CS241024B2 - Method of phenylquinolizidines production - Google Patents

Abstract

Title compds.≮I; X = o-, m-, p-, H, F, Cl, C1-4 alkoxy, C1-4 alkyl, CF3; A' = III(R4 = H, C1-4 alkyl; R5,R6 = H, Me, F, Cl, MeO, CF3, -(CH2)4-)≉their racemates or enantoimers were prepd. by hydrogenation of II at 50≰C under Pt or Pd in org. solvent. I are useful as antipsychotics, antiemetics and analgesics at a daily oral does 0.05-10 mg/kg.

Description

The present invention relates to a process for the preparation of novel pharmacologically active phenylquinololidines.

The phenylquinolizidines produced by the process of the invention are represented by compounds of formula IV

in which

X represents a hydrogen atom, a chlorine atom or a (C 1 -C 4) alkoxy group at the o-, m- or β-position,

Y represents a hydrogen atom or a chlorine atom at the o-, m- or p-position,

R ² represents an alkyl group having 1-5 carbon atoms or phenyl, which is optionally substituted by alkoxy having 1 to 4 carbon atoms,

R ⁷ represents an alkyl group having 1 to 6 carbon atoms or an acyl group, in particular acetyl, trifluoroacetyl and propionyl, in racemic form or in the form of enantiomers as well as in the form of free bases or in the form of acid addition salts. As shown in formula IV and in the various subsequent formulas, the hydrogen atoms at positions 7 and 9a are trans with respect to each other, wherein in these formulas, the hydrogen atom 9a is arbitrarily in the β-position and the hydrogen atom at position 7 is the corresponding as shown in position a.

However, the phenylquinolizidines of the present invention, as well as the corresponding intermediates and starting materials, are not limited to this absolute configuration, but also include the corresponding enantiomeric forms, i.e. the compounds with hydrogen at the 9aa and 7/3 positions, as well as the racemates of these two enantiomeric forms. The same is true with respect to the configuration at position 2 of the quinolizidines.

C 1 -C 4 alkyl and C 1 -C 4 alkoxy in this case are C 1 -C 4 alkyl and alkoxy, wherein the C 3 -C 4 alkyl groups may be straight or branched. The acyloxy group as a possible meaning of the symbol OR ⁷ can be derived from organic, saturated or optionally substituted carboxylic acids, in particular lower or halogen substituted alkanecarboxylic acids, such as

1 0.2 4

acetic acid or trifluoroacetic acid.

Suitable acid addition salts of the phenylquinolizines according to the invention are pharmacologically compatible salts with the organic and inorganic acids usually used for salt formation. Examples of such acids include: mineral acids such as sulfuric acid, nitric acid, phosphoric acid, hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid); organic acids such as tartaric acid, citric acid, aliphatic or aromatic sulfonic acids, maleic acid, mandelic acid, etc. The salt preparation can be carried out in a manner known per se.

Compounds of formula IV are predominantly preferred for their analgesic effect. Of these compounds, compounds of formula IV in which

a) X and Y are hydrogen, OR ⁷ is. as well as a hydrogen in position 9a orientated acetoxy and R ² is n-butyl or

b) X and Y are hydrogen, OR ⁷ is the same as hydrogen at the 9a position, oriented trifluoroacetoxy, and R ² is a target, a butyl group, or

c) X is chloro in the ortho-position, R ² represents a hydrogen at position 9a oriented phenyl group and OR @ ⁷ is acetoxy.

The phenylquinolizidines of the formula IV according to the invention are prepared by reacting an alcohol of the formula II

X, Y and R ² have the above meanings, with an esterifying or etherifying agent yielding the radical R ⁷ in the presence of an organic acid or base at a temperature between room temperature and the reflux temperature of the reaction mixture, and the obtained racemates are optionally cleaved and the base obtained is optionally converted to acid addition salts.

The above process can be carried out by methods known per se.

The diastereomeric mixtures obtained as well as the racemates obtained can be separated by methods known per se.

