5 ^H ii

(1) A solution of 2 _r 70 g (10 moles) of the amine and 1.24 g (10 mmoles) of 1-octin-3-one in 75 ml of dry ethanol is refluxed for 1.75 hours under nitrogen and then cooled transferred with 25 ml of dry ethanol into a hydrogenation bottle containing 1, og of a catalyst made of 5% platinum on activated carbon. Reduction in a Parr chute with hydrogen is complete in about 25 minutes. After 2 hours under hydrogen, the ethanol solution of 7/3 * -Qxo-1 '- (3 "-oxooctyl) pyrazolidin-2'-yljheptanoic acid tert-butyl ester (6) is filtered through a glass frit of porosity M. The light yellow filtrate is cooled in ice and immediately _{treated with 1.5 g of WaBH 4.} The ethanol solution is stirred for 30 minutes with cooling and then for 1 hour without cooling extracted with ether. The ether is washed with water, over

* 309847 / 1U9

Na ₂ SO. dried and evaporated to give a yellow oil which, according to thin-layer chromatography (benzene-acetone 2: 1 on silica gel), consists of about 6o% of the hydroxyoctylpyrazolidinone of the formula 7 (R _f = 0.38).

The pyrazolidinone alcohol was characterized in the manner described below using a sample from another sample carried out on a larger scale, but which had the same infrared spectrum and the same R _f value: The chromatography of 5 g of the crude amino alcohol on 150 g of basic Quality III aluminum oxide and elution with hexane-benzene, benzene and ether-benzene (1: 1) yielded 2.41 g of amino alcohol with a purity of 90% in the last eluate. A fraction which, according to thin layer chromatography, had a purity of almost 100% was analyzed. HRMS m / e of M ⁺ calcd for ^C 22 ^H 42 ^N 2 ° 4 ⁱ 398.3144; observed: 398.3146; * "(CHCl.) '335o (OH bonded to inner molecular hydrogen), 238o (^ NH) 172o (ester CO), 1675 (amide CO) cm" ¹ .

(2) Alternative method;

A solution of 10.8 g of the amine (£) in 50 ml of dry Ethanol is refluxed with 6.0 g of 1-0ctin-3-one for 2 hours, cooled to room temperature and made up to 1oo ml diluted. The dark red solution is placed in a Parr shaker over 3, ο g of a catalyst made of 5% rhodium

on activated charcoal at room temperature and about 2.8 kg / cm

Hydrogenated for 3 hours. The catalyst is filtered off through a glass frit. 3.5 g of sodium borohydride are added to the yellow filtrate while stirring. After 3 hours, the reaction mixture is concentrated to about 25 ml under reduced pressure, poured into 200 ml of water and extracted 3 times with ether. The ether is washed 3 times with water, which is discarded. The ether is then washed twice with a total of 2oo ml of ice water containing 16 ml of concentrated hydrochloric acid, the aqueous extraction layer immediately being converted into excess solid sodium carbonate, the 309 8 47/1 # 4 9

covered with ether, is conducted. By evaporation of the ether, which contains the acidic extracted material, are 2, o7 g of the amine used £ obtained. The one after the Extraction with 2oo ml of aqueous acid remaining original ethereal layer is again 3 times quickly with a total of 16 ml of concentrated hydrochloric acid in 2oo ml of ice water and then extracted with saturated sodium carbonate solution. By evaporating off the ether, 9.6 g of crude amino alcohol 7_ are obtained, which is essentially free from the amine. Of the Amino alcohol is much less easy to extract from the ether phase because of its basic character of the amino nitrogen through intramolecular hydrogen bonding is decreased with the hydroxyl group:

, CO ₂ JbBu

The chemical removal of the amine A_ used is important because it can only be separated from the amino alcohol T_ with difficulty by column chromatography. The amine 4 used can come from a reverse Mannich reaction during the catalytic hydrogenation (6_ - * ■ £) and from the hydrogenolysis of the amino alcohol 1_ by excess sodium borohydride in the ketone reduction stage.

309847/1 US

co "tnu ζ

+ CH20 +

C O

The 7.5 g of amino alcohol T_ can be further purified by chromatography. 23o g of basic aluminum oxide of activity IV when eluted with benzene, ether and ethyl acetate. With the last-mentioned solvent, 3.4 g of pure amino alcohol 2 are obtained as ^a thick oil. HRMS calculates m / e of M ⁺ for C ₂₂ H ₄₂ N ₃ O ₄ ; 398.3142; observed 398.3138; essentially no 27o ion (amine); Thin-layer chromatography (silica gel, acetone-benzene 2: 1, visualization by iodine and visualization by charring with sulfuric acid) showed the presence of only one component.

(3) Other methods of making compounds 5 and

C0 ₂ t_Bu

H C = CHCOC ₅ H ₄ ^ BtOH

309847 / 1U9

EtOH

Amylvinylcarbinol (boiling point 74 ° C / 15 mm Hg) can be converted into of amyl magnesium bromide with acrolein. The carbinol can be oxidized to amyl vinyl ketone suitably according to the oxidation method of H.C. Brown (J.Org.Chem. 3-6, 387 (1971)) with aqueous chromic acid / ether. Here, the oxidizing agent is in excess of 25% used. The reaction is carried out at 5-10 ° C. The ketone is subjected to fractional distillation through a spinning band column. It boils at 64 ° C / 16 mm. A Polymerization inhibitor, e.g., 0.2% by weight p-methoxyhydroquinone, is added to the distillate to prevent polymerization to prevent during storage.

A solution of 10.8 g (40 mmol) of the amine _4 and 6.56 g (52 mmol) of amyl vinyl ketone in 50 ml of dry ethanol is stirred for 4.25 hours at room temperature. The thin-layer chromatography then carried out on silica gel (2: 1 acetone / benzene; visualization with iodine) reveals the presence of the ketone 5_ as spots. R _f ο, 63 and less than 1% of the amine used £. With thorough stirring, 2.0 g sodium borohydride are added to the reaction mixture. After 2.75 hours, a further amount of 1.0 g sodium borohydride is added. After a total reaction time of 3 hours, the mixture is poured into a separating funnel containing 200 g of ice water and a little ether. After mixing, the ethereal layer is drained off and the aqueous layer extracted once with fresh ether. The unite

309847/1149

th ether layers are washed three times with water, and dried over sodium sulfate and evaporated, with about 18g of a yellow oil are obtained, which according to thin layer of substantially pure amino alcohol T_ is in a mixture with little Amylvinylcarbinol. A solution of the amino alcohol in hexane is applied to a chromatography column which contains 500 g of basic aluminum oxide of activity IV and eluted with benzene, ether and ethyl acetate in this order. By evaporating off the ethyl acetate, 8.7 g of pure amino alcohol 7_ are obtained (yield 55%, based on the amine 4).

