DE2505143A1 - PROCESS FOR THE PRODUCTION OF SPIRO (4,5) DECANE DERIVATIVES - Google Patents

Description

Process for the production of spiro- (4,!?) - decane derivatives

Addition to P 22 42 387.0). The present invention relates to a new process for the preparation of spiro - (^ 5) -decane derivatives of the following al " common formula:

R '

in which R stands for ß-phenylethyl, 3 ', 4'-methylenedioxy (ß-phenylethyl), ß- (p-fluoro) -phenylethyl, ß-phenoxyethyl, cinnamyl, diphenylmethyl, ß- (3'-trifluoromethyl) -phenylethyl and R ^{J is} hydrogen or phenyl. The present invention is: in particular an improvement of the method of patent application P 22 42 387.0.

509833/0998

• 2505H3

Compounds of the type mentioned above, in which R ¹ is hydrogen or an alkyl or aryl group, are already known, especially in the pharmaceutical field as anti-inflammatory, antitussive, anti-asthmatic, antisecretive, cardiovascular, analgesic and sedative agents.

British Patent 1,100,281 describes compounds of the above formula (i) in which, however, R ^{1 is} hydrogen, and processes for their preparation are described.

However, these methods have several disadvantages and problems.

As stated in the referenced UK patent, the yields are not high, especially during the reduction process of cyanohydrin and there are substantial amounts of undesirable fabric products present.

Furthermore, the problems and difficulties with cyanidation reactions, mainly due to the highly toxic, highly volatile and difficult to remove substances to be handled, known.

In addition, in the case of the compounds ^{according to the invention, the introduction of substituents R 1} in the position shown in formula (i) by known processes would entail considerable difficulties both in carrying out the reaction and in reducing and removing undesirable endogenous products.

The subject of application P 22 42 387.0 mentioned is a method for the preparation of derivatives of spiro (4,5) decane with the above Formula (i) from an N-substituted 4-piperidone of the formula:

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in which R ^{1 has} the above meaning., as a starting material, which is characterized in that (1) the N-substituted 4-piperidone according to the modified Reformatzkij process in an anhydrous solvent mixture of benzene and ethyl ether (1: 1 vol. / Vol) and at a temperature between 25-70 C. with a ^ i. - Halogen esters of the formula:

R'-CH-COOEt (V) - -

in which X stands for a halogen, such as chlorine, bromine or 3od and R ^{1 has} the above meaning, in the presence of activated elemental zinc with a molar ratio between the reactants and the zinc of at least 1 mol of the compound (IV), 1 mol the compound (V) and 1 KoI activated zinc, preferably in a ratio of 1 mole of compound (IV), 2.5 moles of halogen ester and 5 moles of activated zinc to form a ß-hydroxy ester

product of the formula ■

_R - _N

CH-COOEt ■ _(VI)

converts, in which R and R ^{1 have} the above meaning; (2) the beta-hydroxy ester (Vl) 8-30 hours at a temperature of 40-60 ⁰ C. with excess hydrazine in a molar ratio of ester to hydrazine of from 1: 1.5 to 1: 100, preferably from 1:10 to form the corresponding ß-hydroxyhydrazide:

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CH-CONHNH ₂

(VII)

and (3) finally the ß-hydroxyhydrazide (Uli) according to FIG Curtius rearrangement reaction by reaction with excess nitrous acid in the presence of a dilute mineral acid rearranged at a temperature between room temperature to 60 C., u / obei the acidic aqueous mixture under a blanket of an organic Solvent, preferably a mixture of petroleum ethers with a boiling point between 60-90 C. to form the desired Connection of the formula (i) by closing the 2-oxazolidone ring is held.

The term "Reformatzkij reaction" usually means a condensation reaction between a carbonyl compound and an ester of an aliphatic $ ζ -halogenic acid in the presence of zinc or magnesium.

In the individual stages of the above process according to the invention is now the N-substituted 4-piperidone (IV) with an o (.- halogen ester (V) implemented. Among the possible compounds of the formula R'-CH (X) -COOEt, all chlorine, bromine or dodo derivatives can be used will.

The appropriate choice is a function of the form of the zinc, the metal activation system, the solvents used for the reaction and the physical conditions for carrying out the reaction. Sometimes Zn can be replaced by Hg, where the latter used in some common Reformatzkij reactions

509 83 3/099 8

will.

