DE2241027A1 - PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS - Google Patents

Description

Process for the preparation of new heterocyclic compounds

The invention relates to a process for the preparation of new compounds of the formula I in which R 1 is hydrogen, lower alkyl, fluorine, chlorine, bromine or methoxy and Rp is hydrogen, lower alkyl, chlorine or methoxy or R ₁ and R ₂ together represent the methylenedioxy group form, ^{1 is} R-, hydroxyl, a lower alkylcarboxy or monoalkylcarbamoyloxy group and A is the carbonyl group, the l / 3-dioxolan-2-ylidene group or the l, 3-dioxan-2-ylidene group, and their Acid addition salts and also includes the compounds of formula I and their acid addition salts.

According to the invention, the new compounds of the formula are obtained I by one

a) for the preparation of compounds of the formula Ia in which R ₁ , R_ and R have the above meaning, or the compounds of the formula Ib in which R ₁ , R ₂ and R _{3 have the} above meaning, and A for the l, 3 -Dioxolan-2-ylidene group or dia 1,3-Dloxan-2-yldene group, compounds of the formula II, in which R-, R ₂ and R, have the above meaning, with compounds of the formula HIa, in which X Chlorine, Bros, iodine or the remainder of an organic sulfonic acid and A ¹¹ denotes di @ C & * bonyl groups or a thiooxo or thioketal formation by ketal or thiooxo

309800 / 117S

22A1Q27

protected carbonyl group, or with compounds of the formula IHb, in which X and A ^{1 have the} above meaning, and, for the preparation of compounds of the formula Ia, any protective groups from the compounds of the formula Ic, in which R ₁ , R ₂ , R and A ^{11 have the} above meaning, then splits off again, or

b) for the preparation of compounds of the formula Id in _{which R 1} , R ₂ and A have the above meaning and R. is lower alkyl, compounds of the formula Ie in which R _{1, R?} and A have the above meaning, esterified with compounds of the formula IVa in which Rj has the above meaning and X represents chlorine, bromine or the acid radical of a lower carboxylic acid, or

c) for the preparation of compounds of the formula If, in which R _1, R ₂ , R ^ and A have the above meaning, reacting compounds of the formula Ie with compounds of the formula IVb, in which Rj. has the above meaning

and, if desired, separating any diastereoisomer mixtures of compounds of the formula I into their isomers and / or if desired, the compounds of the formula I obtained are converted into their acid addition salts.

Preferably R 1 and R p are hydrogen or one of the two substituents arranged in the 5-position of the ring structure.

The lower alkyl groups symbolized by R _{1 and R g} preferably have 1 to 3 carbon atoms. The lower alkyl groups R ^ contained in the radical R preferably have 1 to 4 carbon atoms and are in particular methyl.

Process a) can be carried out, for example, in such a way that a compound of the formula II is combined with a compound of the formula IHa or IHb In an organic which is inert under the reaction conditions Solvent, e.g. in an aromatic hydrocarbon such as

..-. ,, 309009/1178

1 & 1027

Benzene or toluene, in a halogenated hydrocarbon such as chloroform, in a cyclic ether such as tetrahydrofuran or dioxane, in a lower alcohol such as ethanol, in dimethylformamide or in acetone, with the addition of an acid-binding agent, for example an alkali metal carbonate such as sodium or potassium carbonate, or a organic base such as pyridine or triethylamine heated to temperatures between preferably about 50 and 150 °. The reaction time can be between 1 and 70 hours. Suitable protective groups of the carbonyl function are, for example, ketals which can be cleaved at low temperatures, preferably at temperatures of at most 25 ^e , and without the use of higher concentrated acids, such as, for example, optionally mixed ketals of lower monohydric or dihydric alkyl alcohols, alkylthioalcohols or mixed alkyloxothioalcohols. Cyclic ketals with 5 to 6 ring members, in particular dioxolane, are preferably suitable. The protective group is split off after the end of the reaction from the crude ketals formed in a manner known per se, for example by hydrolysis with dilute mineral acids, such as, for example, with approx. 2N hydrochloric acid, preferably at temperatures between 0 and approx. are cleaved in a known manner with mercury (II) chloride.

Process b) can be carried out by methods customary for esterification be carried out, for example, compounds of the formula Ie with the acid anhydrides or halides of the formula IVa, optionally in an organic solvent which is inert under the reaction conditions, e.g. in an aromatic hydrocarbon such as benzene or toluene or in a cyclic ether such as dioxane, optionally with the addition of an acid-binding agent By means of, for example, an alkali metal carbonate such as sodium bicarbonate, sodium or potassium cardboard,

3 C 9 8 0 3/11? 8 ORIGINAL INSPECTED

• ''"" -. ^: * 1 ■ ::. 22A1027

or an organic base such as pyridine or triethylamine, which can also serve as a solvent, implement at temperatures between about 10 and 8o °, the reaction time Can be 1 to 20 hours.

For the preparation of compounds of the formula If by process c), for example, the compounds of the formula Ie can be mixed with alkyl isocyanates of the formula IVb in an organic solvent which is inert under the reaction conditions, for example an aromatic one Hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as methylene chloride or chloroform or react a cyclic ether such as dioxane or tetrahydrofuran for 1 to 50 hours at temperatures between about 10 and 80 ° permit.

The compounds of the formula I can be isolated and purified from the reaction mixture in a manner known per se; the free bases can be converted into their acid addition salts and vice versa in a customary manner. The compounds of the formula I can be in 2 diastereolomeric forms, namely as IRS , 3RS isomers

and IRS, 3SR isomers are present. In the previous

The method described above remains the steric configuration of the compounds obtained, so that starting from sterically pure starting compounds, sterically pure compounds of the Formula I and, starting from mixtures of diastereoisomers, also mixtures of diastereoisomers of compounds of the formula I are obtained will. Mixtures of diastereoisomers can be made more suitable in a manner known per se, for example by fractional crystallization Acid addition salts or separated into their individual isomers by chromatography.

The starting compounds can be obtained, for example, as follows:

a ¹ ) Compounds of the formula II can be obtained, for example, by adding compounds of the formula V in which R., R _?

309809/1178

- 5 - '100-3604

and R have the above meaning, hydrogenolytically debenzy- · ■ lured. The hydrogenation can e.g. in the presence of a catalyst, preferably a palladium catalyst, in an organic solvent which is inert under the reaction conditions, E.g. in ethyl acetate or a lower alcohol such as ethanol.

b ¹ ) Compounds of the formula Iia in which R ₁ and R _{2 have the} above meanings can be obtained, for example, by reducing compounds of the formula VI in which R and R have the above meanings. The reduction can -

for example with a complex metal hydride such as
Lithium aluminum hydride in an organic solvent which is inert under the reaction conditions, for example a
aromatic hydrocarbon such as benzene or an ether 'such as tetrahydrofuran, dioxane, diethyl ether or dimethoxyethane. According to another variant of the process, the compounds of the formula VI can firstly be used, for example, with sodium borohydride in a lower alcohol such as methanol or in an alcohol-water mixture or catalytically in the presence of platinum oxide in a lower alcohol to form compounds

the formula

VIa, where R, and R _? have the above meaning, reduced
and then these with lithium aluminum hydride
to be further reduced to the compounds of the formula Ha.

Depending on the nature of the substituents R ₁ and R and the reduction conditions used, the reductions become steric
pure compounds of the formula VIa or Ha or mixtures
their diastereoisomeric forms are obtained based on
known catfish can be separated into their individual isomers, for example by fractional crystallization or by chromatography.