In order to prepare ethers and esters of formula

IV according to the invention may be esterified in known manner carbinol of formula II, for example by reaction with an acid anhydride of formula (R ⁷ CO) in the presence of pyridine or isopropenyl esters of formula

CH ₂ = С (СНз) -O-CO-R ⁷ in the presence of ^{p-toluenesulfonic:} acid, or etherified by reaction with a lower alkyl halide (basic etherification) mixture or R'OH and sulfuric acid (acidic etherification).

The compounds of formula (II) used as starting materials can be prepared by methods known per se, for example by reaction to. of the formula V

in which

X and Y are as hereinbefore defined, with an organometallic compound providing a residue R ² , and optionally separating the mixture into diastereomers.

К converting a ketone of formula V to the tertiary carbinol of Formula II can be used in customary organometallic compounds providing the radical R ^2, as the corresponding Grignard compound R ² Mg-halogen RMithiumderiváty or R ² -L-Cu derivatives.

As carbinol is formed from the ketone of formula V, a third center of asymmetry (at position 2) is formed. Newly incoming R ² can in this case in relation to a hydrogen atom at position 9a occupy cis- and / or trans-position. Thus, for example, in the reaction described in the following Example 2 using the racemic ketone of formula V, two diastereomeric products of the formula II are obtained (always as a racemate), whereas in the reaction of a racemic ketone of formula V described in Example 1 Formula II practically. only one racemate and the R ² s in the position trans to the hydrogen in position 9a, as expressed by formula II-1)

X, Y and R ² have the above meanings.

The ketones of the formula V used as starting materials can be obtained in a manner known per se by decarboxylation of the β-ketoesters of the formula XIV with a relative configuration of uve5

2410.2 4 in this formula relating to positions 1, 7 and 9a

in which

X and Y are as defined above and

R represents a lower alkyl group (cf. e.g. Example 1c).

The β-ketoesters of formula (XIV) can be obtained by hydrogenation from the corresponding unsaturated β-ketoesters of formula (XIII) in a manner known per se.

in which χ; Y and R ^{and are} as defined above (cf., for example, Example 1d).

The Z-ketoesters of formula (XIII) can be obtained from the corresponding phenyl nucleus of optionally substituted 5-phenyl-2-piperidones by methods known per se (cf., for example, Example 1e).

The novel starting materials of formula II also form part of the present invention.

The phenylquinolizidines of the formula IV according to the invention are distinguished by valuable pharmacological properties. These compounds are active neuroleptically, centrally depressant, tranquilizing, antiemetically and / or analgesic and can therefore be used as antipsychotics or as antiemetics in combating psychoses and neuroses, possibly nausea or pain.

The analgesic properties of the compounds were quantified using the following tests:

Writhing test - mouse

8 male mice (weighing about 20 to 22 g) per dose were used to perform the experiment. 60 minutes after oral administration of the test substance, the animals are injected intraperitoneally with 10 mg / kg of the test solution. Then, after a latency period of 5 minutes, the number of animals having more than one characteristic writhing is registered. ED 50 indicates a dose at which 50% of the animals show no more than one convulsive convulsion;

Hot plate test (mouse)

8 mice (20-22 g) are used per dose. Animals are placed on a metal plate heated to 60 ± 0.5 " 60 minutes after oral administration of the test substance. Untreated mice begin licking their paws within a maximum of 10 seconds. The ED50 is defined as the dose at which 50% of the animals only start licking their paws after a latency period of more than 10 seconds.

Some results of the experiments are summarized in Table A below:

TABLE A

compound Writhing 60 '_ EDso p.o. (mg / kg) hot plate 60 ' EDso p.o. (mg / kg) (+) -2-Butylooctahydro-7-phenyl-2H- quinolizin-2-yl acetate hydrochloride 0.19 2.6 rac.- (9a / SH) -2a-n-butyl-7H-phenylooctahydro'2H-quinolizin-2-ylacetate hydrochloride 0.75 25 rac.- (9a / 1H) -2a-tert-Butyl-7/3-phenyl-octahydro-2H-quinollzin-2-yltrifluoroacetate hydrochloride 8.7 86 rac.- (9a / 1H) -2'-Pheny1-7 / 3- (m-methoxyphenyl) octahydro-2H-quinolizin-2-yl-propionate hydrochloride 2.8 12 rac.- (9a / 3H) -2 / 3-Phenyl-Z / 3- (o-chlorophenyl) octahydro-2H-quinolizin-2-ylacetate hydrochloride 116 284 (+) -2-tert-butyl-7- (2-chlorophenyl) -octahydro-2H-quinolizin-2-yl acetate acetate hydrochloride 28 •