In fact, magnesium is required due to its high reactivity a more precise control of the reaction, otherwise it will continue would ', with the carboethoxy group of the ß-Hydrocyyester obtained (Ul) to respond.

The metal can be metal powder, chips, abrasion, thin metal parts used and activated in various ways.

The reaction itself can be further improved by adding catalytic amounts of 3od or alkyl magnesium halides to the medium will.

An anhydrous mixture of ■ benzene and ethyl ether is for the reaction suitable solvent system. .

The full reaction occurs with high yields in just few stages under carefully regulated conditions, namely

a) Formation of the primary adduct

R ¹ -CH-COGEt

ZnX

where R ¹ and X have the above meaning, between the activated zinc and the "^ -haloalkyl ester in an anhydrous fish from benzene and ethyl ether until the" o (-haloalkyl ester has completely disappeared from the reaction mixture, at a temperature between 50-70 ° C.; - "■■ '

b) Formation of the final ariduct

R-N

' ^ CHR'-COOEt (VIII)

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between the primary adduct and the N-substituted 4-piperidone in the same reaction medium at a temperature between 0-20 ⁰ C;

c) "Complete precipitation of the organic metal adduct thus obtained at a temperature of D C. and subsequent. Addition of anhydrous ethyl ether and subsequent separation of the organometallic adduct by filtration, drying and analysis;

d) Decomposition of the final A-dduktes and isolation of the Q-hydroxy-Bster in the form of an oily product, .das by means of a 50 % v / v. Water solution in acetic acid at low temperature

tends to solidify.

In this sense, the above stage is a modification of the usual Reformatzkij procedure. If the latter in the original way applied to the starting compounds according to the invention, it would mainly lead to the formation of undesirable by-products, e.g. compounds from the alkylation on the nitrogen atom of the piperidine and dimerization products of the carbonyl compound.

Furthermore, they can usually be found in the Reformatzkij reaction solvents used, such as diethyl ether, benzene, tetrahydrofuran, etc., do not sufficiently dissolve the reaction intermediates, whereby the reaction cannot be carried out easily and the controls on the individual stages cannot be carried out.

The use of the mixture of benzene and ethyl ether allows the formation of the primary adduct and the further addition of the anhydrous one Ethyl ether enables the quantitative precipitation of the

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definitive addulites.

This production of a filterable precipitate is of the utmost importance Importance as it leads to favorable working conditions and improved yields.

Eventually the decomposition of the final adduct and the Isolation of the ß-Hydrox'yesters expediently according to the invention by dissolving the precipitate after the analytical control in a Solvent mixture of acetic acid and water (in a volume ratio of 1: 1). After neutralizing the obtained Solution to a pH of 7 and extraction with a / organic solvents, u / ie benzene, toluene, etc., can be a pure ß-Hydroxyester obtained u / earth, the purity of which is so high, that further purification stages, and / or distillation, etc., "are unnecessary. _

The ß-hydroxyester is then treated with hydrazine either in the anhydrous form (1) or in the hydrated form Form (2) (70-85% hydration) converted into the ß-hydroxyhydrazide.

1) The reaction is carried out by mixing the reactants in the presence or absence of inert organic solvents, like benzene, and is then made by heating the mixture to 40-60 C. for 8-15 hours or by letting the mixture stand finished at room temperature for 1-21 / ochen.

2) The reaction is carried out by mixing the reactants in the presence of inert organic solvents, such as benzene, and an alcoholic solvent such as ethanol, so that the reaction mixture aei high temperatures (40-60 ⁰ C.) repeatedly in the

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homogeneous state is brought back. The conversion is completed in a hot state (60-80 ⁰ C.) within 15-30 hours.

In both cases it is advisable to work with an excess of hydrazine over the stoichiometric values. The excess should between 1: 1.5 to 1: 100, preferably 1:10.

The Curtius rearrangement of the intermediate leads to the formation of the final spiro (4,5) decane. It takes place through the action of nitrous acid, which is expediently produced in situ by the reaction of a

presence

Alkali metal nitrites with a dilute mineral acid in / des ß-Hydroxyhydrazide is formed. It is necessary with an excess Nitrous acid to work, the ratio of hydrazide to nitrous acid at least 1: 1.6, preferably 1: 5 or more, is; this excess is completely removed at the end by adding appropriate amounts of urea. The Reacticn is done by placing the aqueous acidic mixture under a deck of an organic solvent, such as mixtures of petroleum ethers with a boiling point range of 60-90 C., the Temperatures define the corresponding optimal V.'ert at which the rearrangement is regulated and terminated accordingly can.