309803/117 8

- 6 -. . ioo-

c ¹ ) Compounds of the formula Vb, in which R 1, R 'and R' have the above meaning can be obtained, for example, by combining compounds of the formula Va, in which R 1 and R 'have the above meaning, with compounds of the formula IVa, vile described under procedure b).

d ¹ ) Compounds of the formula Vc in which R _{1, R 0} and R 1 have the above meaning can be obtained, for example, by reacting compounds of the formula Va, as described under process e), with compounds of the formula IVb.

e ^T ) Compounds of the formula Va can be obtained, for example, by reducing compounds of the formula VII ^{in which R 1} and R 1 have the above meaning, as described under process b 1) .

f ') Compounds of formula VII may be obtained, for example, by reacting compounds of formula VI with compounds of formula VIII wherein X' is chlorine or preferably bromine benzylated. The benzylation can be carried out, for example, in an organic solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene or toluene, in the presence of a basic condensing agent such as sodium amide.

g ^% ) Compounds of the formula VI which are valuable intermediates for the preparation of medicaments, for example compounds of the formula I, can be obtained, for example, by adding compounds of the formula IX in which R and R are as defined above and Y is hydroxyl, halogen or lower alkoxy is cyclized. The cyclization is preferably carried out in the presence of an acidic component

309809/1178

241027

Densationsmittel, optionally in the presence of a inert organic solvents under the reaction conditions, s.B. an aromatic hydrocarbon such as benzene or toluene, at temperatures between room temperature and 180 °, preferably between 100 and 160 °. Suitable acidic condensing agents are for example strong inorganic or organic acids such as polyphosphoric acid, phosphoric acid, sulfuric acid, Hydrochloric acid, methanesulfonic acid, trichloroacetic acid, or Acid halides such as phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride or strong Lewis acids such as e.g. ' Aluminum trichloride.

Compounds of formula IX in which Y is hydroxyl or halogen can be obtained, for example, by Compounds of the formula X in which R. and R "have the above meaning

309809/1178

• 100-5604

2241Q27

and R ₅ denotes lower alkyl, hydrolyzed and the acids obtained are, if desired, converted into their acid halides in a manner known per se. The hydrolysis is preferably carried out in an alkaline medium.

i ') Compounds of the formula X can be obtained, for example, by adding compounds of the formula XI in which R 1, R 1 and R _r

Ic 5 have the above meaning in the presence of a catalyst

cyclisic.rend hydrogenated. The hydrogenation takes place

preferably at temperatures between about 50 and 100 ° in the autoclave at about 70 to 90 atmospheres hydrogen pressure in the presence an organic solvent which is inert under the reaction conditions, for example a lower alcohol and can take about 10 to 50 hours. Raney nickel, for example, is suitable as a catalyst.

j ¹ ) Compounds of the formula XI can be prepared, for example, by reacting compounds of the formula XII, in which R 1, R p and R have the above meanings, in a manner known per se with alkyl bromine acetic acid esters in the presence of a basic condensing agent.

k ') Compounds of the formula XII can be obtained by adding compounds of the formula XIII, wherein R,, R ₀ and R ₁ -

12 5

Have the above meaning, optionally in the presence of a water-miscible organic solvent which is inert under the reaction conditions, for example a lower alcohol of the formula XIV, in which R ₁ . Has the above meaning, reacts with an aqueous alkali metal cyanide solution. The reaction is preferably carried out at an elevated temperature, for example at temperatures between 40 and 100 °, and can last between 10 and 20 hours.

309809/1 1 78

• «*. t

■ 100-3Ö04

l ¹ ) Compounds of the formula XIII can be obtained, for example, by reacting compounds of the formula XV, in which R _{1 and R 2 have the} above meaning, with malonic acid ester, of the formula XVI, in which R, - has the above meaning, in a manner known per se .

The compounds of the formula I and their pharmacologically acceptable ones Acid addition salts have not yet been described in the literature. They are interesting pharmacodynamic properties and can therefore be used as remedies. In particular, own they have analgesic properties. These can be seen, for example, in the tail flick test on the mouse with doses of approx. 1 to 30 mg / kg body weight see above, as well as by inhibiting the phenylbenzoquinone syndrome on the mouse with doses of approx. 1.5 to. 50 mg / kg p.o ..

Due to their analgesic effectiveness, the substances can be used to treat pain of various origins. The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained in test animals with a dose of about 1 to 50 mg / kg body weight. If necessary, this dose can be administered in 2 to 4 portions or as a sustained release form. For larger mammals, the daily dose is around 50 to 500 mg. For example, for oral administration, the partial doses contain about 12 to 250 mg of the compounds of the formula I in addition to solid or liquid carrier substances. For example, p-fluoro-4- (2-hydroxyspiro [indane-1,5'-pyrrolidin 1 -1 ^! -Yl) butyrophenone- proved to be particularly suitable.

09809/117

100-3604

In addition, the substances have central damping properties. The central depressant effects can be demonstrated, for example, in mice with doses of approx. 3 to 30 mg / kg body weight in the climbing test and when measuring the motor activity of the mice in the wardrobe cage. The substances cause on mice in doses of approx. JO to 50 mg / kg body weight, this is also one for central dampening substances typical lowering of the rectal temperature.

Due to their central depressant effects, the substances can be used in psychiatry, for example, for sedation and treatment of states of excitement and e.g. sleep disorders

.— find use. The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained with a dose of about 1 to 50 mg / kg of body weight. If necessary, this dose can be administered in 2 to 4 portions or as a sustained release form. For larger mammals, the daily dose is around 50 to 500 mg. For example, for oral administration, the partial doses contain about 12 to 250 mg of the compounds of the formula I in addition to solid or liquid carrier substances. A particularly suitable 4- (5-chloro-3-hydroxyspiro [indane-1, 3'-pyrrolidin] -1'-yl) -p-fluorobutyrophenone proved, for example.

The compounds of the formula I or their physiologically acceptable acid addition salts can be used as medicaments alone or in suitable dosage form with pharmacologically indifferent auxiliaries administered.

If the preparation of the starting compounds is not described, these are known or according to methods known per se or can be produced analogously to those described here or analogously to processes known per se.

309809/1178

100-3604

M. 22-1027

In the following examples, which explain the invention in more detail, but in no way limit its scope should, all Teir, temperature data are given in degrees Celsius.

• l / ¹ J U! «.- - ΐ , t

Example 1: p-Fluoro-4 - (^ - hydroxyspiro [indan ^ 3 ^ -pyrrolidin] -1'-yl) butyrophenone

A) 15 g of spiro [indan-1,3'-pyrrolldin] -3-ol are dissolved in 200 ml of dimethylformamide and mixed with 18 g of sodium carbonate and 23 g of 2- (3-chloropropyl) -2- (p-fluorophenyl) -l , 3'-dioxolane heated to 100 ° for 20 hours. It is then filtered off, the filter residue is washed with 150 ml of chloroform and the organic phases are concentrated. The 2-f3- (3-Hydroxyspirofindan-1,3'-pyrrolidin] -1'-yl) propyl] -2- (p-fluorophenyl) -l, 3 "-dioxolane which remains as a yellow oil is converted into 300 ml of chloroform and stirred with 250 ml of 2N hydrochloric acid for 1 1/2 hours at room temperature.Then it is made alkaline with sodium hydroxide solution, extracted three times with 100 ml of chloroform each time and the chloroform phase is concentrated is added of 8 g of fumaric acid in I50 ml of ethanol. After addition of a little ether the hydrogen fumarate of the title compound 174 fails. mp. I76 to ⁰ (from ethanol / ether).

B) ⁸ * 5 g of spiro [indan-1,3'-pyrrolidin] -3-ol, 12.0 g of 4-chloro-fluorobutyrophenone and. 11.5 g of sodium carbonate are refluxed in 100 ml of dimethylformamide with stirring for 20 hours. After cooling, it is filtered off, evaporated to dryness, taken up in 300 ml of chloroform and extracted three times with 50 ml of 2N hydrochloric acid each time. The acidic extract is made alkaline with 2N sodium hydroxide solution while cooling and extracted with chloroform. The crude title compound remaining as oil after evaporation of the chloroform phase is converted into the hydrogen fumarate with fumaric acid. Mp. Of the hydrogen fumarate of the title compound: 174 to 176 ° (from ethanol / ether).