2410.24 hot plate 60. *

ED 50 p.o. (mg / kg) compound

Writhing 60 'ED 50 po (mg / kg) (-) -2-tert-butyl-7- (2-chlorophenyl) octahydro-2H-quinolizin-2-yl acetate hydrochloride rac.- (9a, ЙН) -2a-tert-Butyl-7S- (o-fluorophenyl) octahydro-2H-quinolizin-2-yl acetate acetate hydrochloride

The phenylquinolizidines of the present invention in the form of the racemate or enantiomers as well as in the form of the free bases and acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example by suppository, locally or percutaneously. for example in the form of ointments, creams, jellies, solutions or parenterally, for example in the form of injectable solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules, the compounds of the invention may be formulated with pharmaceutically inert, inorganic or organic excipients. As such excipients lactose, corn starch or as derivatives, talc, stearic acid can be used, for example, for tablets, dragees and hard gelatine capsules. or salts thereof, etc.

For soft gelatine capsules, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. are suitable as excipients, however, depending on the state of the active substance, no auxiliaries are required at all for soft gelatine capsules.

Water, polyols, sucrose, invert sugar, glucose and the like are suitable as excipients for the production of solutions and syrups.

For injection solutions, water, alcohols, polyols, glycerin, vegetable oils, etc. are suitable as excipients.

For suppositories, further for local and percutaneous dosage forms, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as auxiliary substances.

> 30

The pharmaceutical preparations may additionally contain preservatives, co-solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for influencing the osmotic pressure, buffer, coatings or antioxidants. They may also contain other therapeutically valuable substances.

The amount of active ingredient in said pharmaceutical preparations may range from 0.5 to 100 mg. For oral administration, about 0.05 to about 10 mg / kg per day is contemplated and, for parenteral administration, an amount of active compound of from about 0.01 mg / kg to 1 mg / kg per day.

Example 1

20.0 g of rac- (9a, lH) -2a-tert-butyl-70- (o-chlorophenyl) octahydro-2H-quinolizin-2-ol were dissolved in 130 ml of isopropenylacetate and 11.7 g of anhydrous p. -toluenesulfonic acids. The reaction mixture was then heated under reflux (argon atmosphere) for 1 hour with stirring. After cooling, 20 ml of ether were added to the reaction solution. The solution is allowed to stand for 2 hours and then the precipitated product p-toluenesulfonate is filtered off and dried. 22.5 g of product are obtained. The base [rac .- (9a, dH) -2a-tert-butyl-7S- (o-chlorophenyl) octahydro-2H-quinolizin-2-ylacetate] can be liberated from p-toluenesulfonate by treatment with sodium bicarbonate solution. Yield 15.8 g (70% of theory). The hydrochloride melts at 241-242 ° C.

If equimolar amounts of alkylcarbinols are used to react, the acetates listed in Table 1 may be obtained:

TABLE 1 rac.- (9a.6H) -2 "- (R _b) -70- _(Ra) octahydro-2H-quinolizine-2-yl acetate:

R _b ^R , Melting point tert-butyl phenyl hydrochloride 247 to 248 tert-butyl p-chlorophenyl hydrochloride 244 to 246 tert-butyl 2,4-dichlorophenyl hydrochloride 246 to 247 n-butyl phenyl hydrochloride 248 to 250

(- H 2-Butylooctahydro-7-phenyl-2H-chloroizin-2-yl acetate) _{to the} hydrochloride, m.p. 242-243 ° C.