In the same way, heptyvinylcarbinol (boiling point 94 ° C / 5 mm Hg) can be obtained by reacting 1-bromoheptane with acrolein getting produced. Oxidation of the carbinol with Jones reagent produces amyl vinyl ketone (boiling point 9o - 92 ° C / 10 mm Hg). The treatment of 5.4 g of amine with 3.5 g of amyl vinyl ketone in 75 ml of ethanol at room temperature for 18 hours gives 7 ^ 3'-Oxo-1 · - (3 "-oxodecyl) pyrazolidin-2'-yl2heptanoic acid tert-butyl ester. By reducing this ketone with sodium borohydride in ethanol and subsequent chromatography on 45o g of basic aluminum oxide Activity IV becomes, after elution with ether, the 7 ^ 3'-oxo-1 '- (3 "-hydroxydecyl) pyrazolidin-2'-yl / heptanoic acid tert-butyl ester obtain. Treatment of this ester with excess hydrogen chloride in moist chloroform gives the corresponding acid, namely 7 ^ 3 * -oxo-1 '- (3 "-hydroxydecyl) pyrazolidin-2'-yl7heptanoic acid, those by treatment with one or more equivalents of sodium hydroxide or acid sodium phosphate in their sodium salt is converted.

309847/1149

- ID -

(f) -7 ^ 3'-OxO-I ¹ (3 "-hydroxyoctyl) pyrazolidin-2'-yl7heptan-

acid hydrochloride

About 3.5 g of the amino alcohols T_ from example e (2) are dissolved in 25 ml of chloroform. Gaseous hydrogen chloride is bubbled through the solution for 5 minutes. The mixture is allowed to stand at room temperature for 1 hour, after which 1 drop of water is added. An oily phase appears immediately. The mixture is stirred for 1 hour and the chloroform is evaporated. This gives 4.0 g of the hydrochloride iJ as a brown glass-like substance, for which a purity of about 90% is determined.

This brown glass-like substance can be cleaned by heating them on the steam bath with 35 ml of 2N hydrochloric acid up to a temperature of 7o ° C and then heating the mixture diluted with 100 ml of distilled water, cooled and extracted twice with ether. The clear, colorless one aqueous layer is evaporated to dryness, whereby 2.74 g of the above-mentioned hydrochloride (8) as colorless vitreous substance is obtained. By silylation

3098A7 / 1U9

with N-triraethylsilylimidazole in pyridine, the bis-trimethylsilyl derivative (of the free amine) is obtained. Analysis by mass spectroscopy with high resolution: m / e M calculated for ^c ₂ 4 ^H 5o ^N 2 ° 4 ^Si 2 ^{486 '33} ° ⁶ ? found 486.3319.

(g) 7 / 3'-Oxo-1 '- (3 "-hydroxyoctyl) pyrazolidin-2'-yl7heptanoic acid Sodium salt

H ⁺ Cl-OH 8

CO ₂ ^- Na ⁺

In 29.6 ml of 5% aqueous sodium bicarbonate 1.56 g of pure acid hydrochloride i | under Mchcem warming solved. The solution is cooled and filtered to remove a small trace of flocculated material. That clear filtrate thus contains about 5% by weight of the above mentioned sodium salt · (9) in an aqueous solution buffered with sodium bicarbonate.

By using known homologues of the esters of 7-bromoheptanoic acid and of homologues of amyl vinyl ketone or 1-octyn-3-one and subsequent reduction, homologues of the ester T_un ⁽ * of the acid £ can be prepared in the manner described below, where X (CH ₂ ) CO ₃ for X CH ₂ (AJm (CH ₂ J _n CO ₂ R where m = 0 and q =

309847/1149

_ 1 Q I Ö ~

η + 1, can be produced:

.ι · + X (CH _O ) CO R

N- (JOCH ₃ Ji ² «I

O π - 1 η -z ■ h

= Cl, Br or I ■ = alkyl

C-0CIU9
H ²
O

309847/1149

ro

ο υ

Il O

309847/1149

The halogenated esters mentioned below are typical of the esters that can be used to prepare the 2-alkanoate derivatives. The radical R in X (CHJqCO ₂ R can be any customary hydrolyzable group, for example an alkyl radical with 1 to 12 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms or an aralkyl radical with 7 to carbon atoms, including those with one Phenyl radical which is substituted by 1 to 3 alkyl radicals or 1 to 3 chlorine atoms. Some of these esters are commercially available. Others can be prepared from the corresponding omega-bromic acids and the corresponding alcohol by conventional esterification processes (see, for example, C. Buehler, D Pearson, Survey of Organic Synthesis, Wiley-Interscience, NY 197o, Chapter 14).

X (CH ₂ ) CO ₂ R

q = 1 methyl iodoacetate

q = 2 ethyl ß-bromopropionate

q = 3 tert-butyl 4-bromopropionate

q = 3 tert-butyl 4-chloropropionate

q = 3 p-chlorobenzyl 4-bromobutyrate

q s 4 methyl 5-bromobutyrate

q = 4 n-octyl 5-bromovalerate

q = 4 isooctyl 5-chloro valerate

q = 5 isopropyl 6-bromohexanoate

q = 5 valeryl 6-bromohexanoate

q β 5 tert-butyl 6-bromohexanoate

q = 6 ethyl 7-bromoheptanoate

q = 6 tert-butyl 7-iodoheptanoate

q = 6 cyclopentyl 7-bromoheptanoate

q = 6 cyclohexyl 7-bromoheptanoate

q = 6 3-phenylpropyl-7-bromoheptanoate

q s = 6 n -dodecyl 7-bromoheptanoate

The iodine esters are replaced by Finkelstein halide (Buehler and Pearson, loc. Cit. P. 339) (NaI in

309847/1149

Acetone) with the corresponding bromine ester, or the bromine esters can be used directly for the preparation of the 2-alkanoate derivatives in the presence of sodium iodide, the more reactive iodine ester being formed in situ. The bromo esters also alkylate compound 2 of Example 1 in the absence
of sodium iodide, but more slowly. Dimethyl sulfoxide can be used as a solvent, but confused *
Hexamethylphosphoric triamide (HMPA) preferred when the protecting group is in the next by hydrogenolysis
Level should be removed.

The protective benzyloxycarbonyl group of the 2-alkanoate derivatives can conveniently by hydrogenation in one
Solvents such as ethanol can be removed using palladium-on-carbon as a catalyst under mild conditions.
Removal of the benzyloxycarbonyl group is also
possible by treatment with hydrogen bromide in glacial acetic acid, but this is less practical because the
Ester group of the molecule is hydrolyzed under these conditions. Other protecting groups of the type well known in peptide chemistry can also be used for the conversion of pyrazolidinone hydrochloride to 2-carbalkoxyalkyl-3-pyrazolidinones. For example, the reaction of 3-pyrazolidinone with ß, ß, ß-Trichloräthylchlorformiat (Windholz and Johnston, Tet. Letters, 2555 (1967) under Schotten-Baumann conditions
1- {β, β, β-trichloroethyloxycarbonyl) -3-pyrazolidinone as follows;

CICOCH ₂ CCl.