The following example shows in detail the application of the invention Process for the preparation of 8-N-phenethyl-1-oxa-3,8-diaza- (4,5) -decan-2-one with the following formula:

f.

(C ₁₅ H ₂₀ N ₂ O ₂ )

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The IR-3 spectra are on a Perkin-Elmer device, Mod, "257, * The letters in brackets next to the values of the wavelengths refer to the intensity of the absorption peaks: (s) = strong, (m) = medium; (iü) = weak - (b) = widened.

The thin-layer chromatographs from which the values of the frontal ratios (Rr-) of the spots inferred occurred on silica gel chromatographic plates immersed for one hour at 120 ° C. using a 6: 2: 6: 1 mixture Activated chloroform / benzene / ether / methanol as eluent and by spraying to find the stains with a solution of alkalized potassium permanganate (yellow-green spots on a dark red background). The alkalized Potassium permanganate was obtained by mixing equal volumes of a 2% aqueous potassium permanganate solution and a 4% Solution of sodium bicarbonate.

B β is ρ ie 1 1_

A) [\ l-Phenethyl-4-hydroxy-4-ethyl-acetate-piperidine.

A suitable electromechanical one with a column reflux condenser! Iturde stirrer, dropping funnel and gas inlet tube provided flask with 32 g (0.5 mol) activated zinc, 100 ecm anhydrous benzene / Ether-fishing (1: 1 Vol./UoI) and crystals of bisublimated 3od loaded. -

At an internal temperature of 50 C. was with stirring and under an inert gas blanket the dropwise addition of a solution of 20 ecm (0.25 mol) of ethyl bromoacetate in 50 ecm of anhydrous ether /

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-ΙΟΝ -

Benzene mixture (1: 1 V / ol. / L / pl) started.

After adding about two-thirds of the feed, the reaction started initiated; the temperature rose and the dropping rate was adjusted so that the solvent was gently Was held at reflux.

When the addition was complete, the reaction mixture was refluxed for 2 hours and then left to stand for 1 hour.

Before beginning the second stage, the complete disappearance of the free bromoacetic ester from the solution must be examined. For this purpose, a sample of the bromine-containing solution is analyzed by thin layer chromatography using absorbent silica gel "Merck G 254" and a 10: 2 mixture of n-hexane / chloroform tested as eluant; under these conditions the ethyl bromoacetate becomes a fluorescent spot with R "= about 0.2 established.

At the same time it is advisable to also carry out a spectrophotometric control by diluting one drop of the solution in 10-15 ecm of a 1: 1 mixture of chloroform and methanol. That Ethyl bromoacetate shows under these conditions in a 1 cm cell a strong absorption at around 238 nm.

After ensuring the absence of free bromine ester in the reaction mixture, the temperature is raised to about 15 C. increased, and it is made up with the dropwise addition of a solution 20 g (0.1 mol) of N-phenethyl-4-piperidone in 30 ecm of an anhydrous 111 mixture of benzene-ether started with stirring.

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During the addition, it is advisable to add further amounts of 10-20 ecm of ether to the reaction mixture in order to accelerate the separation of the end product in the form of a solid and dispersed in the solvent. After this addition, the suspension is violently and / pus stirred for 2 hours at 0 ^0C.

The above procedure allows the various controls of the reaction with high precision, resulting in high yields of pure Product achieved that is not made up of unwanted by-products

the reaction is impaired. /

■ ·. ■ L '

The completion of the reaction is determined by thin layer chromatography by examining both the disappearance of the spot of the N-phenethyl-4-piperidone starting material and the appearance of the more polar spot with R _f = 0.3.

The final Reaktionsprddukt is isolated by conventional filtration and then dried under acuum V / ^Q at 40-50 C..

Before the hydrolysis of the reaction product is carried out, the

carried out the following checks:

Dosing the zinc with ethylenediaminetetracetic acid (.EDTA);

acidimetric titration;

Chromatography.

The solid reaction product with "the" formula: "

O-Zn-Br

CH ₂ -COOEt

50983 3/0996

is in a 1: 1 (v / v) mixture of acetic acid and water hydrolyzed with stirring at low temperature.

After the product has been completely solubilized, the solution is neutralized to a pH of 7 with 20% w / v NH.OH, the temperature being kept at ⁰ ° C. The solution is then extracted a few times with 100 ecm of benzene each time.