(+) - (2-Butylooctahydro-7-phenyl-2H-quinolizin-2-yl acetate) hydrochloride,

242 to 243 ° C,

410.24

The starting compounds can be prepared as follows:

(b) 22.2 g of rac .- (9a / 3H) -7 / 3- (dropwise) of a solution of tert-butyllithium in pentane (100 ml, 1.2 molar) cooled to -75 ° C under vigorous stirring under an argon atmosphere are added dropwise. o-, -chlorophenyl) octahydro-2H-quinolizin-2-one dissolved in 300 mL of absolute tetrahydrofuran. Thereafter, the reaction mixture was left at -75 ° C for a further 30 minutes and then worked up as follows: Hydrolysis was carried out by adding 100 ml of saturated ammonium chloride solution and then partitioned between ethyl acetate and water. After re-traction with ethyl acetate, the combined organic phases are dried over magnesium sulfate and evaporated. The residue can be reacted.

the product, i.e. rac- (9a / 2H) -2a-tert-butyl-7S- (o-chlorophenyl) octahydro-2H-quinolizine-.

-2 ol, crystallized as the hydrochloride from 1400 ml of ethyl acetate by introducing hydrogen chloride gas. Yield: 20.4 (71%). M.p. 276-278 ° C. Another variant of this purification procedure is the chromatography of the residue on silica gel using a 1: 1 mixture of ether and hexane as eluent.

If equimolar amounts of appropriately substituted ketones are used instead of rac .- (9a / 3H) -7 / 3- (o-chlorophenyl) octahydro-2H-quinolizin-2-one, the following tert-butylcarbinols can be obtained:

TABLE 2 rac .- (9a / 3H) -2a-tert-Butyl-7 / 3- (R _and Joctahydro-2-quinolizin-2-ol):

Salt Melting point (° C)

Ra = phenyl hydrochloride 230 (decomposition) p-chlorophenyl hydrochloride 286 to 288 2,4-dichlorophenyl hydrochloride 270 to 272 2,6-dichlorophenyl hydrochloride 262 to 263 p-trifluoromethylphenyl hydrochloride · 285 to 286

When, instead of tert-butyllithium, an equimolar amount of analogous alkyl or aryilithium derivatives is used, and these are reacted with the corresponding ketones, the following carbinols can be obtained:

TABLE 3 rac.- (9a / 3H) - (R _b) -7β · _(Ra) octahydro-2H-quinolizine-2-ol:

^R b ^R a Form Melting point (° C) . 2a-sec-butyl 2,4-dichlorophenyl hydrochloride, 244 to 246 2a-n-butyl 2,4-dichlorophenyl hydrochloride 227 to 230 2a-isopropyl 2,4-dichlorophenyl hydrochloride 201 to 205 2 (a + / 3) methyl 2,4-dichlorophenyl hydrochloride 149 to 151 2a-n-butyl phenyl ...... base 100 to 102 2'-phenyl o-chlorophenyl hydrochloride 266-267 2/3-phenyl o-chlorophenyl hydrochloride _; 175 (amorphous) 2a-phenyl m-methoxyphenyl base 153 to 155 2/3-phenyl m-methoxyphenyl base 122 to 124 2a-phenyl phenyl base 156 to 158 2/3-phenyl phenyl base 99 to 102 2a-m-methoxyphenyl phenyl 1 H-NMR (CDCl 3): 3.77 (s) · 2/3-m-methoxyphenyl phenyl 1 H-NMR (CDCl 3): 3.82 (s) ' 2a-p-chlorophenyl · phenyl hrochloride 249 to 250 2a-m-Trifluoromethyl- phenyl p-chlorophenyl base 119 to 12Э Z / Mn-trifluoromethyl- phenyl p-chlorophenyl base 122 to 124

hours under reflux. The cooled reaction solution was poured onto ice and the mixture basified with concentrated sodium hydroxide solution. Extract! 3 x 500 ml of methylene chloride and evaporation of the organic phase dried over magnesium sulfate gave 68 g of crude product. 50.4 g of rac .- (9a / 3H) -7 / 3- (o-) crystallized from a mixture of ether and hexane.

с) г.- (9α / ЗН) -7 (8- (o-chlorophenyl) octahydro-2H-quinolizin-2-one), which is used as starting material, can be obtained as follows:

Dissolve 76.2 g of methyl rac .- (1α, 9a, # H) -7 / 3- (o-chlorophenyl) octahydro-2-oxo-2H-quinolizine-1-carboxylate in 1.2 L of 6 N hydrochloric acid acid and the reaction mixture is boiled

The quinolizine carboxylate decarboxylates the equimolar amount of the substituted β-ketoester, then the following products are obtained:

(chlorophenyl) octahydro-2H-quinolizin-2-one.