308847/1149

49.6 g (0.4 mol) of 3-pyrazolidinone hydrochloride in 400 ml Water are stirred in a round-bottom flask, 42.4 g (0.4 mol) of sodium carbonate being added in portions. The resulting solution, which is cooled with an ice bath and vigorously stirred with a paddle stirrer, 86.4 g (408 mol) of β, β, β-trichloroethyl chloroformate are obtained added dropwise in 30 minutes. The reaction mixture is stirred overnight without cooling, whereupon the solid is filtered off. The white solid becomes good with water and then with ether-hexane (volume ratio 1: 1) washed. After drying, 94 g (90%) 1- (β, β, β-trichloroethyloxycarbonyl) -3-pyrazolidinone are obtained. Through crystallization. Chloroform (about 350 ml) gives about 84 g of the pure compound. Another sample prepared in the same way had a melting point of 151 to 152 ° C.

Elemental analysis; calculated for C ₆ H found

^ Max ^{<CHCl 3): 2 '95} sharp (NH) and 5.84 u (C = O)

The ester is obtained by treating this compound with X (CH ₃ J ₂ CO ₂ R. The protective group is removed by the action of zinc in acetic acid or hot methanol, the pyrazolidinone being obtained according to the following equation:

C. 55 H N 27 34 2.7ο 1ο, 7ο 27 2.64 to, 9o

(CH _a ) _q CO ₂ R

C u

NC-OCHpCCl, u

3098.4771.Uft

Another protective group is the p ~ nitrobenzoyl group, This group can be removed by saponification with 1 equivalent of a base. R. Boissanas (Advances in Org. Chem. 3, 175 (1963)) and Fieser and Pieser (Reagents for. Organic Synthesis, Wiley-Interscience, N.Y., Vol. I, II and III) describe a number of other F-Sohutz groups, many of which can be used for the conversion described above.

The N-alkylation of the 2-substituted pyrazolidinones can be carried out with the acetylenic ones mentioned in the table below Ketones are carried out. 0

It

■ an = n_ri_

P = O ethynyl methyl ketone

ρ = 1 ethyl ethyl ketone

ρ = 2 ethynyl propyl ketone

ρ = 3 ethynyl butyl ketone

ρ = 4 amyl ethinyl ketone

ρ = 5 hexyl ethinyl ketone

ρ = 6 heptyl ethinyl ketone

These ketones are prepared according to the general method of Bowden, Heilbrow, Jones and Wiedon, J. Chem. Soc. 1946, 39, or according to the general method of Price, J.Am.Chem. Soc. 72, 2613 (1950).

As examples of typical homologous 1,2-disubstituted Pyrazolidinone compounds obtained by reacting the aforementioned esters and acetylenic ketones the processes described above and illustrated by the reaction schemes can be prepared, be the following compounds of the formula

(CH ₂ ) _q CO ₂ R

-CH-CH -0 (CH ₉ ) CH, 0

3088A7 / 1U8

2 / 5'-Οχο-Ι '(3 ^H -oxooGt ~ 1 "-enyl) pyrazolidin-2'-yl7acetic acid methyl ester (q = 1, ρ = 4, R = CH,)

4/5 ¹ -Oxo-1 · (3 "-oxooct-1" -enyl) pyrazolidine-2 ^t -y] -7t> tert-butyl butyl ester (q = 3, P = 4, R = C (CH ₅ ) ^) 6 / 5'-0xo-1- (3 "-oxooct-1 ^H -enyl) p3'razolidin-2» -yl / hexanoic acid isopropyl ether (q = 5, P = 4, R = CH (CH ₅ ) ₂ ) 3 / 3'-Oxo-1 ^f (3 "-oxobut-1 ⁿ -enyl) pyra2olidin- -2'-yl / propionic acid ethyl ester (q = 4, p = 0, R = C ₂ Hc) 7/3 ' -Oxo-1 ^l (3 ^tI -oxopent-1 "-enyl) pyrazolidin-2'-yl7heptanoic acid ethyl ester (q = 6, ρ = 1, R = C ₂ Hc).

7 / 3'-Oxo-1 • (3 "oxohex-1" -enyl) pyrazolidin-2 • -yl. acid ethyl ester (q = 6, ρ = 2, R = C ₂ Hc) 7 / 3'-Oxo-1 '(3 "-oxohept-1" -enyl) pyrazolidine-2 ^! -yl7heptanoic acid tert-tiutyl ester (q = 6, ρ = 3, R =

By catalytic reduction of the above Compounds via Pd / C or, preferably, Rh / C, the corresponding saturated ketones are obtained. The reduction can also be made using an equivalent of lithium aluminum hydride in tetrahydrofuran or ether or using other aluminum hydrides, e.g. sodium bis (2-methoxyethoxy aluminum hydride, be carried out in benzene or ether. The preferred double bond reduction in place of the keto group by catalytic reduction or reduction with lithium aluminum hydride typical for many "vinylogous amides" (Martin, J.Org.Chemo 21, 943 (1966), Walker, loc. Oit. 27, 4227 (1962)).

The saturated ketones or their further reaction products can be prepared directly by reacting 2-substituted pyrazolidinones with vinyl ketones of the formula H ₂ C = CHCO (CH ₂ ) CH-.

309847/1149

p = 0 methyl vinyl ketone

ρ '= 1 x ethyl vinyl ketone

ρ = 2 propyl vinyl ketone

ρ = 3 butyl vinyl ketone

ρ = 4 amyl vinyl ketone

ρ = 5 hexyl vinyl catone

ρ = 6 heptyl vinyl ketone

The first two ketones are commercially available ^. Others can easily be prepared by oxidation of the corresponding vinyl alkyl carbinols, for example in the manner described above for the preparation of amyl vinyl ketone and heptyl vinyl ketone.

By further reducing the pyrazolidinone with 'one Ι-γ-keto substituents either by prolonged treatment under conditions of catalytic hydrogenation or preferably with sodium borohydride, the saturated 1-γ-hydroxyl compound obtained. More typical as examples Alcohols which can be prepared in this way are the following compounds of the formula

Ii

called:

2/3 ~ '-Oxo-1' (3 "-hydroxyoctyl) pyra2olidine-2 ^! -Yl7acetic acid methyl ester (q. = 1, ρ = 4, R = CH,)

4 / 3'-OxO-I '(3 "-hydroxyoctyl) pyrazolidine-2 ^f -yl.7butyric acid tert-butyl ester (q = 3, ρ = 4, R = C (CH ^) ₃ ) 6/3' -Oxo-1 · (3 "-hydroxyoctyl) pyrazolidin-2'-yl thexanoic acid ethyl ester (q = 5, P = 4, R = C ₂ H ₅ ) 3 / 3'-Oxo-1 · (3 ^M -hydroxybutyl) pyrazolidine- 2 ^l -yl7p ^r ° P ^ion isopropyl acid ester (q = 4, P = O, R =

309847 / 1U9

7 / 5'-0xo-1 '(3 ^M -hydroxypentyl) pyrazolidine-2 ^f -yl7heptanoic acid ethyl ester (q = 6, ρ = 1, R = CpHc) 7 / 3'-Oxo-1 ^f (3 ^M -hydroxyoctyl) pyrazolidine -2'-yl theptanoic acid ethyl ester (q = 6, ρ = 4, R = C ₂ H ₅ )