309809/1 178

': "■ ·'."" ^: Ιόόι-36ο4

C) IRSi3§R - ^ a-ϊΐυοr ^ ² I- Cl-ülXäEaXXSEÄEQ.Li.nd.an-_1 JJ.LiBXXLCQ.! 4 & LQ.L-1 ^f -yl) butyrophenone. Nuclear magnetic resonance measurements using a europium complex show that the hydrogen fumarate of the title compound obtained according to Example 1 A) or 1 B) with a melting point of 174-176 ° represents a mixture of diastereoisomers which is 50% of the IRS, 3RS isomers and 70% of the IRS, 3SR isomers. 12 g of this mixture are dissolved in ethanol and mixed with a little ether. The compound which slowly crystallizes out is, as can be shown by its NMR spectrum, sterically pure and represents the hydrogen fumarate of the IRS, 3SR —p-fluoro-4- (3-hydroxyspiro [indan-1,3'-pyrrolidine] -1 ') -yl) butyrophenons, m.p. 183 ° "

B) IRS, 3RS-p-fluoro-4- (3-hydroxyspiro [indan-1,3'-pyrrolidin] -l'-yl) butyrophenone. The mother liquor obtained in Example 1 C) is concentrated, the residue with 50 ml of chloroform added and shaken with 50 ml of 2N sodium hydroxide solution. The crude IRS, 3RS-p-fluoro-4- (3-hydroxyspirofindan-1,3'-pyrrolidin] -1'-yl) butyrophenone remaining after concentrating the washed and dried chloroform phase over magnesium sulfate is purified by chromatography on silica gel and treated with 20 ml of ethanol saturated with hydrogen chloride gas offset. Upon addition of a little ether, the hydrochloride of the, IRS, 3RS isomer crystallizes out, mp 210-211 °

The starting product can be produced as follows:

a) 200 g of malonic acid ethyl ester, 144 g of benzaldehyde, 14 ml of piperidine, 11.7 S benzoic acid are heated in 400 ml of benzene for 14 hours under reflux of the water separator (bath temperature 130 to 140 °, water separation about 25 ml). After cooling, it is mixed with 200 ml of benzene and washed successively with twice 200 ml v / water, twice 200 ml IN hydrochloric acid and 100 ml saturated sodium bicarbonate solution and the benzene is distilled off on a rotary evaporator. The remaining benzalmalonic acid diethyl ester is purified by distillation,% * 143 to ' 152 °, Kpo _{A Ί} 127 Ws 134 ° ₀

9 Ϊ »tr

ΐυο-> 6ο4

. 22Α 1027

b) 120 g of benzalmalonic acid diethyl ester, 33.6 g of potassium cyanide, l6üO ml of ethanol and 1βθ ml of water are 12 to 14 hours

stirred for a long time at a bath temperature of 60 °.

Then it is cooled with ice water, filtered off from the thorn crystallized potassium bicarbonate, the filtrate is neutralized with about 15 ml of IN hydrochloric acid, air is sucked through the solution for 1 hour with the water jet pump, the solvent is distilled off on a rotary evaporator, the oily residue is decomposed with 100 ml of water and with Extracted 6 times 250 ml of ether each time. The ethyl 3-cyano-3-phenylpropionate remaining after the ether has been distilled off is purified by vacuum distillation. Kp. _Lr 125 to 130 °.

U, J. J

c) 42 g of sodium amide suspended in 400 ml of absolute ether are added dropwise at room temperature to a solution of 158 g of ethyl 3-cyano-3-phenylpropionate and 144 g of ethyl bromoacetate in 1 absolute ether. After adding about half the amount of the suspension, the reaction solution turns light brown and comes to the boil. After the end of the dropping in, the mixture is refluxed for 2 hours, cooled, excess sodium amide is decomposed by careful dropwise addition of water, the ether solution is washed with 250 ml of 2N hydrochloric acid and 250 ml of water and evaporated. The remaining 3-cyano-3-phenylglutaric acid diethyl ester is purified by vacuum distillation. Kp. _Q g 172 to I75 ⁰ .

d) 45 g of Raney nickel are added to 254.2 g of 3-cyano-3-phenylglutaric acid diethyl ester in 1.5 l of absolute methanol and hydrogenated in a 5 l autoclave for 30 hours at 80 ° and 80 atmospheres of hydrogen pressure. After cooling, the catalyst is filtered off, concentrated on a rotary evaporator, the pale yellow oil that remains is taken up in 1.5 l of chloroform and washed with 25 ml of 2N hydrochloric acid, 100 ml of saturated sodium bicarbonate solution and 100 ml of water. The ethyl 5-oxo-3-phenyl-3-pyrrolidine acetate which remains after concentration of the chloroform phase crystallizes on trituration with ether. M.p. 49 to 51 ° (from tTssZ

309809/1178

C β β

1027

e) 195 S 5-0x0-3 ™ phenyl-3-pyrrolidinessigsäureäthylester are dissolved in a mixture of 200 ml of water, k'J g of sodium hydroxide and 750 ml of ethanol with stirring at room temperature. After standing at room temperature for one hour, the sodium salt of 5-oxo-3-phenyl-> pyrrolidinacetic acid has crystallized out. It is dissolved in 600 ml of water and acidified with about 600 ml of 2N hydrochloric acid while cooling with ice, the 5-0x0-3-phenyl-3-pyrrolidine acetic acid separating out in crystalline form. "

f) 200 g of polyphosphoric acid are heated to 160 ° with stirring, 20 g of 5 ~ 0xo-3-phenyl ~ 3-pyrrolidinessigsäur-e are quickly introduced and the mixture is kept at this temperature for 5 minutes, then it is cooled and poured onto 8θΟ g of ice, extracted ten times with 150 ml of chloroform and concentrated the chloroform phase in vacuo. The residual spiro _[indan-5 I 3'-pyrrolidin] -3,5'-dione, which becomes crystalline upon rubbing and seeding is from 70 to 80 ml of ethanol recrystallized »mp. 152-153 °.

g) 17 * 1 g of lithium aluminum hydride in 300 ml of absolute tetrahydrofuran and 600 ml of absolute benzene are placed in a Soxhlst apparatus. 30 g of the reducing spiro [indan-1,3'-pyrrolidine] -3,5'-dione are placed in a Soxhlet tube in the Soxhlet apparatus. The mixture is then refluxed for 20 hours, all of the product being dissolved. The reaction mixture is then cooled and carefully decomposed with 25 ml of water in 25 ml of tetrahydrofuran, the precipitate is filtered off and the filtrate is concentrated. Dae Spiro [indan-l, 3'-pyrrolidin] '- 3-ol remains as a pale yellow oil back and is converted by reaction with a solution of 17 g of fumaric acid in 400 ml of ethanol in its hydrogen fumarate mp, I55 to I58 ⁰ (off. Ethanol / ether).

3098 0 9/117 8 · '

100-3604

Example 2; p-Fluoro-4- (3-hydroxy-6-methoxyspiro [indan-1,3'-pyrrolidin] -1'-yl) butyrophenone

A) 15 g of 6-methoxyspiro [indan-1,3 "-pyrrolidin] -3-ol (diastereo-

mixture of isomers) and 15 g ^ -

Chlor-p-fluorobutyrophenone are heated to boiling temperature in 300 ml of absolute toluene. 22 g of sodium carbonate are added in small portions within 30 minutes and a further 10 g of sodium carbonate are added after 20 hours and the mixture is refluxed for a total of 30 hours. After cooling, it is filtered, the filter residue is boiled up with chloroform and the combined organic phases are evaporated. The crude, light brown, oily title compound that remains is converted into the hydrogen fumarate using fumaric acid. Mp. Of the hydrogen fumarate of the title compound (mixture of diastereoisomers 35:65), 163 to 165 ° (from ethanol / ether).

B) 15 g of 6-methoxyspiro [indan-1,3'-pyrrolidin] -3-ol and 22 g of 2- (3-chloropropyl) -2- (p-fluorophenyl) -l, 3'-clioxolane are according to the in Example 1 A) implemented method described. . Mp Hydrogenfumarates of the title compound: I63 to I65 ⁰ (from ethanol / ether).