Mp 80-82 ^° C (81%).

If instead of methyl-rac .- (1α, 9α, 8H) -7H- (O-chlorophenyl) octahydro-2-oxo-2HTABLE 4 rac.- (9α, δ) -7,8- (Ra) -octahydro-2H-quinolizin-2-one

R aphenyl p-chlorophenyl p-trifluoromethylphenyl o-methylphenyl m-methoxyphenyl

2,4-dichlorophenyl

2,6-dichlorophenyl o-fluorophenyl

Melting point (° C)

'71 to 72 80 to 82 103 to 104 IC (film) 1726 cm @ -1. iC (film) 1726 cm @ -1 116 to 117 116 to 118 74 to 76

(d) The octahydrocarboxylate used as starting material in (1c) may be obtained from the corresponding hexahydrocarboxylate as follows:

180 g of methyl rac-7- (o-chlorophenyl) -3,4,6,7,8,9-hexahydro-2-ox-o-2H-quinolizine-1-carboxylate was suspended in 3.6 liters of dimethoxyethane suspension. The mixture was cooled to -30 ° C and 1.33 L of diisobutylaluminum hydride (20% solution in toluene) was added with stirring. The reaction mixture was then added. The mixture is stirred at -20 to -30 ° C for 1 hour and hydrolyzed at this temperature by the addition of 1.72 liters of 2 N sodium hydroxide solution. For working-up, the mixture was partitioned between 25 liters of water and 20 liters of chloroform, the organic phase was washed again with 2x5 liters of water, dried over magnesium sulphate and evaporated. Gets; se 185.2 g of crude product. From a mixture of ether and hexane. 109 g of product crystallized. Chromatography of the mother liquor on 1 kg of silica gel with ethyl acetate yields again 37 g of the product. The total yield of methyl rac- (1α, 9α-H) -78- (o-chlorophenyl) octahydro-2-oxo-2H-quinoisine-C-carboxylate is 136 grams (81%), mp 122-124 Deň: 32 ° C.

When used for reduction instead of methyl rac-7- (o-chlorophenyl) -3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-C kaгboxylátu equimolar ^<Ar whom you and the reduction is carried out with diisobutylaluminum hydride, then the following compounds are obtained:

...... - ------ TABLE · 5

Methal-rac.-11aH, 98HH) -7 H - (R a) -octahydro-2-oxo-2H-quinolizine-1-carboxylate

Ra Melting point · (° C) bitches! p-chlorophenyl p-trifluoromethylphenyl o-methylphenyl m-methoxyphenyl IC (film): 1752, 1723, 1660 cm @ -1 2,4-dichlorophenyl. 2,6-dichlorophenyl o-fluorophenyl 114 to 116 102 to 105 108 to 111 94 to 98 116 to 118 130 to 131 109 to 110

(e) The hexahydrocarboxylate used as starting material in (1d) may be obtained as follows: 150 g of 5- (o-chlorophenyl-2-piperidene) are dissolved in 2 liters of methylene chloride and this solution is stirred while stirring Add dropwise to 410 g of triethyloxonium tetrafluoroborate in 1 liter of methylene chloride at room temperature for 1 hour, then reflux at room temperature for 4 hours and leave at room temperature for a further 15 hours. vigorous stirring

372 g of potassium carbonate in 370 ml of water. The reaction mixture is stirred for a further 2 hours at room temperature, then the methylene chloride phase is decanted off and the residue is extracted twice with 500 ml of methylene chloride. The methylene chloride phase dried over potassium carbonate was concentrated to an oily, partially crystalline residue, boiled in 1 liter of hexane, and filtered the hot solution. Evaporation of hexane is obtained from the filtrate

151.4 g of oily laktimetheru O-Jo-chlorophenyl) -6-ethoxy-2,3,4,5-Cetrahydr opyridin (IR: 1684 ^cm-1 film).