7/3 '-Oxo-1' (3 "-hydroxyhexyl) pyrazoliäin-2 ^l -yl7heptansäüx ^ decylester (q = 6, ρ = 2, R = \ nCjQHp ..) 7 / 3'-Oxo-1 '(3 "-hydroxyheptyl) pyrazolidin-2'-yl7heptanoic acid tert-butyl ester (q = 6, ρ = 3, R = C

6 / 3'-Oxo ~ 1 '(3 "-hydroxyoctyl) pyrazolidine-2'-y] _; 7heptanoic acid tert-butyl ester (q = 5, P = 6, R =

These esters can be easily converted into the corresponding metal salts of the acids by saponification with a molar equivalent of an alicali hydroxide of the formula MOH, in which M is a pharmaceutically acceptable metal, ζ.Bc sodium. For example, the saponification of 6/3 '-Oxo-1' (3 "-hydroxyoctyl) pyrazolidine-2 ^? -Yl7hexanoic acid ethyl ester with 0.1N NaOH in methanol gives the sodium salt of 6/3"'-0xo-1' (3 "- hydroxyoctyl) pyrazolidin-2'-yl.7hexanoic acid, which can be isolated by evaporating the solvent under reduced pressure.,

By acidifying the acid salt with 1 molar equivalent of a strong acid, e.g. hydrochloric acid, the carboxylic acid becomes obtain. Tert-butyl ester can be prepared with a little more than 1 molar equivalent of a strong acid HY, e.g. Hydrochloric acid, can be decomposed in water or chloroform to isobutylene and the carboxylic acid amine salt. The latter Salt of pyrazolidinone nitrogen can also be obtained by reacting the excess acid HY with the esters or Salts are obtained, but these methods are not preferred because of lower yields. Carboxylic acid amine salts can be made from acids or from acids with a

0 9 8 4 7/1149

Salt group on the heterocyclic pyrazolidinone nitrogen produced with pharmaceutically acceptable amines will.

Using homologues of the “known acetylenic ester methyl 7-iodheptinoate XOH ₂ CsC (CHg) _n CO ₂ CH ₅ ; X = I, η = 3, R = CH ^ ₅ ) (Perdinandi and Just, Can ₀ J. Chem 49 , 1070 (1971)) the corresponding acetylenic and ethylenic 2-substituted pyrazolidinone compounds can be prepared.The preparation of these esters, in which η has the value 1 to 3, is represented by the following sequence of synthetic steps Perdinandi and Just (loc cito) for the preparation of methyl 7-iodoheptanoate (where χ stands for bromine or iodine) analogous to the sequence described

Br (CH ₂ J _n CH ₂ OH

HIGH ₉ CSCH * ^{η 2} VX 2 LiNH,

^Χ 2

CH ₃ SO ₂ OCH ₂ CSc (CH ₅ J _n CH ₀ O

₂ J _n CH ₂ O 4 J ^ 5 ____ v

acetone

309847 / 1U9

ο +

XCH-CHC (au) CH _o 0- \ ) - ^ 3 > XCH_C = C (CH_) CIUOH

RCIiN ₂ or

acetone

Starting from the ester I, this sequence gives the ester II, in which the halogen atom, depending on whether MX is in the fifth stage stands for LiBr or ITaI, a bromine atom or Iodine atom is.

I. II

η = 1 ethyl bromoacetate ethyl 5-halogenpent-3-ynoate

η = 2 ethyl 3-bromopro- 'propyl-6-halogenhex-4-ynoate pioneer

η = 3 ethyl 4-bromobutyrate, methyl 7-halogenhept-5-inoate

For the synthesis of ethyl 7-halobut-5-ynoate, i. In the case where η stands for 0, the following synthesis sequence can be used starting from ethyl propionate:

λιττ ζ \ OTT QO Ol HCSC-CO ₂ Et HOCH ₂ -C = O-CO ₂ Et 2- Z

CH ₃ SO ₂ OCH ₂ CHC-CO ₂ Et ^ - XCH ₂ C = C-CO ₂ Et

^ Acetone

(n = 0)

Acetylenic halogen-substituted esters of the general structure above are used to prepare the acetylenic and ethylenic analogs (the latter by reduction over ITi ₂ B or the Lindlar catalyst) or by the following reaction sequence (where P is a protecting group):

309847/1149

CN O

OJ

5?

O CM

fit

te

St. V

• Η Ό *

LiA

to Xi

O O

d 'Ki

O CU in ο

IN

S H-

U C *

C)

0 Ci

4Y

ti υ

ie

Ό CMC

K -rf v-1

3098A7 / 1U9

-3ο-

-Ό

(M

cm tn

8 B

cm

III

I. > * a CM O co U K CJ , · » CU CM K CM CJ E. O CJ III v U > CM

309847/1149

The Lindlar catalyst (HoLindlar, Helv.Chim.Actä 35, 446 (1952)) "consists of palladium on calcium carbonate, which has been deactivated by adding lead acetate and quinoline. This catalyst is inactive for the hydrogenation of olefins. The hydrogenation of acetylenes over this material practically ceases after 1 mol of hydrogen has been absorbed. Palladium on barium sulfate with synthetic quinoline is a similar catalyst, but it is somewhat better in terms of reproducibility and ease of manufacture (D ₀ J ₀ Cram and N ₀ L ₀ Allinger , J "AnuChem. Soc" 78, 2518 (1956)). Both catalysts give olefins with the cis configuration. It is also possible to use nickel borite (Ni ₂ B), in particular that designated as P-2 (H.0. Brown and C ₀ A. Brown, JACS 85., 1005 (1963)) as a catalyst for the catalytic reduction of the acetylenic compounds to cis-olefins The other reactions mentioned above are carried out in a manner analogous to those already described Manufactures specified, carried out.

The cis-ethylenic analogs shown in the above scheme can be prepared by a series of reactions analogous to those described in Example I (ag) using the cis-allylic tv-halogen esters XCH ₂ CH = CH (CH ₂ ) _n C0 ₂ R instead of the saturated to-haloalkanoates X (CH ₂ ) CO ₂ R are produced -152 ⁰ C, as already described »By treating the compound with ethyl 7-bromo-5-heptenoate (German Auslelegungsschrift 21 21 361) in the presence of sodium carbonate in hexamethylphosphoric acid triamide by a process analogous to that described in Example 1b 1- (ß, ß, ß-Trichloräthyloxycarbonyl) -2 (6'-ethoxycarbonyl-2'-hexenyl) -3-pyrazolidinone obtained as an oil.

309847 / 1U9

The protective group can be removed smoothly by treating a solution of this oil in 90% acetic acid with zinc powder at room temperature for 3 hours and then isolating the 2 (6 ^l -ethoxycarbonyl-2-hexenyl) -3-pyrazolidinone via its water-soluble hydrochloride, as in Example 1c described. The free amine is obtained by gentle distillation under high vacuum, as described in Example 1c.