The starting material can be produced as follows:

a) jn-Methoxybenzalmalonsäurediethylester, prepared analogously to Example la), Kp. _{Λ (} - I ¹ K) to I50 ⁰ , m.p.

b) 3-Cyano-3- (m-methoxyphenyl) propionic acid ethyl ester ^{, prepared analogously to Example Ib), Kp. _, I 1} K) to ^{150 0} .

c) 3-cyano-3- (m-methoxyphenyl) glutaric acid diethyl ester, prepared analogously to Example lc), bp _no . 163 to 168 °.

309809/1178

d) 3- (m-Methoxyphenyl) -5 ~ oxo-3-pyrrolidinessigsäureäthylester, produced analogously to example ld). The raw compound remaining as a tough gel is processed further without purification.

e) 3- (n> -Methoxyphenyl) -5-oxo-3-pyrrolidl acetic acid analogous to Example Ie) .. The alkaline reaction solution is shaken once with 100 ml of methylene chloride, to remove hydrogenation by-products. Then with 750 ml of 2N hydrochloric acid and 5 times with 150 ml of methylene chloride each time extracted, the methylene chloride phases concentrated and the remaining compound recrystallized from ethanol. 144-146 °.

f) 3- (m-Methoxyphenyl) -5-oxo-3-pyrrolidine acetic acid is reacted analogously to Example If). The yellow, oily crude product formed is an isomer mixture of 6-methoxyspiro [indan-1 * 3'-pyrrolidine] -3,5-dione and 4-methoxyspiro [indan-1,3'-pyrrolidinj-3,5 ^t -dione. When about 20 ml of ethanol are added, the 6-methoxyspiro [indane-1,3'-pyrrolidine] -3,5'-dione crystallizes out in the form of white crystals. M.p. 225 °.

g) 6-Methoxyspiro [indan-1,3'-Py ^ oIIdIn] -3-O1, prepared analogously to Example Ig) from 6-Methoxyspiro [indan-1,3'-pyrrolidine] -3.5 ^! -dion. M.p. 135 to 138 ⁰ (from ethanol / ether)

Example 3: ^ ri§iOhlor-3-hydroxyspiro [indan-1,32-pyrrolidin | -l-yl) -p-fluorobutyrophenone

6-chloro-spiroiindan-1,3'-pyrrolidinj-3-ol (mixture of diastereoisomers) is reacted analogously to Example 1 A) or analogously to Example 2 A). The crude, light brown oily title compound is purified by chromatography on silica gel and then converted into the hydrogen fumarate. . Mp Hydrogenfumarates of the title compound (Diastereo.isomerengemisch): I65 to I67 ⁰ (from methanol / ether). _x

309900/117 8

The starting product can be obtained as follows:

a) m-chlorobenzalmalonic acid diethyl ester, prepared analogously

Example la), Kp. _, = ¹ ^ to 139 °.

"» J

b) 3- ( ^m -Chorphenyl) -3-cyanopropionic acid ethyl ester, prepared analogously to Example Ib), bp. _Λ ^ 158 to 162 °.

c) 3- (m-Chlorophenyl) -3-cyanglutaric acid diethyl ester, prepared analogously to Example lc), _{boiling point Q} * 166 ° to 171 °.

d) 3- (n> -chlorophenyl) -5-oxo-3-pyrrolidinesslgsäureäthylester, produced analogously to Example Id), the crude product is processed further without purification.

e) 3- (ro-Chlorophenyl) -5-oxo-3-pyrrolidine43acetic acid, prepared analogous to example 2e). Mp 178-181 °.

* ■

f) 3- (m-Chlorophenyl) -5-oxo-3-pyrrolidine acetic acid is reacted analogously to Example If), reaction time 15 minutes. The reaction mixture is extracted with methylene chloride. The crystallizate obtained after evaporation of the methylene chloride phase is an isomer mixture of 6-chlorospiro [indanl, 3'-pyrrolidine] -3,5'-dione and 4-chlorospiroIindan-1,3 ^f pyrrolidine] -3 # 5'-dione Both isomers are separated by fractional crystallization from methylene chloride / ethanol. M.p. de3 6-chlorospiro [indan-1,3'-pyrrolidinl-3.5 ^l dione: 210 to 220 °. M.p. of 4-chlorospiro [indan-1,3 * -pyrrolidine] -3,5'-dione: 176 to 179 °.

g) 25 g of 6-chlorospiro [indan-1,3'-pyrrolidine] -3 * 5 * -dione become dissolved in 100 ml of dimethylformamide and 250 ml of methanol and with a suspension of 2 g of sodium borohydride in 50 ml Water and 5 drops of sodium hydroxide solution are added dropwise at room temperature. By cooling the temperature held at 25 °. The solution will be at for another hour

300809/1178

JH

Stirred at room temperature, then poured into water and extracted several times with chloroform. That after evaporation the mixture of the diastereoisomeric forms of 6-chloro-3-hydroxy [indan-1,3'-pyrrolidin] -5'-one obtained from the chloroform phase is processed directly on the market.

h) A solution of 25 g of 6-chloro-3-hydroxyspiro [indan-1,3'-pyrrolidin] -5 'one in 100 ml of ether is added to a suspension of 8.5 S lithium aluminum hydride in 200 ml of tetrahydrofuran and 200 ml of ether and 100 ml of tetrahydrofuran were added dropwise. The mixture is refluxed for 20 hours, then carefully decomposed with 75 ml of water and filtered, and the organic phases are concentrated. The yellow oil that remains is the mixture of the diastereoisomeric forms of β-chlorospiro- [indan-1,3 ¹ -pyrrolidin] -3-ol and is reacted without further purification.

Example 4; 4 ₌ Xif

l-yl ^ -p-fluorobutyrophenone

^ -Chlorspiro-findan-l, 3 '-pyrrolidin] -3-ol (diastereo- - ~ ■ -

isomer mixture) is analogous to example 1 A) or analogous to example

game 2 A) implemented. After cleaning the

The crude product by chromatography on silica gel gives the diastereoisomeric forms of the title compound as ÖIE melt whose Hydrogenfumarate after recrystallisation from methanol / .aether at 161 to I63 ⁰ and 190 to 192 °.

The starting material is obtained starting from 4-chlorospiro [indan-1,3 '· pyrrolidine] ~ 3 / 3'-dione (for preparation see Example 3f)) analogously to Example 3s) to Ja) .

30Θ809 / 1178

80

Example 5: 4- (5-chloro-3-hydroxyspiro [indan-1,3'-pyrrolidin] -l-yl2 ~ p -fluorobutyrophenone

5-Chlorspiro- [indan-1,3'-pyrrolidin] -3-ol is analogous to the example 1 A) or Example 2 A) implemented. M.p. of the hydrogen

fumarate s _;

of the title compound: 148 to 149 °.

The starting material can be obtained as follows:

a) p-chlorobenzalmalonic acid diethyl ester, prepared analogously to Example 4a), _{b.p. o} 135 to l42 °.

b) 3- (p-chlorophenyl) -3-cyanpropionsäureäthylester, prepared analogously to Example Ib), bp. _3141-145 °.

c) 3- (p-Chlorophenyl) -3-cyanglutaric acid diethyl ester, prepared analogously to Example lc), Kp. _Q , 166 to I69 ⁰ .

d) ethyl 3- (p-chlorophenyl) -5-oxo-3-pyrrolldinesse acetate, produced analogously to example Id). The raw product is processed further directly.

e) 3- (p-Chlorophenyl) -5-oxo-3-pyrrolidine acetic acid, prepared analogously to Example 2e). Mp. I90 to I9I ⁰ .

f) 5-chlorospiro (indan- ^{1,3 t} -pyrrolidine] -3.5 ^l -dione _# prepared analogously to Example If), melting point 220 to 222 °.

g) 5-chloro-3-hydroxyspiro [indan-1,3'-pyrrolidin] -5'-one, prepared analogous to example 3g). 172-174 °.

309809/1 178

• «· ·· ft

22A1027 ..

h) 5-chloro3piro ~ (indan-1,3'-pyrrolidin] -3-ol, prepared analogous to example j5h) · The raw product is further processed directly.