R _a Melting point ( ^e C)

The lactimether (151.4 g) was dissolved in 1.4 L of methanol, 1.3 g of anhydrous p-toluenesulfonic acid was added, followed by the addition of 85 g of Z5-oxo-5-pentenoic acid methyl ester (Nazar reagent) over 60 minutes. After 20 hours at room temperature, the volatiles were removed in vacuo, the residue was then taken up in methylene chloride and washed with 500 ml of saturated sodium carbonate solution. The methylene chloride phase was dried over magnesium sulfate, concentrated again, and the residue was crystallized from ethyl acetate / ether (4: 1) (800 mL). 123.7 g (54%) of methyl rac-7- (o-chloro phenyl) -3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate are obtained. . Melting point 145-147 ° C.

When equimolar amounts of appropriately substituted piperidones are used instead of 5- (o-chlorophenyl-2-piperidone), the following compounds are obtained:

TABLE 6

Methyl-rac-7 (R _a ) -3,4,6,7,8,9-hexahydro-2-oxo-2H-2H-quinolizine-1-carboxylate

R, Melting point (° C) phenyl. 148-149 p-chlorophenyl 185-187

p-trifluoromethylphenyl 144 to 145 o-methylphenyl 183 to 184 m-methoxyphenyl 133 to 134 2,4-dichlorophenyl 153 to 155 2,6-dichlorophenyl 159 to 162 6-fluorophenyl 165 to 167

Example 2

a) 5.0 g of rac- (9a / 3H) -2a-tert-butyl-7 / 3- (chlorophenyl) -tahydro-2H-quinolizin-2-ol were dissolved in 20 rolls of pyridine and added dropwise over 15 minutes ml of trifluoroacetanhydride at room temperature. After 22 hours at room temperature, the solution is evaporated in vacuo, the residue is dissolved in 50 ml of toluene and concentrated again. The oily residue is then chromatographed on 100 g of silica gel using ethyl acetate as the eluent. The eluate afforded 5.4 g (83.5% of theory) of the base product [rac .- (9a, 8H) -2a-tert-butyl-7,8- (o-chlorophenyl) octahydro-2H-quinolizine-2]. -yl-trifluoroacetate. The hydrochloride has a melting point of 172-173 ° C.

If equimolar amounts of the alkyl or arylcarbinols listed in Example 1b) are used in the reaction, the trifluoroacetates shown in Table 7 can be obtained.

TABLE 7 rac - (9a / 3H) -2a- _(Rb) -7 / J (R _a) octahydro-2H-quinolizine-2-yl trifluoroacetate

Rb

R.

2a-tert-butyl

2a-phenyl phenyl phenyl hydrochloride hydrochloride

Melting point (° C)

170 to 172

164 to 166.

If equimolar amounts of alkyl or arylcarbinols are reacted with analogous carboxylic anhydrides instead of trifluoroacetanhydride, the following carbinolacylates are obtained:

TABLE 8 rac.- (9a / 3H) - (R _b ) -7,8- (R _a ) -octahydro-2-quinolizin-2-yl 1- (R _b ) _;

Rb ^R _and C Melting point 2a-phenyl o-chlorophenyl acetate hydrochloride 220 to 222 2S-phenyl o-chlorophenyl acetate hydrochloride 218 to 220 2a-phenyl phenyl propionate hydrochloride 242 to 243 2a-phenyl m-methoxyphenyl propionate hydrochloride 212 to 214 2-8-phenyl m-methoxyphenyl propionate hydrochloride 233 to 235 2a-m-methoxyphenyl phenyl propionate hydrochloride 233 to 234 2,8-m-methoxyphenyl phenyl propionate oxalate 120 to 122

2.64 g of rac.- (9a, 8H) -7,8- (p-chlorophenyl) octahydro-2H-quinolizin-2-one (obtained as described in Example 1c) was added dropwise to 0 ° C. in 25 ml of absolute ether, and the reaction mixture is stirred for an additional hour at room temperature under atmosphere

Starting materials can be obtained as in Example 1 or as follows:

b) From 0.54 g of magnesium shavings in 5 ml of absolute ether and 5 g of m-bromobenzotrifluoride in 10 ml of ether are first prepared.

Grignard reagent for 2 hours at reflux. The suspension was cooled to 2410.24 argon. For hydrolysis, saturated ammonium chloride solution was added and the reaction product was extracted with methylene chloride. The organic phase washed with saturated sodium chloride solution is dried over magnesium sulphate and evaporated. Yield 4.60 g. This residue is chromatographed on silica gel using a mixture of ethyl acetate and methanol 2 dia.