This amine can then be treated with 1 equivalent of i-octin-3-one in ethanol, as described in Example 1d, with 7 / 5'-oxo-1 '(3 "-oxooct-1» -enyl) pyrazolidine-2 ^! -y] -7-hept-5-en-1-acid ethyl ester is obtained as an orange-amber oil.

3098A7 / 1U9

CO ₂ et

NaBH ^

The corresponding monounsaturated ketone is prepared by treating the amine with ethyl vinyl ketone in ethanol in the manner described in Example 1e-3, with 7 / 3'-0xo-1 ^f (3 ^H -oxooctyl) pyrazolidin-2-yl7hept-5-ene -1-acid ethyl ester is obtained as a viscous oil which is colorless in the pure state. This oil is reduced with sodium borohydride in ethanol as described in Example 1e-3, the alcohol being 7/3 "'- Oxo-1' - (3 ⁿ -hydroxyoctyl) -pyrazolidin-2'-yl7hept-5-en-1 ethyl acid ester 'is obtained »

3098Λ7 / 1149

This ester can be obtained by treating its solution. ¹ in. Methanol with exactly 1 equivalent of 1, ON sodium hydroxide quantitatively into the corresponding sodium salt of the acid, doh. of 7/3 "-oxo-1 '- (3-hydroxyoctyl) pyrazolidin-2'-yl / -hept-5-en-1-acid. Evaporation of the reaction mixture to dryness after standing at room temperature for a few days (under nitrogen) gives the pure sodium salt.

° 2 " ^Ma lHSl ^ CO ₂ H

OH

The carboxylic acid is obtained by acidifying the sodium salt with 1 equivalent of hydrochloric acid. If 2 equivalents of the acid are used, the carboxylic acid amine salt is obtained as described above. The sodium salt, the carboxylic acid and the carboxylic acid amine salts are pharmacologically essentially equivalent _o

309847/1149

Example 2

A) 1-Benzyloxycarbonyl-2 (3'-oxo-n-octyl) -3-pyrazoliclinone (10), 1-benzyloxycarbonyl-2 (3'-hydroxy-n-octyl) -3-pyrazolidinone (11), 2- (3 ^l -Hy <3roxy-n-octyl) -3- pyrazolidinone (12)

NH
NC-OCH20

It

■>

^: EiOH

EtOH

309847 / 1U9

i-Octen-3-ol -will with the CrO, reagent according to Jones in acetone oxidized to amyl vinyl ketone (AVK). It boils at 64 ° / 16 mm Hg and is used to prevent polymerization a trace of p-methoxyphenol stored »

To a suspension of 22 g (0.1 mole) of benzyloxycarbonyl-3-pyrazolidinone are dissolved in 75 ml of anhydrous ethanol C 13.0 g (15.6 ml, 0.103 mol) and then 0.20 ml of 40 Amylvinylketon öiges at 45 ^0? Tetramethylammonium hydroxide (Triton-ß) given in methanol. The reaction mixture is heated in the reflux condenser for 1 hour and then cooled, whereupon 2 drops of glacial acetic acid are added. This ethanolic solution contains the almost pure compound K). After isolation of the product by successive treatment with water, ether and 5% NaHCO * in thin-layer chromatography, an aliquot part shows a single component (silica gel, development with acetone-benzene 2: 1,

R "= 0.63 by visualization with iodine); K _möV (without χ λ max

Solvent) 1720 wide, 1500 cm "; PIiR (CDCl ₅ ) 447 Hz (singlet, phenyl) 316 (singlet, area 2, OCH ₂ 0) etc. at 60 1 (Hz; HRMS m / e calculated for C ₁ QH ₂₆ N ₂ O .: 346.1889, measured 346.19333 · The remainder of the ethanolic solution of the compound 10 is stirred in an ice bath while 1.6 g of sodium borohydride ^1. The reaction mixture is cooled for 30 minutes and then without Stirred cooling and poured into 300 ml of ice water.This aqueous mixture is extracted twice with 150 ml of ethyl acetate each time, which in turn is washed with NaHCO ^ 5, dried over sodium sulphate and evaporated to give 33 g ($ 96) of the almost pure compound JJ_ R _f = about 0.58; thin layer chromatography under the conditions described above for compound 10; Λ _mQV (without solvent 3400 cm

(OH)); PMR is consistent with the expected spectrum; HRMS m / e calculated for C ^ HggNgO .: 348.2047, found 348.2076, excluding '346-1.On ₀ A solution of 32 g of this oil

309847/1149

in 75 ml of ethanol is then hydrogenated with 10 ml of glacial acetic acid in a Parr shaker over 3.0 g of 5% palladium carbon. Has stopped after the rapid V / asserstoffaufnehme, the ethanolic solution is filtered and the filtrate ml concentrated under reduced pressure (temperature below 40 ⁰ C) to about 40 microns. The remaining liquid is poured into 150 ml of ice water containing 10 ml of concentrated HCl and extracted twice with ether, which is discarded. The cold aqueous phase is then covered with about 100 ml of ethyl acetate and adjusted _{to ρ Η 9 by adding Na 2} CO while stirring. The ethyl acetate is drawn off and the aqueous phase is extracted again twice with a total of 250 ml of ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulfate and evaporated under reduced pressure, 13.6 g (69 $) of the almost pure compound 1_2 being obtained as a slightly air-sensitive, pale yellow oil. This oil is insoluble in ether. The pure compound 12 is isolated by distillation with a ball condenser, 12 g of a thick, colorless or very light yellow oil being obtained at 130-140 ° C./0.017 mm Hg.

Elemental analysis: Calculated for C ₁₁ H ₂₂ N ₂ O ₂ : Found:

HRMS calcd 214.1863, measured 214.1703 »/ C _fflax (CHCl ₃ ) 2.95, 3.09, 3.39, 3.49, 5.96 (C = 0), 9.25

(CHOH) u;

R „= · 0 * 20 on silica gel, acetone-benzene 2: 1, visualization through iodine,

A solution of the compound _12_ in isopropanol reacts with p-chlorophenyl isothiocyanate to form a p-chlorophenyl thiourea derivative from melting point 194-197 c * This derivative is identical (according to the mixed melting point and infrared spectrum) with the p-chlorophenylthioureid of 4_, that according to the synthesis described in the following part (B)

3098A7 / 1U9

C. 1 3 H 1 3 N 61 , 65 1 0 , 07 1 3 , 07 66 , 69 , 13 , 29

procedure is obtained,

B) 1 (ß, ß, ß-trichloroethoxycarbonyl) ~ 2- (3 '--oxo-n-octyl) -3-pyrazolidinone (14), 1 (ß _J ß, ß-trichloroethoxycarbonyl) -2- (3 -hydroxy-n-octyl) -3-pyrazolidinone (15) and another

Method of making the compound (12) .