Example 6; p-Pluoro-4- ^ 3-hydroxy-4-methoxyi5piro [indan-1,3'-pyrrolidin] -l'-yl) tautyrophenone.

4-Methoxyspiro [indan-1,3'-pyrrolidin] -3-ol is analogous to the example 1 A) or Example 2 A) implemented. ·

M.p. of the hydrogen fumarate of the title compound: 152 to 154 ° (from ethanol / ether).

The required starting product -

4-Methoxysplro [indan- ^{1,3 l} -pyrrolidin] -jj-ol, Snip. 184 to 186 °, starting from 4-methoxyspiro [indan-1,3'-pyrrolidine] -3,5'-dione, melting point 184 to 186 °, which is obtained from the example 2f) after the 6-methoxyspiro [ indan-1,3'-pyrrolidinJ-3,5'-dione obtained mother liquor is obtained analogously to Example 2g). .

Example 7: p-Fluoro-4 - (^ - hydroxy-o-methylspiroU pyrrolidin] -l * -yl) butyrophenone

6-Methylspiro [indan-1,3'-pyrrolidin] -3-ol is analogous to the example 1 A) or Example 2 A) implemented. M.p. of the hydrogen fumarate Title compound: 172 to 174 ° (from ethanol / ether)

The starting material can be obtained as follows:

a) m-MethylbensalmalonsäurödiUthylester, prepared analogously Example la), Kp. ^ 135 bis

3 0 9 8 0 9/1178

b) ethyl 3-cyano-3- (m-tolyl) propionate prepared

analogous to example Ib), bp. 1 ^ 3 to 148 °.

O, J-

c) 3-cyano-3- (m-tolyl) glutaric acid diethyl ester, prepared analogously to example lc), bp. _Q 160 to 167 °.

d) 5-0x0-3- (m-tolyl) -3-pyrrolidinessigsäureäthylester prepared analogous to example Id). The raw product is processed further directly.

e) 5-Oxo-3 ~ (m-tolyl) -3-pyrrolidinessigsä'ure, prepared analogously Example 2e). M.p. 152 to 154 °.

f) 6-methylspiro [indan-1,3'-pyrrolidine) -3,5'-dione analogous to example If). M.p. 188 to 192 °.

g) 3-Hydroxy-6-methylspiro [indan- ^{1,3 f} -pyrrolidin) -5'-one, prepared analogously to Example 3g) further processed as a crude product.

h) 6-methylspiro [indan-1,3'-pyrrolidinl-3-ol, prepared analogous to Example 3h), further processed as a crude product.

Example 8: p-fluorine _r 4- ^ 5 _r fluorine _r 3 _r hydroxy§plr9ilD ^ 34i _r 1,3'-pyrrolidin] -1'-yl) butyrophenone

Vol becomes analog

Example 1 A) or Example 2 A) implemented. M.p. of the urydrogen fumarate of the title compound: 1 ^ 3 to 1 ^ 5 ° (from ethanol / ether).

309809/1178

Si

The starting material can be obtained as follows:

a) p-Fluorbenzalmalonsäurcdiäthylester, prepared analogously to Example la), Kp. _ _N 149 to 155 °.

b) ethyl 3-cyano-j5- (p-fluorophenyl) propionate, prepared analogously to Example Ib), bp. _c 146 to 160 °.

c) 3 ~ cyano-3 ~ (p-fluorophenyl) ßlutaric acid diethyl ester, prepared analogous to example Ic), m.p. 68 to 70 ° (from ether / petroleum ether)

d) 5- (p-Pluophenyl) -5-oxo-3-pyrrolidinessigsäureäthylester, produced analogously to example Id). The one that remains as a tough oil raw compound is processed directly.

e) J> - (p-fluorophenyl) -5-oxo-3-pyrrolidl acetic acid, prepared analogously to Example 2e). M.p. 17 ^ to 176 °.

f) 5-Pluorspiro [indan-1,3'-pyrrolidine] ~ J>, 5'-dione, prepared analogously to Example If). M.p. 198-202 °.

g) 5-fluorospiro [indan ~ 1,3'-pyrrolidine] -3-0I, prepared

analogous to example Ig). The raw connection.

is converted into hydrogen fumarate. M.p. 162 to 164 ° (from ethanol / ether).

Example Q ; p-Fluoro-4- (3-hydroxy-5-methoxyspiro [indan- ^1,3! 2 pyrrolidin] -l'-yl} butyrophenone

5 «Methoxyspiro [indan-1,3'-pyrrolidin] -3-ol (mixture of diastereoisomers) is implemented analogously to Example 3 A) or Example 2 A). M.p. of the hydrogen fumarate of the title compound (Diasterooisoinernn, 5emisch 70:30), 113 to 115 ° (from Aefchanol / Ether).

309909 / 1.176 "

The starting material can be obtained as follows:

a) p-Methoxybenzalmalonsäurcdiät'thylester, prepared analogously

Example la), Kp. 1 ^ 5 to l6o °.

ο »ο

b) 3-cyano-3- (p-methoxyphenyl) proplonic acid ethyl ester, prepared analogously to Example Ib), bp. _Λ , 190 to 200 °.

c) 3-cyano-3- (p-methoxyphenyl) glutaric acid diethyl ester prepared analogous to example Ic). Mp. 65 to 75 ° (from ether / petroleum ether).

d) 3- (p-methoxyphenyl) -5-0X0-3-pyrrolidinessis acid ca'thyl ester, produced analogously to example Id). The connection is processed further raw.

e) 3- (p-Methoxyphenyl) -5-oxo-3-pyrrolidinacetic acid analogous to example 2e). 172-175 °.

f) 5-Hethoxyspiro [indan- ^{1,3 l} -pyrrolidine] -3i5'-dione _J prepared analogously to Example If). M.p. 179 to 180 °.

g) 5-methoxyspiro [indan-l, 3'-pyrrolidin] -3 _ _o l, prepared as in Example Ig). The crude compound (mixture of diastereoisomers) is processed further without purification.

Example 10: p-Pluoro-4- (3-hydroxy-5-methylspiro [indan-1,3 'pyrrolidin] -l'-yl] butyrophenone

5-methylspiro [indan-1,3'-pyrrolidin] -3-ol (mixture of diastereoisomers) is implemented analogously to Example 1 A) or Example 2 A). Mp. Of the hydrogen fumarate of the title compound (mixture of diastereoisomers 25: 75), 163 to 164 ° '(from ethanol / ether),

309809/1 178

2241Q27

- & r- 100-3604

That. Starting material can be obtained as follows:

a) ethyl p-methylbenzalmalonate, prepared analogously to Example la), Kp. _L I60 to I67 ⁰ .

b) 3-Cyano-3- (p-tolyl) propionic acid ethyl ester, prepared analogously to Example Ib), Kp. _Q ^ 145 to 155 °.

c) 3-Cyano-3- (p-tolyl) glutaric acid diethyl ester, prepared analogously to Example 1c), Kp. _Q ~ I85 to I90 ⁰ .

d) 5-0x0-3- (p-tolyl) -3-pyrrolidinessigsäureäthylester prepared analogous to example Id). The connection is raw processed.

e) 5-0x0-3- (p-tolyl) -3-pyrrolidl acetic acid, prepared analogously Example 2e). M.p. 184 to 186 °.

f) 5-methylspiro [indan-1,3'-pyrrolidine] ~ 3,5'-dione, prepared analogous to example If). M.p. 162 to 164 °.

g) 5-methylspiro [indan-1,3'-pyrrolidine] -3-0I, prepared analogous to example Ig). The compound (mixture of diastereoisomers) is processed further raw.

Example 11: 4-jf5,7-pichlor _:: 3rhydro ^ spirg | indan _r l ₂ ^ _z pyrrolidin] -1'-yl] -p-fluorobutyrophenone

-ol will

implemented analogously to Example 1 A) or Example 2 A). Of the hydrogen fumarate of the · -> "" _ "..