1.4 g of rac (9a / 3H) -2c - (m-trifluoromethylphenyl) -7 / 3- (p-chlorophenyl) octahydro-2H-quinolizin-2-ol, m.p. 119-123 ° C, yield 34 % of theory, and

1.2 g of racemic (9α / 3H) -2H- (m-trifluoromethylphenyl) -7β- (p-chlorophenyl) octahydro-2H-chlorolizin-2-ol.

mp 122-124 ^° C (29% of theory).

Example 3

a) 3.0 g of rac- (9a, 4H) -2 / 3-phenyl-7 / 3- (o-chlorophenyl) octahydro-2H-quinolizin-2-ol were dissolved in 75 ml of methanol and over 15 minutes 15 ml of concentrated sulfuric acid (96%) are added and the mixture is refluxed for 2 hours The cooled reaction solution is poured onto a mixture of concentrated sodium hydroxide solution and ice and extracted with ethyl acetate (3 x 200 ml). The crude product was chromatographed on 300 g of silica gel with hexane / ether to give 1.7 g (54% of theory) of rac.- (9a / 3H) 2. 3-methoxy-2-phenyl-7 _and D- (o-chlorophenyl) octahydro-2H-quinolizine. hydrochloride mp 258-260 ° C.

If substitution of the substituted arylcarbinols with appropriately substituted arylcarbinols is used instead of g- (9α / ЗН) -2- (ε-chlorophenyl) octahydro-2H-quinolizin-2-ol, by reaction with alcohols with 1 The following O-alkyl derivatives are obtained in which the alkyl contains 1 to 4 carbon atoms.

TABLE 9 rac.- (9a / 3H) -2 / 3- (R _b) 2-phenyl-7 / 3- (R _a) octahydro-2H-chinollzin

Rh R _a

Melting point ° C methoxy ethoxy phenyl hydrochloride 277-279 phenyl hydrochloride 254-255

b) 0.5 g of rac .- (9a / 3H) -2a-phenyl-7 ₁ d (o-chlorophenyl) octahydro-2H-quinolin-2-ol [prepared according to Example la) J was dissolved in 5 ml hexamethvltriamidu phosphoric acid and 0.1 g of sodium hydride (50 to 60% in mineral oil) are added at 0 ° C. The reaction mixture was stirred at 0 ^° C for 1/2 hour and then 0.2 ml of methyl iodide was added. The reaction mixture was then stirred at room temperature for 15 hours. For working-up, the reaction mixture was poured into 50 ml of water and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate phase is washed three times with 50 ml of water each time, then dried over magnesium sulphate and evaporated. Chromatography on 50 g of silica gel with hexane / ether gives 0.2 g (38% of theory) of rac- (9a, dH) -2, d-methoxy-2-phenyl-7, d- (o-chlorophenyl). octahydro-2H-quinolizine.

The hydrochloride of this compound melts at 258-260 ° C.

Example 4

The following compounds were prepared in the same manner as described in Example 1:

from (+) -2-tert-butyl-7- (2-chlorophenyl) octahydro-2H-quinolizin-2-ol hydrochloride, m.p. 294-295 ° C, [α] D ²⁰ = + 29.7 ° (c = 1, in methanol) gave (+ ') -2-tert-butyl-7- (2-chlorophenyl) octahydro-2H-quinolizin-2-yl acetate hydrochloride, m.p. 226-227 ° C, [.Alpha.] _{D @} ²⁰ = + 24.9 DEG (c = 1, in methanol). Yield: 91%;

from (-) -2-tert-butyl-7- (2-chlorophenylooctahydro-2H-quinolizin-2-ol hydrochloride, m.p. 293-295 ° C, [α] D ²⁰ = -29.9 ° (c = 1, in methanol) gives (-) -2-tert-butyl-7- (2-chlorophenyl) octahydro-2H-quinolizin-2-yl acetate hydrochloride, m.p. 228-229 ^° C. ²⁰ = -24.3% (c = 1, in methanol), yield: 96% az rac- (9.i / 3H) -2a-tert-butyl 1-7 / 3- (o-fluorophenyl) octahydro- 2 H-quinolizine-2-ol-hydrochloride, m.p. mp 245-246 ° C, yield: 73%.