CH ₂ = CH-CC ₅ H ₁₁ (Ii)

13th

II

C-OCKoGX ₃

Zn

X = Eq (15) or H (16)

■ IT

\ / NH

■ 34% 847 / 1U9

A solution of 26.2 g (0.1 mol) of 1 (β, β, β-trichloroethoxycarbonyl) -3-pyrazolidinone (13) in 75 ml of ethanol is treated with 15.6 ml of amyl vinyl ketone and tetramethylammonium hydroxide and refluxed for 1 hour . The reaction mixture is then treated with 0.15 ml of glacial acetic acid to give a solution of almost pure 1 (β, β, β-trichloroethoxycarbonyl) -2- (3-oxo-n-octyl) -3-pyrazolidinone (14) Thin-layer chromatography of an aliquot on silica gel, acetone-benzene (1: 1); R ^ = 0.67 with visualization by carbonization with H ₂ SO-. The alcoholic solution of the compound (14) is cooled and at 15 to 20 ⁰ G kept while 3.0 g of sodium borohydride were added. After 1 hour, the reaction mixture is poured into 500 ml of ice water and extracted with ether. The ether is washed with water and 5% HOl, dried over sodium sulfate and evaporated, whereby 22. 5 g of an oil are obtained which consists of a mixture of compounds 15 and 16. Thin-layer chromatography R ^ = O..A7 and 0.54 under the conditions described for thin-layer chromatography of compound 14. HRMS: Calculated for C ₁₄ H ₂₅ N ₂ O ₄ Cl ₅ 388.0724, measured 388.0725; calculated for C ₁ -H ₂₆ N ₂ O. 286, found 286 (more intense). By treating 39 g of the compounds 15 and 16 with 4.0 g of zinc dust in 20 ml of 90% acetic acid for 2 hours at 25 ^° C., 0.54 g (25 #) of the compound 12 is obtained as an oil. This compound is isolated as the water-soluble hydrochloride and as its derivative with p-chlorophenylisothiocyanate
(isopropanol) identified.

with p-chlorophenyl isothiocyanate of melting point 106-110 ° C

Elemental analysis: C_ HN

Calculated for C ₁₈ H ₂₆ N ₅ SO ₂ Cl: 56.2 7.06 10.94 Found: 56.15 7.18 11.10

1- (ß, ß, ß-'J} richloräthyloxycarbonyl) -3-pyrazolidinon is produced in the manner already described «

309847 / 1U »

C) 7 / 5'-0xo-2 '(5 "-hydroxy-n-octyl) pyrazolidin-1'-yl7- heptanoic acid ethyl ester (17) and its hydrochloride (17a)

! (CHpV.COpEt Na ₂ CO ₃

HCl

CO ₂ et

17a

A mixture of 8.56 g (40 mmol) of pyrazolidinone J_2 ,. 12.5 g of ethyl 7-iodoheptanoate. (44 mmol) and 10 l of anhydrous sodium carbonate in 75 ml of letramethylene sulfone is stirred for 7 days in a sealed flask at room temperature and then kept on the steam bath at 80 to 85 ° C for 1.5 hours The reaction mixture is cooled, poured into 500 ml of a 5% NaHCO, solution and extracted twice with ether. The ether is washed three times with water and then dried well over anhydrous sodium sulfate. The dry ether solution (300 ml) is filtered into a separatory funnel. Excess gaseous HCl is bubbled through, the hydrochloride of 7 / 3'-Oxo-2 ^f - (3 "-bydroxy-n-octyl) pyrazolidine-1'-yl / ethyl heptanoate (17a) being obtained as an insoluble heavy oil« After 5 minutes the supernatant ether layer is through

309847/1149

Decanting and centrifuged to a small amount of Hydrochloride to remove, to the main part of Hydx'ochlorids in the S _c is heath funnel returned ο The hydrochloride is washed with fresh ether and the ether and centrifuged as removed by decantation before. Excess saturated NaHCO ^ solution / about 250 ml of fresh ether are then added to the hydrochloride in the separating funnel. The mixture is stirred and the ether layer is drawn off, washed with 5% NaHCOy solution, dried over anhydrous sodium sulfate and evaporated, 8.37 g (yield 57%) of the almost pure compound being obtained. Thin-layer chromatography (silica gel ·, acetone-benzene 2: 1, visualization with iodine: R _f = 0.59? For another sample produced on a smaller scale: / """(without solvent) 3400 (OH), 1725 (0O ₀ Et),

1675 (CON) cm "¹;
HRMS: calcd for C ₂₀ H ₅₈ N ₂ O .: 370.2829, measured 370.2824

According to another method, the connection 1_7 becomes like prepared as follows: A mixture of 8.6 g (40 mmol) of pyrazolidinone 1_2, 13 g of ethyl 7-iodheptanoate (46 mmol), 10 g sodium bicarbonate and 75 ml tetramethylene sulfone is stirred for 48 hours at 60 + 1 ° C (oil bath). The reaction mixture is cooled, poured into 500 ml of a 5% NaHCO, solution and extracted twice with ether. Of the Ether is washed three times with water, dried over anhydrous sodium sulfate, and placed in a separatory funnel filtered. Dry HCl is bubbled through in excess, the hydrochloride (17a) of the ester J_7 being insoluble heavy oil is obtained. After 15 minutes the supernatant layer of ether is pulled off with an injection syringe and the oil divided into 200 ml of ether and excess saturated NaHCO 3 solution. The ether is over dried and evaporated to give 7.37 g of des

Esters r? can be obtained. / C _mQ "2.95, 3.40, 3.49, 5.78, 5.9, 6, OyUo

309847/1148

Example 3

Sodium salt (18) of 7 / 3'-Oxo-2 ¹ (3 "-bydroxy-n-octyl) pyrazolidin-1'-yl / heptanoic acid

A solution of 4.69 g (12.6 mmol) of the ester YJ. 14.0 ml of aqueous 1, ON sodium hydroxide in 75 ml of ethanol is stirred for 4 days at room temperature under nitrogen and then evaporated to dryness under reduced pressure. The residue is taken up in 82 ml.

Example 4

5/5 ^f -0xo-2 '(3 "-hydroxy-n-octyl) pyrazolidine-1 ^f -yl7pentanoic acid ethyl ester (19) and its hydrochloride (19a)

For formulas see page 42a

309847/1149

12th

OH

HCl

H ⁺ Cl "

309847/1149

A mixture of 2.14 g (10 mmoles) of the amine VZ, 3.0 g (14.4 mmoles) of ethyl 5-t> romvalerate, T, Q g of anhydrous sodium carbonate and 20 ml of anhydrous tetramethylene ^ fon is heated on the steam bath for 16.5 hours, cooled and poured into 150 ml. 5% KaHCO 3. By extracting twice with 100 ml of ether each time, washing the ether with water, drying and adding gaseous HCl in the manner described for the synthesis of the ester 17, the hydrocorride (19a) is raised as a heavy oil . This oil is divided between excess saturated KaHCO and ether, with 1.4 g of the ester being obtained in the ether phase after drying. Thin-layer chromatography shows a single component (silica gel, acetone-benzene 2: 1, visualization with iodine). R = 0.5; X * _mnv (without solvent) 2.95 (OH), 3.40,

X UicLX

3.49, 5.75 (ester), 5.95 (OOji); HRMSi calcd for ^C 18 ^C 34 ^N 2 ° 4 ^: 542.2250, measured 342.2547.