309806/1173

• * 9 4

Title compound: 149 to 152 ° (from ethanol / ether). The starting material can be obtained as follows:

a) 2, ^ - dichlorobenzalmalonic acid diethyl ester, prepared analogously to Example la). Kp. _K 172 to 178 ⁰ .

b) ethyl 3- (2, ^ - dichlorophynyl) -3-cyanopropicnoate, prepared analogously to Example Ib). Kp. IbO to I85 ⁰ .

c) 3- (2,4-D1 chloropheny 1) -3-cyanglu tar acid diet, hy lest er, produced analogous to example Ic), the connection is further processed raw.

d) 3- (2,4-Dlchlorophynyl) -5-oxo-3-pyrrolidinesölgsäUreäthylester ₎ prepared analogously to Example Id), the compound is further processed in the raw.

c) 3- (2,4-dichlorophenyl) -5-oxo-3-pyrrolidine acetic acid analogous to example 2o). Mp. 188 to 192 °, from ethanol / Ether.

f) 5,7-dichlorospiro [indan- ^{1,3 l} -pyrrolidine] -3 ₁ 5 ^l -dione, prepared analogously to Example If). M.p. 226-228 °.

g) 5 _f 7-dichlorospiro (indan- ^{1,3 l} -pyrrolidin) -3-ol, prepared

analogous to example Ig), light yellow oil,

that is processed further without cleaning.

Example 12; k- (^. ^ - dichloro - ^ - hydroxyspiroi ^^^ din) -1'-yl) -p-i'luorobutyrophenone

4,5-dichlorospiro [indan-1,3'-pyrrolidin) -3-ol (diastereoisomers mixture) is implemented analogously to Example 1 A) or Example 2 A)

309809/1178

- «fr - 100-3604

M.p. of the hydrogen fumarate of the title compound: 190 to 193 ⁽

The starting material can be obtained as follows:

a) Diethyl 3,4-dichlorobenzalmalonate, prepared analogously Example la). Kp. ■ I69 to 173 °.

b) 3- (3 * 4-dichlorophenyl) -3-cyanopropionic acid ethyl ester _i prepared analogously to Example Ib). Kp. _Λ ^ 1Ö5 to 195 °.

c)> · (3i4-dichlorophenyl) -3-cyanglutarsäurediäthylester, prepared analogously to Example Ic), white crystals of mp. 65 to 67 ^0th :

d)> - (3i4-dichlorophenyl) -5-oxo-3-pyrrolidinessigsäureäthylester, produced analogously to example Id), the raw connection is further processed without prior cleaning.

e) j5- (3 »4-dichlorophenyl) -5-oxo-3-pyrrolidine acetic acid prepared analogous to example 2e). M.p. 19I to 195 °.

f) k, 5-dichlorospiro [indan-1 _J 3 ^t -pyrrolidine] -J>, 5'-diene, prepared analogously to Example If). That after recrystallization

The crystallizate obtained in ethanol is by a little 5> 6-

Dichiorspiro [indan-1,3'-pyrrolidine] -J>, 5'-dione contaminates and melts at 202 to 205 °. It is processed further directly.

g) 4,5-D ^ chloro: piro [indan-1,3'-pyrrolidin] ~ 3-ol, prepared analogous to example Ig). The crude compound is converted into its llydrogen fumarate with an ethanolic fumaric acid solution. M.p. J.67 Vjis 170 °.

309809/1178

- loo-jGoh

Example 13: k- i [3-Hydroxy-5,6-diir.eth.oxyspiro [indan-1,3'-pyrrolidine] -1'-yl 1-4 -p-fluorobutyrophenone

5,6-Dimethoxyspiro [indan-1,3'-pyrrolidin] -3-ol is analogous Example ^ Λ) or Example 2 A) implemented.

The crude oily title compound is added to an ethanolic solution of naphthalene-1,5-disulfonic acid, the Naphthalene-1,5-diculfonate of the title compound kriutallisJcrt, which after crystallization from ethanol melts at 1 ^ 6-1 ^ 8 °

The starting material can be obtained as follows:

a) 3,4-DiiTiethoxybenzalmaionäureäthylester, prepared analogously to Eebeispiel la). Kp. _Χ 190 to 210 °.

b) 3-cyano-3- f3 * ^ - di'nethoxyphenyl) propionic acid ethyl ester _i prepared analogously to Example Ib). Kp. _Q ^ 205 to 212 °.

c) 3-cyano-3- {? >> 4-dimethoxyphenyl) glutaric acid diethyl ester, prepared analogously to Example lc). Kp. _{Q χ} 215 to 225 °. ·

d) 3- (3 # ^ - Dimethoxyph9nyl) -5-oxo-3-pyrrolidinessigsäureäthylester, produced analogously to example Id). The connection is processed further raw.

o) 3- (3 "^ - Di. ^r " ethoxyphenyl) -5-oxo-3-pyrrolidinacetic acid, prepared analogously to Example 2e). Mp. 162 ° to 165 °.

f) 5> 6-Dimethoxyspiro [indan-1,3'-pyrrolidine) -3,5'-dione, prepared analogous to example If). M.p. 193-195 °.

g) Sjo-Diincthoxyspirofindan-lO'-pyrrc-lidinJ - ^ - ol, produced analogous to example ig), yellow oil that is processed directly v / ird.

309809/1 173

Example 14: 4-i [3-Hydroxy-5-isopropylspiro [indan- ^{1,5 l} pyrrolidin] -1'-yl) -p-fluorobutyrophenone

5-isopropylspiro [indan-l, J5 ¹ -pyrrolidine] -3-ol (mixture of diastereoisomers) is reacted analogously to Example 1 A) or Example 2 A) and transferred to the title compound in its hydrogen fumarate, mp. I67 to I74 ^0th

The starting material can be obtained as follows:

a) ethyl 4-isopropylbenzalmalonate, prepared analogously Example la). Kp. = 152 to 154 °.

b) 3-cyano-3- (4-isopropylphenyl) propionic acid ethyl ester, produced

is analogous to example Ib). Kp. = 146 to 149 °.

O, J-

c) 3-cyano-3- (4-isopropylphenyl) glutaric acid diethyl ester _J prepared analogously to example lc). Kp .. _o . . = 166 to I90 ⁰ .

d) ethyl 3- (4-isopropylphenyl) -5-oxo-3-pyrrolidinesse acetate, produced analogously to example Id). The connection becomes raw further processed.

e) 3- (4-Isopropylphenyl) -5-oxo-5-pyrrolidine acetic acid, prepared analogously to Example 2e). M.p. 175 to 178 ⁰ .

f) 5-Isopropylspiro [indan-1,3'-pyrrolidine] -3 * 5'-dione, prepared analogously to Example If). M.p. I65 to I67 ⁰ .

g) 5-Isopropylspiro [indan-1,3'-pyrrolidin] -3-ol, prepared analogous to example Ig), yellow oil that is further processed directly will.

309809/1178

Example 15: 4- (3-Hydroxy-5,7-dimethylspiro [indan-1,3'-gyrrolidin} -l'-yl) -p-fluorobutyrophenone

5,7-Di " ⁱ ethylspiro [indan-1,3'-pyr * rolidin] -3-ol is reacted analogously to Example 1 A) or Example 2 A) and the title compound is converted into its hydrogen fumarate with a melting point of 164 ° to 167 °

The starting material can be obtained as follows:

a) 2,4-Dimethylbenzalrnalonsäureäthylester, prepared analogously to Example la). Kp. _{Q 15} ^el 3 ⁸ to I4l °.

b) 3-cyano-3- (2,4-dimethylphenyl) propionic acid ethyl ester prepared analogous to example Ib) -Kp._ __ _, .- = 140 to 150 °.

0.25-0.35

c) 3-cyano-3- (2 _J 4-dimethylphenyl) glutaric acid diethyl ester, prepared analogously to Example lc). Kp. " _Lf - = 180 to 190 °.

d) ethyl 3- (2,4-dimethylphenyl) -5-oxo-3-pyrrolidine acetate, produced analogously to example Id). Is processed further raw.

e) 3- (2,4-Dimethylphenyl) -5-oxo-3-pyrrolidine acetic acid analogous to example 2e). M.p. 225 to 230 °.

f) 5,7-dimethyl spiro [indane-l, 3 ^l -pyrrolidine) -3,5 -dione ^I prepared analogously to example If). M.p. 208 to 210 °.

g) 5,7-Dimethylspiro [indan- ^{1,3 1} -pyrrolidin) -3-ol, prepared analogously to Example Ig), yellow oil, which is further processed directly. After prolonged standing, the compound crystallizes, m.p. 14U-IAi? ⁰ .