The combined Behzol extracts are dried over anhydrous CD, filtered and concentrated to a specific residue

The residue (20 g, namely 70 % of the theoretical molar yield) showed the following properties:
TLC: R _f = about 0.3

IR (liquid film); Peaks at 3200-3700 cm " ¹ (b) 0 -OH

1730 cm " ¹ (s) V ¹ C = 0 of -C-CC-R

700 cm ",, (-m) Z with aromatic 750 cm "(m) J substitution

NMR (CdCl,): triplet centered at 1.5 j (pprn) = = 3H -C *

Quadruplet centered at 4.4 d (ppm = = ^2H " ^C- O-CH ₂ -CH ₃

To determine the presence of the ß-hydroxyester group u / urde-nit Thionyl chloride treated. - ^. ·

The test was carried out simultaneously in two test tubes. To a solution 1 ecm SCCl was added from 0.5 ecm β-hydroxyester in 1 ecm benzene. One of the two samples was taken for 15 minutes at room temperature.

- even more-

temperature while the second sample / 15 minutes in a water bath at about 75 C. was kept »after elapsing

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After the prescribed time, both solutions were treated with 2 ecm of water each, the whole was passed into a separating funnel and the aqueous phase obtained was made alkaline by adding ammonium hydroxide and extracted repeatedly with 2-3 ecm of benzene each time. The combined benzene solutions were thoroughly salted out, washed neutral with water _{, dried over K 9} CQ-, and concentrated under vacuum. The samples obtained had the following chromatogram:.

a) Test at room temperature. Spots with R = 0.3; 0.5; 0, 6

b) Test at 75 ° C.

Spots with R "= 0.5; 0.6

B) N-Phenethyl-'i-hydraxy- ^ acetohydrazidpiperidine A 500 ccm flask equipped with a reflux condenser was filled with 20 g (about 0.07 mol) of I-phenethyl-4-hydroxy-4-athylacetatpiperidin, in 20 ecm ". Benzene dissolved, charged. A large excess of hydrazine hydrate (30 ecm of the 85- ^ strength reagent; about 0.6 mol) was added to the solution and the mixture obtained was heated to about 50-60 ° C. Then ethyl alcohol was added to added to obtain a homogeneous solution under hot conditions. the mixture was kept for 1 hour at 50-60 ⁰ C., then cooled to room temperature and 5 days allowed to stand. After completion of the reaction, the excess hydrazine was 1 / aku.um in a desiccator over H ₅ SO removed, then the solution was again evaporated under vacuum to dryness, and yielded a solid brown product in a yield \ / on 75-85 wt -.% d.Th.Das from üiäthyläther crystallized ß-Hydroxyhydrazid had the following properties :.

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- 14 -

F .: 1TO- ° C. (not corrected)

TLC: R _f = about 0

IR (in Nujol), bands at 3200 cm " ¹ (b) O-OH

3380 cm " ¹ (m) \ J -! \! H from -CuMHNH ₂

3300 cm " ¹ (m) i / -NH by CONHNH-

1650cm " ¹ (s) / -C = O from -CONHNH ₀

-1 750 cm (m), _{monosubstituted}

700 cm "(m)) aromatic

C) 8N-phenethyl-1-oxa-3,8-diaza-spiro- (4,5) -decan-2-one
25 g of β-hydroxyhydrazide were dissolved in 150 ecm of 2N HCl in a 100 cc flask and the solution was placed under a blanket of petroleum ether (bp 65-90 ° C.). In the previously cooled to ⁰ C. 5-1O reaction vessel an aqueous solution of excess sodium nitrite was added dropwise (about 10 g of salt in 100 cc of water).

When the addition was complete, the nitrous acid present was decomposed with about 5 g of urea; A reflux condenser was attached to the flask and heated gently with stirring. Even at room temperature, nitrogen evolution was observed to be very violent at 50-60 ^0C. The reaction is eoxthermal and the return of the petroleum ether layer is intended to remove the accumulated heat. After the evolution of nitrogen had ceased, the mixture was cooled, poured into a separatory funnel and the acidic aqueous phase was collected. This was by adding conc. Ammonium hydroxide made alkaline, salted out thoroughly and extracted a few times with benzene. The benzene extract was washed neutral, dried over KoCD and the solvent was evaporated off under vacuum. The spirodecane obtained

5098 33/0903

(Mol yield: 80 % of theory) crystallized from benzene / petroleum ether and showed the following properties: F .: 154-156 ° C. "■

TLC: R _f = 0.1

UU in methanol X _max = 285 nm IR (in Nujol), bands at 3280 cm " ¹ (m) J -NH

1730 cm " ¹ (s) \) -C = O of -Q-CO-NH-

750 cm (m). _{monosubstituted} -1 / χ Χ aromatic

750 cm (m).