Example 5

4 / 3'-Oxo-2 '(3 "-hydroxy-n-octyl ·) pyrazol · idin-1' -yl.7butter acid ether (20) and its hydrochloride

OH

Na ₂ CO ₃

S ^

12th

309847/1 U9

The above-mentioned ester (20) and its hydrochloride are made from 4.28 g of the amine j_2, 7.0 g of ethyl 4-bromobutyrate, 0.5 g of sodium iodide, 40 ml of tetramethylene sulfone and 4 g of anhydrous sodium carbonate by treatment for 4 days 60 ^° C., 1.90 g of the ester 20 (28 #) being obtained. HRMS calcd for C ₁ → H ₅₃ N ₂ O ₄ «328.2360, measured 328.2370.

Example 6

7 / 3'-Oxo-2 '(3 "-hydroxy-n-octyl) pyrazolidine-1' -ylTbeptanoic acid tert-butyl ester (21) and its hydrochloride

A mixture of 2.14 g of the amine E, 2.9 g of tert-butyl 7-bromoheptanoate, 25 ml of tetramethylene sulfone, 2.0 g of sodium carbonate and 0.5 g of sodium iodide is stirred in a sealed flask for 9 days at room temperature . The ester obtained 2J_ and the hydrochloride are isolated in the same way as in the previous example (for 20). Thin-layer chromatography of the ester on silica gel (acetone-benzene (2: 1) gives a single component R ^ = 0.6; HRMS m / e of M: calculated for 022 ^ 2 ^ 0 ^ 4 398.3142, measured 398.3142 ; / ^ _00x (OHCl ₃ ) 2/93, "5 ', 8I, 5.95, 7.17, 7.30, 8.68 and the like.

309847 / 1-49

The following schemes further illustrate the preparation of the novel 1-hydrocarbon esters-2- (γ-hydroxyalkyl-3-pyra2! Olidinones) according to the invention. In these schemes "P" is a protecting group. The other variables have the meanings already mentioned here, where R ¹ is generally a lower alkyl radical.

Il

N-P

base

Γη 7

base

Removal of P

309847/1149

HX *

O OH

1ί / \ Λ

OH

MOH

> P ^CH 3

'CH ₂ (A) _n (GHa) _n COa M ⁺

IHX "

H OH

H +
0 OH

309847/1149

The compounds A are produced by reacting 3-pyrazolidinone hydrochloride with the corresponding protective group reagent, for example of the type known in the peptide industry (RoBoissanas, loc.cit «) Fieser and Fieser, (loco.cit.). The use in the reaction sequence of the synthesis and the exact method of removing the protecting group (P) will depend on the nature of the protecting group, but in general the protecting groups which are removable by reduction or mild alkaline hydrolysis (for example, when P is p-nitrobenzoyl group is), most expediently removed after the Michael addition of the vinyl ketone CH ₂ = CHCO (CH ₂ ) CH * and reduction of the ketone side chain.

The vinyl ketones H ₂ C = CHCO ( ¹ CH ₂ ) CH ₅ are either commercially available or can be easily prepared by oxidation of the corresponding alkyl vinyl carbinols. These alkyl vinyl carbinols are either commercially available for their part or can be prepared from alkyl halides in the manner described above by reacting acrolein with the Grignard compounds.

The Michael addition of A to the alkyl vinyl ketones can be carried out in an alcohol or an aprotic solvent, e.g., an ether, using a catalytic amount of a base, e.g., a hydroxydione or tertiary Amines, to be carried out »

The reduction of the ketones B is carried out with a reducing agent, ZoB. Boron or aluminum hydride, which is the protective group the reduction of the keto group does not split off, carried out. Sodium borohydride is preferred for this purpose. However, if the reduction of the ketones B is carried out with hydrogen, for example over a rhodium catalyst will find. Hydrogenolysis of the protecting group as competing Reaction with the reduction of the carbonyl group and reducing cycloalkylation to form the compound

309847/1 U9

instead of.

The amine D obtained after the protective group has been removed from compound C is then subjected to N-alkylation with the corresponding halogen compound XCH ₂ (A) _1n (CIL)) _ß -CO ₂ R, in which X is a chlorine atom, bromine atom or iodine atom and R has the abovementioned meaning, but is preferably an alkyl radical having 1 to 12 carbon atoms. Some of the esters X (CH ' ₂ ) qC0 ₂ R that can be used have already been described.

The alkylation of the amine D is slow at room temperature. Elevated temperatures (50 to 125 ^° C.) are preferred. The alkylation can be carried out in ethanol, but tetramethylene sulfone is the preferred solvent. The presence of a base, for example NaHCO * or Na ₂ CO. ,, increases the yield of alkylation product E.

The alkylation product E is expediently derived from the by-products, for example unchanged halogen esters or olefinic! Esters, which are formed in the dehydrohalogenation of the halogen ester, are separated off as the hydrochloride salt by precipitation from ether. The alkylation product E can be regenerated by treatment with aqueous NaHCO and converted into a new salt 3? for example by treatment with maleic acid or perchloric acid, or it can be hydrolyzed with 1 equivalent of an alkali hydroxide to a carboxylate / hydrolyzed. The salt G can in turn be converted _{into the free acid H (inner salt) by neutralization to ρ Η} 6 in an aqueous system, or it can be converted into the

309847/1149 '.

- m ■ -

Compound J, the HX salt of the carboxylic acid, is converted to an atom become »If R stands for a tert-butyl radical, that can Analysis product E by treatment with 1 or more Equivalents of a strong acid HX in water or chloroform into the corresponding acid or the Hydrohaloge'nide the acid can be converted. Amine salts can be made by reaction of acids H with pharmaceutically harmless Amines are produced »

By using homologues of the acetylic ester, ie methyl 7-iodohept-5-inoate XCH ₂ CSC (CH ₂ J _n CO ₂ CH ₅ (X = 1, η = 3, R = CH,) (Ferdinand! And Just, loc.cit.), the analogous acetylenic and ethylenic / ~ pyrazolidinone compounds can be prepared.The preparation of these esters, in which η has the value 1 to 3, has already been described above / ~ 1-substituted

The ^ -alkylation of the amines D with XCH ₂ (A) _m (CH ₂ ) _n CO ₂ R to give the compounds E can be carried out without solvents or in solvents, for example ethanol, dimethylformamide or hexamethylphosphoric acid triamide. With the use of tetramethylene sulfone for this purpose, however, CO ₂ ,, good results are particularly at elevated! Temperatures, for example 50 to 11O ⁰ C, and in the presence of proton acceptors such as NaHCO or ITa obtained. The compounds E are expediently purified as hydrochlorides by precipitation from ether. The free amines E can be regenerated by treatment with an aqueous base, for example NaHCO2. The saponification of the arainoesters of E is carried out in the presence of 1 equivalent of an aqueous base, the carboxylate salts G being obtained, which in turn are converted into the acids (inner salt) H or by conversion with 1 or 2 equivalents of the acid HX into the acid hydrohalide can. By treating the carboxylates G with a physiologically harmless amine, for example iriethanolamine, the amine salts K are obtained.