309809/1 1 78

100-3604

Example 16: 1 ^R § £ .3.PS-p-fluoro-4- (3-hydroxyspiro [indan-1,3 'pyrrolidin2-l ^ -yl) t) utyrophenone

IRS, 3RS — Spiro [indan-1,3'-pyrrolidin] -3-ol is made according to the in Example 1 A) or 1 B) described method implemented. The crude title compound is extracted with ethanolic hydrochloric acid added and the hydrochloride of the title compound crystallized out by adding a little ether. M.p. 210 to 211 °.

The starting product can be obtained as follows:

a) Spiro [indan-1,3'-pyrrolidine] -J>, 5'-dione is reduced with sodium borohydride as in Example 3g). The resulting 3-hydroxyspiro [indane-1,3'-pyrrolidin] -5'-one provides a Diastereoisoroerengemisch, mp. 120 to I30 is ^0, which is about 50 $ IRS.3RS isomer and about 50 $ IRS, 3SR -Isomeres contains. 30 g of the crude mixture are extracted with 3 × 100 ml of chloroform at the boiling point. The 1RS, 3RS-3-Hydroxyspiro [indan-l _i 3'-pyrrolidin] -5'-one with a melting point of 150 to 152 ° remains as the extraction residue, which is further reduced with lithium aluminum hydride analogously to Example 3h).

On addition of ether, the IRS, 3RS-3-Hydroxyspiro [indan-1,3'-pyrrolidin] -5'-one crystallizes from the chloroform solution from m.p. 120 to 123 °.

Example 17: ¹ RS ^ SR-p-fluorine - ^ - ^ - hydroxyspiro [indan-1,3_ ^ - pyrrolidine] -! '- yl) butyrophenone

IRS, 3SR — spiro [indan-1,3'-pyrrolidin] -3-ol is reacted analogously to Example LA) or Example 1 B). Mp. Of the hydrogen fumarate of the title compound: I83 ⁰ (from ethanol / ether).

³⁰⁹⁸⁰⁹ ^ ¹⁷⁸ BADORK ₅₁ NAL

1ΟΟ-3βθ4

The starting material can be obtained by reducing the IRS, 3SR - 3-Hydroxyspiro [indan-1, J5'-pyrrolidine] obtained in Example 16 a)

5'-ons analogous to example J5h) can be obtained.

Example .18: 4- (3-Acetoxyspiro [indan-1,5'-pyrrolidine] -1'-yl) -p-fluorobutyrophenone

Ί) 5 S p-fluoro - ^ - (5-hydroxyspiro [indane-1,5'-pyrrolidin] ^-! Yl) butyrophenone are stirred with 15 ml of pyridine and 15 ml Sssigsäureanhydrid 18 hours at room temperature. The mixture is then poured onto Sis, made alkaline with 2N sodium hydroxide solution and extracted three times with 50 ml of ether. The ether phase is washed with water, dried over sodium sulfate and evaporated. The oily residue is converted into the hydrogen fumarate, which is recrystallized from ethanol / ether. Snip, the hydrogen fumarate of the title compound I5 · '! · To I56 ⁰ .

Example 19 : p-Fluoro - ^ - (Vmethylcarbamoyloxyspiro [indan-1,3 ^? -Pyrrolidin | -l'-yl] butyrophenone

9.0 g of p-fluoro - ^ - (5-hydroxyspiro [indan-1 ^{,. "5'-pyrrolidine] -1 f} -yl) butyrophenone and 2.0 g of methyl isocyanate are dissolved in 50 ml of methylene chloride. anzigstündigem standing at room tempera ture is evaporated and supplies the remaining oil into the hydrogen fumarate about Recrystallization from ethanol / ether, mp of the _{hydrochloride:} jenfu; r.arats the title compound 1œ7 to I69 ^0th..

309809/1 1 78

BATH ORIGINAL

100-3004

Example 20; p-Fluoro-4- (5-methyl-3-propionyloxyspiro £ indaril, 3'-pyrrolidin2-l ^t -yl) butyrophenone

* p -]? luoro-4- (3-hydroxy-5-methylspiro [indan- ^{1,3 t} -pyrrolidine] -1'-yl) butyrophenone is reacted with propionic anhydride as in Example 18. Mp. Of the hydrogen fumarate of the title compound: 153 to 155 ° (from ethanol / ether).

Example 21: 4- (5-chloro-3-methylcarbamoylspiro [indan-1,3'-pyrrolidin} -1'-yl) -p-fluorobutyrophenone

4- (S-chloro ^ -hydroxyspirofindan-1,3'-pyrrolidin] -l'-yl) -p-fluoro butyrophenone v / earth with 3 * 2 g of methyl isocyanate in 150 ml of chloroform implemented analogously to Example 19. Response time: 24 hours at boiling temperature. M.p. of the hydrogen fumarate of the title compound: 151 to 153 ° (from ethanol / ether).

Example 22: 2- {3- ^ 3 ^^

propyl} -2- (p-fluorophenyl) -1,3-dioxolane

15 g of spiro [indan-1,3'-pyrrolidin] -3-ol are dissolved in 200 ml of dimethylformamide and mixed with 18 g of sodium carbonate and 23 g of 2- (3-chloropropyl) ~ 2- (p-fluorophenyl) -1.3 ^t ~ dioxolane heated to 100 ° for 20 hours. It is then filtered off, the pilter residue is washed with 150 ml of chloroform and the organic phases are concentrated. The title compound which remains as a yellow oil is purified by chromatography.

TLC: Rf-value: 0 _Λ 600 (adsorbent: silica gel, .Pliessmittel: benzene / ethanol / ammonia 15: 4: 0.2). M.p. of the hydrogen fumarate of the p-fluoro-4- (3-hydroxyspiro [indanl>3'-pyrrolidin]-l'-ol) butyrophenone obtained by hydrolysis of the ketal grouping of the title compound: 174 to 176 ⁰ (from ethanol / ether).

308809/117 8

100-36g

For hydrolysis, the title compound is dissolved in 300 ml of chloroform and treated with 250 ml of 2N hydrochloric acid for 1 1/2 hours at room temperature touched. Then it is made alkaline with sodium hydroxide solution, the chloroform phase is separated off and that after concentration the crude p-fluoro-4- (3-hydroxyspiro- [indan-1,3'-pyrrolidin] -1'-yl) butyrophenone remaining in the chloroform phase converted into hydrogen fumarate with fumaric acid.

The following compounds of the formula Ig) can also be prepared analogously to Example 22 and by the melting point of the hydrogen fumarate of the butyrophenone derivative obtained by hydrolysis of the compound is characterized. "

309809/1 1 78

jjepiel ·

24 25

27 28 29 30

32 33

^R i

5-eq

4-CH ₃ O H 6-CK-.0 H 4-Cl H 6-Cl H 6-CK ₅ H 5-CH -f H 5-P H 5-CH ₃ H 4-ci I 5 5-ci 7th

5-Cl

.KiV value (DC. Silica gel, benzene / ethanol / ammonia 15: 4: 0.2)

0.700

0.610 0.645

0.570 0.630 0.590 0.680 0.610 0.530

0.790 0.675

Srr.p. of the hydrogen fumarate of the butyrophenone derivative

148 to 149 ° (ethanol / ether)

152-154
163 to

178 to
165 to
181 to s
113 to
143 to
163 to

190 to
149 to

(Ethanol / Aethei)

165 ° (ethanol / ether)

ISO ° (ethanol / ether)

I67 ⁰ (ethanol / ether)

I83 ⁰ (ethanol / ether)

115 ° (ethanol / ether)

145 ° (ethanol / ether)

164 ° (ethanol / ether)

193 ° (ethanol / ether)

152 ° (ethanol / ether)

100-3604

Example 34; 4- (3-Acetoxyspiro [indan-1,3'-pyrrolidin] -1'yl) -ρ-fluorobutyrophenone

3-Acetoxyspiro [indan-1,3'-pyrrolidine] is analogous to Example IB implemented. The crude title compound obtained as OeI is converted with fumaric acid into its hydrogen fumarate, which is recrystallized from ethanol / ether. 154-156 °.