The final molar yield of stages ft, B and C in total was 41.6 % of theory, based on the starting piperidone-4.

In the following Examples 2 to 9 the procedure of Be; game 1 repeated, the N-substituted 4-piperidone used as starting material different iuar. Example 2

1-0xa-2-oxo-3,9-diaza-8 (3 ^l , 4'-methylenedioxyphenethyl) spiro (4,5) decane

F .: 183 ° C.

(XXXVI)

The starting material 1- (3 ', 4 -r ^/ iethylGndioxyphenyäthyl) -p ^ eric: cr ·, -

9833/09 «:?

■; - ..: · 2505U3

- 16 - j

was obtained by alkylating piperidone-4- with 3,4-methylenedioxyphenethyl chloride manufactured. The β-hydroxy ester was prepared by reacting the compound ('IX) with ethyl bromoacetate according to the modified Reformatzkij method.

The FioliAusbeute of compound (XXXVl) as the free base was 24) 'z of theory, based on the starting piperidone-4 (IX).

Example 3

i-üxa-2-OKO-J, 8-diaza-8 (4'-fluorophenethyl) -spiro- (4,5) -decane.

(XXXV)

F. a) as free base = 152 ⁰ C.

b) as hydrochloride 247 ° C. ''.

The starting 1- (4 ^l -fluorophenethyl) -pieridOn-4 (X)

(X)

ujurde u / ie is made as follows:

ORIGINAL INSPECTED

5 O 9-8 ^ 3 /

2505H3-

CH ₃ NO ₂ ^ _F / \ _{CH = CH} . _N o ₂

2CH ₂ = CH-COOE ^

, CH ₂ -CH ₂ -COOEt

CH ₂ -CH ₂ -N

CH ₂ -CH ₂ -COOEt

1) Dieckmann ff

2) H + CT

CH ₂ -CH ₂ -NV

'AL

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The ß-rlydroxyester was by reaction of the compound (X) - with Ethylhromacetate according to the modified Reformatzkij reaction

manufactured.

The molar yield of Compound (XXXV) as a free base was

46 % of the total based on the starting piperidone-4.

Example 4

1-0xa-2-oxo-3,8-diaza-8-phenoxyethyl-spiro- (4,5) -decane

.0

0-CH ₂ -CH ₂ -N

N-H

(XXXIII)

Q .: a) as free base = 138 ⁰ C.

b) as hydrochloride = 226 ⁰ C.

- The starting 1-phenoxyethylpiperidone-4 (Xl)

0-CH ₂ -CH ₂ -N Vo

^: ■:. (χι)

was obtained by alkylating piperidone-4 with phenoxyethyl bromide

manufactured.

The ß-hydroxy ester was prepared by reacting the compound (Xl) with ethyl bromoacetate according to the modified reform matzkij reaction.

The molar yield of the compound (XXXIII) as free base was 55 % of theory. based on the starting piperidone-4 (Xl).

JMSPECTED

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example

1-0x3-2-0X0-3,8-diaza-8-cinnaffiyl-spiro- (4,5) -decane

N-H

(XXXII)

F .: a) as free base = 175 ° C.

The starting i-cinnamyl-piperidnn-4 (XIl)

(XII).

prepared by alkylating piperidone-4 with ginnamyl chloride. .

The corresponding β-hydroxy ester was obtained by modified Reformatzkij reaction on compound (XIl) using ethyl bromoacetate.

The molar yield of the compound (XXXIl) als.frei base was 31 ) l d.Tb ·, based on the starting piperidone. ~ "-

B ejs ρ 1 each. .6 . -

1-uxa-2-oxo-3,8-diaza-8-diphenylmethyl-spiro- (4,5) -decane

(XXXIV)

F. the free base = 20Q ^a C.

< _NsPe0TED

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- 2D The starting 1-diphenyl meth yIpiperidon-4 (XIII)

-CH

(xiii)

was obtained by alkyl terene of piperidone-4 with diphenylmethyl bromide manufactured.