30S847 / 1U9

The compounds according to the invention have biological properties similar to prostaglandins or are antagonists of prostaglandins.

The compound of section (g) of Example 1, ie the sodium salt of 7/3 '-oxo-1' - (3 "-hydroxyoctylpyrazolidiri-2'-yl / heptanoic acid, also as the sodium salt of 8,12-diaza-9- keto-15 (+) hydroxyprostanoic acid, has a prostaglandin-like effect. For example, stimulation of the rat ileum (smooth muscle) occurred when the compound was present in a concentration greater than about 50 μg / ml of the perfusion bath, all two of which until three seconds of rhythmic contraction jerks occurred. Acetylcholine (10 moles) induces a strong contraction that increases to maximum tension in 2 to 3 seconds and maintains this tension for 1 to several seconds before relaxation. When using the pyrazolidinone derivative described above with acetylcholine the voltage drops to half the peak value and remains there for a long time. This effect has been reported for the prostaglandins PG-E and PGF ₂ a ^by Horton, British Journal of Pharmacology 24, 472 (1965) reported. The stimulation of the smooth muscles by prostaglandins is also dealt with by JE Pike and colleagues in "Prostaglandins", Nobel Symposium No. 2, S. Bergstrom and B. Samuelsson, Interscience, Stockholm 1967, page 161. The increase in the onus of the smooth muscles by these Diazaprostanoic acid is not inhibited by compounds that block the receptors for neurotransmitters when these compounds are used in concentrations sufficient to block the neurotransmitters. However, at much higher concentrations, some of the neurotransmitter blockers block the effects of diazaprostanoic acid.

309847/1149

The lowering of the blood pressure is also typical of the prostaglandins, in particular the prostaglandins of the series E (Pike, loccit ») and A (J ₀ Lee et al. In Ann.N.YoAcad-Sciences, Vol _o 180, Ramwell and Shaw, NY Acad , Sciences, 1971, 218). When the compound described in section (g) of Example 1 was administered to anesthetized bypertensive rats that were. treated with deoxycorticosterone acetate is injected intravenously, the SD ™ is 0.2 mg / kg, with the ED _{50 being} the dose necessary to lower the blood pressure in a group of rats by an average of 30 mm Hg.

Some of the esters are prostaglandin antagonists when tested in vitro using rat uterine strips. For example, the ethyl ester YJ_- in a concentration of 80 μg / ml causes a 50% inhibition of the contraction caused or caused by a test dose of a natural prostaglandin PGE. The test dose of the natural prostaglandin is adjusted to the concentration required to achieve about 75% of the maximum smooth muscle stimulation. Under similar conditions, the corresponding tert. The inhibition of the prostaglandins is pharmacologically important because it is assumed that the prostaglandins are involved in inflammation, fever and pain processes. Aspirin, for example, exerts its beneficial effects on these processes, apparently on G _r and its ability to inhibit the synthesis of prostaglandins in vivo. Prostaglandin antagonists therefore become of potential value as anti-inflammatory agents or antipyretics or analgesics, or for the treatment of certain forms attributed to diarrhea or shock »

Some of the esters and acids according to the invention inhibit or prevent experimentally generated ulcers in rats.

309847/1 149

"The acids according to the invention, their metal salts or amine salts and their hydrohalides have other prostaglandin-like ones Properties. The salt Jj3 "causes" at 25 µg / ml an increase in smooth muscle tone in vitro on the rat uterus. At lower concentrations, it sensitizes the muscle to the stimulating ones Effects of prostaglandin E., <> The pharmacological value of prostaglandin-like compounds "for example as a means for swelling of the nasal mucous membranes, as bronchodilators, abortion agents, labor inducers Means, antihypertensive agents, etc. "is generally recognized"

The compounds according to the invention can be incorporated into polymeric embedding media for long-term release. will be working. Biodegradable polymeric substances, e.g. homopolymers of Lactic acid or glycolic acid, their mixtures or copolymers. These consist of active ingredient and polymer Drugs can be injected as small particles in suspension, implanted as a grain, or as an egg Skin or wounds are sprayed. The active ingredient, either a prostaglandin antagonist or a compound with Prostaglandin action, is then slowly released, and the polymer reacts to physiologically normal substances reduced.

309847/1149

Claims (22)

Paten tans priiche ! / Compounds of the formula -CH ₂ -CH ₂ CH (GH ₂ ) _p3 OH
Z wherein A is CH = CH or C ^ c, Amine salt, R is a hydrogen atom, an alkali metal / a hydrocarbon or chlorinated hydrocarbon residue with up to; 12 carbon atoms is m stands for 0 or 1, η stands for 0 to 6, ρ stands for 0 to 6 and Y and Z stand for 0 or H ₂ with the proviso that in cases in which one of these radicals stands for 0, the other stands for Hp. 2. 7/5 '-oxo-1' - (3 "-hydroxy-n-oetyl) pyrazolidine-2 '-y_17 * ieptanoic acid. ; 5. The tertiary butyl ester of the compound of claim 4. The sodium salt of the compound of claim 2 5 · 7Z5 ¹ -oxo-! '.- (3 "-hydroxy-n-decyl) pyrazolidine-2 ¹ -yljhe ptanoic acid. 6. The tert-butyl ester of the compound according to claim 5 7. The sodium salt of the compound according to claim 5 b. ' 7/5 ¹ -oxo-1 '(3 "-hydroxy-n-octyl) -pyrazolidine ¹ -y_l7keptcis-5-en-l-acid, 9. The ethyl ester of the compound according to claim 8. 10. The sodium salt of the compound according to claim 8. 309847/1 U9 11. 7 / 3'-OxO-I ¹ (3 "-hydroxy-n-octyl) -pyrazolidin-2'-y _> 17hept-5-yn-1-acid. 12. The ethyl ester of the compound according to claim 11. IJ. The sodium salt of the compound of claim 14. γ /? ^1- Oxo-2 ¹ (3 "-hydroxy-n-octyl) -pyrazolidin-1'-yl? - heptanoic acid. 15 · The ethyl ester of the compound according to claim 14. 16. The tert-butyl ester of the compound according to claim 17. The sodium salt of the compound of claim 18. 7/3 ¹ -oxo-2 ¹ (3 "-hydroxy-n-decyl) pyrazolidine-1 '-yjL7pentanoic acid. 19. The ethyl ester of the compound according to claim 18. 20. 7.Z3 ^f -oxo- ² '(3 "-hydroxy-n-octyl) pyrazolidin-1 * -yl / Wpt ~ cis-5-en-1-acid. 21. The ethyl ester of the compound of claim 20. 22. The sodium salt of the compound of claim 23 · Pharmaceutical preparations containing wenirstsns a compound of claims 1 to 22 with carriers. 309847/1 149