The starting material can be obtained as follows:

a) 56 * 0 g of l'-benzyl-3-hydroxyspiro [indan-l, 3'-pyrrolidine] are stirred with 120 ml of pyridine and 120 ml of acetic anhydride for 20 hours at room temperature. The mixture is then poured onto ice, made alkaline with 2N sodium hydroxide solution and extracted three times with 250 ml of ether each time. The ether phase is washed with water, dried over sodium sulfate and evaporated. The 1 ^l -benzyl-3-acetoxyspiro [indan- ^{1,3 t} -pyrrolidine] remains as a pale yellow oil, which is processed further without purification.

b) 30.0 g of the product described above are dissolved in 300 ml of ethanol, 3 »0 g of palladium carbon are added and the mixture is hydrogenated at 50 ° and 75 atmospheres hydrogen pressure for 12 hours. Then it is filtered off, the ethanol is distilled off and obtained as a residue the 3-acetoxyspiro [indan-1,3'-pyrrolidine] in the form of an almost colorless oil, which continues as such is implemented.

Example 35; p-Fluoro-4-j [3-methyIcarbamoyloxyspiro [indan-1,3 ';; pyrrolidin] -1'-yl) butyrophenone

3-Methylcarbamoyloxyspiro [indan, 1,3'-pyrrolidine] is analogous Example IB implemented and the title compound in its hydrogen

309809/1 1 78

fumarate transferred, m.p. IGJ to I69 ⁰ (ethanol / ether). •. The starting material can be obtained as follows:

A. 56.0 g of l'-benzyl-3-hydroxyspiro [indan-1,3'-pyrrolidine] and 10.0 g of methyl isocyanate are dissolved in 500 ml of methylene chloride. Distilled after standing for twenty hours at room temperature the solvent is removed; the oily remaining l'-benzyl ; 3-methylcarbamoyloxyspiro [indan-l, j5'-pyrrolidine] becomes without Cleaning processed.

B. 250 g of the product described above is dissolved in

300 ml of ethanol and hydrogenated in the presence of 3.0 g of palladium carbon at 50 ° and 50 atmospheres hydrogen pressure for 15 hours. The catalyst is then filtered off, the ethanol is distilled off and the residue obtained is 3-methylcarbamoyloxyspiro [indane-1,3 ^f -pyrrolidine]. The oily product is reacted further without further purification.

309 80 9/1178

100- ^ 604

Yes

Ic

(CH ₀ ), -

) -G0-R,

- P

Ie

II

309809/1 178

100-30

Ha

X- (CHp) .-

- ■ J ~ \ -f

IHa

X- (CH J -, - A ¹ - / \ VF HIb

IVa OCN-R ₂

it, -

Va

309809/1 1 78

100-2604

Vc

iH

VIII [^

R,

yj

A ^

CK-COOR,
2 ■

; h-co υ

CK ₀ -COOR ₁ .

Via

IX

XI

R.

CH-CH

XII

* c;

CIi = C

Ai IΛ

R ₁ XH XIV 5

-CHO

, COOR5

^l] 2 ~ ° ~ -COOR

XVI

₁ -

309809/1178

BAD ORJGINAL

COPY

Claims (11)

Patent claims: Q / Process for the preparation of new compounds of the formula I, in which R, represents hydrogen, lower alkyl, fluorine, chlorine, bromine or methoxy and Rp represents hydrogen, lower alkyl, chlorine or methoxy or R, and R together form the methylenedioxy group, R denotes hydroxyl, a lower alkylcarboxy or monoalkylcarbamoyloxy group and A denotes the carbonyl group, the 1,3-dioxolan-2-ylidene group or the 1,3-dioxan-2-ylidene group, and their acid addition salts, marked thereby that he a) for the preparation of compounds of the formula Ia in which R ,, R 'and R have the above meaning, or the compounds of the formula Ib in which R- ,, R _? and R ^ have the above meaning, and A ^{1 represents} the 1,3-dioxolan-2-ylidene group or the 1,3-Dl * oxan-2-ylidene group, compounds of the formula II in which R, , Rp and R_ have the above meaning, with compounds of the formula IHa in which X is chlorine, bromine, iodine or the residue of an organic sulfonic acid and A is the carbonyl group or a carbonyl group protected by ketal or thiooxo or thioketal formation, or Reacts with compounds of the formula IHb, in which X and A have the above meanings, and then again for the preparation of compounds of the formula Ia, any protective groups from the resulting compounds of the formula Ic, in which R 1, R ', R and A have the above meanings splits off, or b) for the preparation of compounds of the formula Id in which R-, R ₂ and A have the above meaning and R ₁ ^ is lower alkyl, compounds of the formula Ie in which R 1, Rp and A have the above meaning, with compounds of the formula IVa, where R ^ has the above meaning and X is chlorine, bromine or the acid residue of a lower carboxylic acid, esterified, or GOPY 309809/1178 ο) for the preparation of compounds of the formula If, in which R, R, _M , R ^, and A have the above meaning, compounds of the formula Ie, with compounds of the formula IVb, in which R ₁ . has the above meaning, implements and possibly any diastereo isomeric mixtures of Separates compounds of the formula I into their isomers and / or the compounds of the formula I obtained, if desired, into their isomers Acid addition salts transferred. 2. The method according to claim 1, characterized in that one as a compound of the formula II spiro [indan-l, j5'-pyrrolidine] -j5-oi begins. J5. A method according to claim ^1: characterized in that the compound of the formula II in a 5-position substituted Spiro [indan-l, J 5'-pyrrolidin] -3-ol used. 4. The method according to claim 1, characterized in that the compound of formula II is 5-chlorospiro [indan-1,3'-pyrrolidin] -3-ol begins. 5. A process for the preparation of compounds of the formula VI in which R _{1 is} hydrogen, lower alkyl, fluorine, chlorine, bromine or methoxy and R _{3 is} hydrogen, lower alkyl, _{chlorine or methoxy, or R 1} and R_ together form the methylenedioxy group , characterized in that compounds of the formula IX in which R ₁ and R _{2 have the} above meanings, cycllsiert. 309809/1 178 U * s Germany-West 6. Compounds of the formula I in which R _{1 is} hydrogen, lower alkyl, fluorine, chlorine, bromine or methoxy and R _{2 is} hydrogen, lower alkyl, chlorine or methoxy or R ₁ and R together form the methylenedioxy group, R _{5 is} hydroxyl, denotes a lower alkylcarboxy or monoalkylcarbamoyloxy group and A denotes the carbonyl group, the 1,3-dioxolan-a-ylidene group or the 1,3-dioxan-2-ylidene group, and their acid addition salts. 7. Compounds of the formula VI in which Ε _{χ is} hydrogen, lower alkyl, fluorine, chlorine, bromine or methoxy and R _{2 represent} chlorine, hydrogen, lower alkyl or methoxy, or R ₁ and R ₂ together form the methylenedioxy group. 8. p-Fluoro-4- (3-hydroxyspiro [indan-1,3'-pyrrolidinj-1'-yl) -. Butyrophenone and its acid addition salts. 9 _# p-piuor-4-O-hydroxyspiro [indan-1,3'-pyrrolidin] -l'-yl) butyrophenones and their acid addition salts which are substituted in the 5-position by fluorine, chlorine or lower alkyl. 10. · 4- (5-Chloro-3-hydroxyspiro [indan-1,3'-pyrrolidin] -l'-yl) -fluorobutyrophenone and its acid addition salts. 11. .. Medicines, characterized in that they contain compounds of the formula I or their acid addition salts. 0 9 8 0 9/1179 ORIGJNAL INSPECTED