The modified Reformatzki j reaction took place on the linkage (XIII) with ethyl bromoacetate. ...... The molar yield of the compound (XXXIV.) Was 34 % of theory, based on the starting piperidone-4. ......

Example 7

1-0xa-2-oxo-3,8-diaza-8 (3 ^l -trifluoromethylphenethyl) -spiro- (4,5) -decane

V-CH ₂ CH ₂ Λ I /> f > NH

F. des Hydrochloride = 232 ⁰ C.

(XXXIΊ

The starting 1- (3 ^I -trifluoromethylphenethyl) -piperidön-4 (XIV)

was obtained from m-trifluoromethylbenzaldehyde according to Example 2.

The modified Reformatzki j reaction with d'er union (XI \?) Took place with ethyl bromoacetate. The molar yield of the compound (XXXl) was 60 ρ of theory, based on the starting piperidone-4.

_; ^; - ^: "" 509 83 ^ / ^ 0 9 9 8- ^ ^OR 'QrNAL inspected.

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B eispi β 1

1-0xa-2-oxo-3,8-diaza-8-benzyl-spiro- (4,5) -decane

CH

- (Xt

(XXX)

F. Free base = 178-179 ° C.

The starting i-benzylpiperidone-4 is a known, commercially available product. The modified Reformatzkij reaction was carried out using ethyl bromoacetate. The molar yield of compound (XXX) was 80 % of theory, based on the starting piperidone.

Example 9

1-Üxa-2-oxo-3,8-diaza-8-phenethyl- * 4-phenyl-spiro- (4,5) -decane

N-H

F. = 211 ^U C. "^^. (XXXVII)

The starting 1-phenyethyl-piperidone-4 (XV)

(XV)

was made according to the following scheme:

CH ₂ -CH ₂ -NH ₂

2 CH = CH-COOEt

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CH ₂ -CH ₂ -N

XH ₂ -CH ^ -COOEt

^ CH ₂ -CH ₂ -COOEt

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) Dieckmann

-CH ₂ -N) = 0

(XVI)

The modified Reformatzkij reaction took place through implementation of the compound (XVl) with ethylbromophenyl acetate. The molar yield of the compound (XXXVIl) was 31 Jib.d.Th. based on the Starting piperidone.

In the above examples, the modified Reformatzkij reaction took place with ethyl bromoacetate, but this is not a restriction, because it. all that is necessary is that a five-membered ring should be formed ..

The following table 1 gives results of pharmacological tests which show the interesting properties of the compounds according to the invention confirm.

509S33 / 0 998

L SUSPECTE

Table 1

CD OO Ca).

Connection

1 2

3 4

5 6

O — ι

R-N

NR ¹ H

R-

R m F (O) -CH. -CH -

^ Q) -O-CH ₂ -CH ₂ .

_B I Ph-CH- ^R "I, ph

CF ₃

(Sy-CE -CH ₉ -

CoV-CH ₂ -

.CM ₂ -CH ^

^LD 50 -

(in rats)

mg / kg i.p.

Broncho spasm test

ä ^. Dose for 50% inhibition

mg / kg i.v.

2 35 (i907282)

282 (256-312)

344 '(32 3-365)

346 (325-368)

344 (286-412)

• 319 (33ΟΓ-339)

230 (198-266)

Hystamxn '

SerolAcetyl

0.2

> 0.5

> 0.5

, 0.5

> 0.5

tonin

> 2.5

0.5

> o, 5

> 0.5

> 0.5

0.2

choline

> 2.5 2

> 0.5

> 0.5

> 0.5

> 0.5

Table 1 continued

CJl O CO CD CO CO

CD CD CD CO

d. i
1 . Test with
plate heated
(Mice) Caesin-induced edema
Rats ί % volumen
[■ change \ Connect
No. 2 i ii.p. mg / kg
I. { % Increase
ι · d. threshold!
worth Total dose
i-mg / kg per os *
(48 hours) 39.5 3 40 80 310 j 19.4 4th ! ίο 41.7 70 I 26.3 VJl 100 49 440 4.6 7th 100 U9 440 [10 7th 50 45.6
• 310 9.4 · 100. : 93 340; 16.1 25 i '
I. 63.4 190
I.
I.

cn ο cn \

In Table 1 above are the analgesic / efficacy data expressed as the percentage change in stimulation schujellenujertes in mice;

anti-inflammatory efficacy data are expressed as volume change of kaolin-induced edema in Wistar rats;

the tests with regard to the antagonistic activity against bronchospasm were carried out on guinea pigs according to the experience of Konzett and Roessler (Arch. Exper .Pathol.Pharm., 71 ^ (1940), 195). -: / .. ['