The following examples illustrate pharmaceutical formulations containing phenylquinolizidines produced according to the invention:

2410.24

..Tablets

Per 1 tablet (+) - (2-Butyloctahydro-7-phenyl-2H-quinolizin-2-yl acetate hydrochloride 10.0 mg lactose 129.0mg • corn starch 50.0mg gelatinized corn starch 8.0mg calcium salt stearic acid 3.0mg total weight 200.0mg

The active ingredient, maize starch and gelatinised maize starch are thoroughly mixed with each other, and the resulting mixture is then ground and moistened with water to form a thick paste. The wet mass thus obtained is passed through a sieve, the wet granulate is dried at 45 DEG C. and the dried granulate is well mixed with the calcium salt of stearic acid. This granulate is now compressed into tablets weighing 200 mg and having a diameter of about 8 mm.

Example В

Capsule

V. per capsule (+} -2-butylooctahydro-7-phenyl-2H-quinolizin-2-yl acetate hydrochloride 10.0mg lactose 175.0mg corn starch 30.0mg talc 5.0mg

The active ingredient, lactose and corn starch are mixed intimately with each other and the resulting mixture is ground on a comminution machine. This mixture is now intimately mixed with talc and filled into hard gelatine capsules.

Example C

Parenteral dosage form (0.5 mg)

Each ampoule of 1 ml contains:

(+) -2-Butylooctahydro-7-phenyl-2H-quinolizin-2-yl ·

-acetate hydrochloride 0.510 mg (2% excess glucose for injection 40.0 mg water for injection up to 1.0 ml

To 5.10 g of the active substance 400 _{µg of} glucose dissolved in water for injection is added and the volume is made up to 10 000 ml with water for injection. The resulting solution is either sterile filtered, filled into colorless ampoules, vented with nitrogen and sealed, or the solution is filled into colorless ampoules that are vented with nitrogen, sealed, and optoma sterilized for 30 minutes in a steam stream or autoclave at 120 ° C. Deň: 32 ° C.

total weight 220.0 mg

Claims (4)

OBJECT OF THE INVENTION Process for the preparation of phenylquinolizidines of the general formula IV by carbon atoms or an acyl group, in particular acetyl, trifluoroacetyl and propionyl, in the form of a racemate or in the form of emantiomers, as well as in the form of free bases and acid addition salts, of formula II X represents a hydrogen atom, a chlorine atom or a (C 1 -C 4) alkoxy group at the o-, m- or β-position, Y represents a hydrogen atom or a chlorine atom at the o-, m- or p-position, R ² represents an alkyl group having 1-5 carbon atoms or phenyl, which is optionally substituted by alkoxy having 1 to 4 carbon atoms, R ⁷ represents an alkyl group having 1 to 6 wherein X, Y and R ² have the above meanings, with etherifying or esterifying agent yielding the radical R ⁷ in the presence of an organic acid or base at a temperature between room temperature and the reflux temperature re241 0.2 4 Action mixtures · racemates obtained is optionally cleaved and the obtained base optionally converted to their acid addition salts. 2. Process according to claim 1, characterized in that the corresponding compounds of the general formula are used as starting materials. of formula II and the corresponding reagent introducing the radical R ⁷ to form a compound of formula IV wherein X and Y are hydrogen, OR 7 is O-oriented acetoxy and R 2 is n-butyl. 3. A process according to claim 1 wherein the corresponding compounds of formula (II) and the corresponding reagent introducing the radical R @ ⁷ are used as starting materials to form a compound of formula (IV) wherein X and Y are hydrogen, OR 7 is a C 3 position -trifluoroacetoxy group and R 2 is a tert-butyl group. 4. A process according to claim 1, wherein the starting materials are the corresponding compounds of the formula II and the corresponding reagent introducing the radical R @ ⁷ to form a compound of the formula IV in which X is an ortho-position chlorine. OR7 is an a-position-oriented acetoxy group, Y is a hydrogen atom, and R2 is a phenyl group.