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Claims (7)

^ Process for the preparation of spiro (4,5) decane derivatives of Formula: -N-H in which R stands for ß-phenylethyl, 3 ', 4 ¹ -methylenedioxy- (ß-phenylethyl) -ß- (p-fluoro) -phenylethyl, ß-phenoxyethyl, cinnamyl, diphenylmethyl or ß- (3'-trifluarmethyl) -phenylethyl and R ^{1 is} hydrogen or phenyl, characterized in that one (1) a 1-substituted piperidone-4, which contains a group R, according to the modified Reformatzkij reaction in an anhydrous one Solvent mixture of benzene and ethyl ether at a temperature between 25-75 ° C. with Einsm oC-haloalkyl acetate Formula: R ¹ -CH-CODEt (V) in u / hich R ¹ has the above meaning and X is Cl, Br or I, in the presence uon activated elemental zinc in a molar ratio of at least 1 mole of l \ i-substituted piperidone-4, 1 Hol compound (V) and 1 Shark activated zinc to form a ß-hydroxy ester product of the formula: "Λ 0H CH * - COOEt R ¹ ORIGINAL INSPECTED 509833/0998 in which R and R ^{1 have} the above meaning, reacts and wins the ß-hydroxy ester product; (2) the beta-Hydroxyesterprodukt with excess hydrazine 8-30 hours at a temperature of 40-60 ⁰ C. · in a molar ratio of ester to hydrazine of from 1: 5 to 1: 100 Hydroxyhydrazidsder ß-to form the corresponding formula ■ ή / " ^ - ' \ h-conhnh ₂ (ν !!) implements; and (3) the beta-Hydroxyhydrazid according to the Curtius Umlagerungsreakticn by reaction with excess nitrous acid in the presence of a v'erdünnten mineral acid at a temperature from room temperature to 6O ⁰ C. for formation of the spiro- (4,5) -decanderivates of formula ( i) surrounded. 2.- Uerfahren according to claim 1, characterized in that the reaction of stage (1) is carried out in four stages, which are characterized in that one
a) a primary adduct of the formula: R'-CH-COOEt ' ZnX "the ~ obic welch'er R ¹ and X | e bedeutühgTfiüiien, by reaction of activated elemental zinc with demo ^ -Halcgenalkylacetat at a temperature between 50-60 ⁰ C. in an anhydrous solvent mixture of benzene and" forms in ethyl ether until Deroc -Halogenalkyl ester has completely disappeared from the reaction mixture j '- - "- ORIGINAL INSPECTED 50983 3/0998 - 28 b) Gin final adduct of the formula: CH COOEt by reacting the primary adduct and N-substituted A-piperidone in the same reaction medium as in step (a) and in one Temperature between 0-20 ° C. forms; c) the complete precipitation of the final adduct at a temperature of 0 C. by intermittent addition of anhydrous -Ethyether causes and the final organometallic adduct filtered off and dried; and d) decomposes the final solid adduct to form the desired β-hydroxy ester product of the formula (l / l) and the latter as wins as an oily product that solidifies at low temperature. 3. - Method according to claim 2, characterized in that the The reaction of step (a) is continued until it is confirmed by analysis of the reaction mixture that the, ^ - haloalkyl acetate is absent. 4.- V / experience according to claim 2, characterized in that the * Reaction from step (b) is continued until analysis of the reaction mixture reveals the absence of the substituted 4-pipsridone is confirmed. 5, - The method according to claim 2, characterized in that the Decomposition stage (d) of the final adduct by hydrolysis with a mixture of acetic acid and water in a volume ORIGlNAL INSPECTED 509833/0998 2505U3 ν ratio of 1: 1 with the solid product of step (c) takes place. 6.- The method according to claim 2, characterized in that the reaction medium of step (a) is an anhydrous mixture Benzene and ethyl ether in a volume ratio of 1: 1 is. 7.- A method according to claim 1, characterized in that dia step (3) is carried out under a blanket of petroleum ethers with a boiling point between 60-90 ⁰ C.. B, - organs-metallic complex with the formula: R-I -COOEt / V N Υ in which R, R ¹ and X have the meaning given in claim 1 to have. The patent attorney: 11 509833/0998