FI68830B - DL-ELLER D-TRANS-8-FLUORO-5- (P-FLUORPHENYL) -2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) INDOL SOM ANVAENDS SOM MELLANPROTUKT VID FRAMSTAELLNING AV THERAPEUTIC ANVAENDBARA 2-SUBSTITUERADE DL- OCH D-TRANS-8-FLUOR-5- (P-FLUORPHENYL) -2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) INDOLER - Google Patents

Description

1,68830 Intermediate therapeutically useful 2-substituted dl- and d-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [3] -d- or d-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H / 4,3-hjindole for use in the preparation of -b7indoles

The invention relates to dl- and d-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyridoZ4, 3-b./indole of formula

B

F.

^ -------- i9b NH I

10. I '4a;

v N

] <* L j 15 i and its acid addition salts. The compound of formula I is used as an intermediate in the preparation of therapeutically useful 2-substituted dl- and d-trans-8-fluoro-20- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido- (A, 3-b / indoles of formula

F ~ \ ^ - (CH2> n- M II

25 ^ V--> 4 v

30 F

wherein M is CHOH or C = O, n is 3 or 4 and Z is hydrogen, fluorine or methoxy. The compounds of formula II have a very potent sedative effect. The compounds of formula II and their therapeutic properties are described in F1-pa-35 patent application 78 1612 - patent 63402.

2 63830

The intermediate of the invention can be prepared according to the following reaction scheme.

F H

5 (1) BH3 / ether Y '"^ j £ b N-R2 N- \' -; - *" - J - N · j (2) h,:

I J H

j!

F F

III IV

15 F V

--------------------------> i '\ ~~ \ "nh i!

H I

20

L

τ \

F

25

In the above formulas, R 2 is preferably benzyl for economical reasons. However, it will be appreciated that other R2 groups may be used, such as a benzyl group having a benzene ring substituted with one or more methyl, methoxy, nitro or phenyl groups, and a benzhydryl group.

3 6 δ 8 3 Ο

The reduction of a tetrahydro-f-carboline of formula (III) to a 4a, 9b-trans-hexahydro compound of formula (IV) is carried out in an ether solution, usually tetrahydrofuran. In order to ensure the completeness of the reduction, a boron / tetrahydrofuran complex (BH 2 .THF) is usually used in excess, in which case a molar excess of 100-200% is preferred. The reaction can be carried out at a temperature of -10 to 80 ° C, preferably 0 to 65 ° C. Usually, a tetrahydrofuran solution of the starting material of formula (III) is added to an ice-cold BH 2 · THF solution. After the addition, the mixture is heated to reflux and maintained at this temperature for about 1-2 hours or longer. The reaction is usually carried out in the presence of an inert gas such as nitrogen. When the reaction 15 is substantially complete, the solvent is evaporated and the residue is acidified with an excess of acid, e.g. 2-12 M hydrochloric acid. The preferred acid is a mixture of equal volumes of acetic acid and 5 M hydrochloric acid. The resulting acidic mixture is heated to reflux, usually for 1-2 hours or longer. The desired product can then be isolated, for example, by evaporating any remaining ether solvent and part of the acid mixture, collecting the precipitated product and washing. Alternatively, the product (IV) can be isolated by filtering the reaction mixture after reflux, cooling the filtrate and basifying by adding, for example, sodium hydroxide, potassium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a water-insoluble organic solvent such as coloroform, methylene chloride or benzene, the extracts are evaporated and the residue is purified on a silica gel column using, for example, ethyl acetate or hexane-ethyl acetate as eluent.

4,60830

Treatment of the tetrahydro-N'-carboline with a BH-β-THF complex followed by acid treatment gives hexahydro-'-carbolines in which the hydrogen atoms attached to the carbon atoms at positions 4a and 9b are in the trans-5 position relative to each other, cf. e.g., U.S. Patent 3,991,199.

The 2-benzyl compound of formula (IV) can then be converted to the corresponding 2-hydrogen compound of formula (I), for example by hydrogenation using a palladium / -10 carbon catalyst. The starting material of formula III

The 2-benzyl-1,2,3,4-tetrahydro-T-carboline derivative according to the invention can be prepared from the corresponding compound in which R 2 is hydrogen (see US 4,001,263) by reacting it with a benzyl halide such as benzyl bromide using equimolar amounts.

The compound of formula I can be used as an intermediate for the preparation of compounds of formula (II) according to the following reaction scheme O O

20 z \ ^ C- (CH) -Ö) H F O ° A (v) a./1 1 t

f '(VI) I

z J: 25 ^ i!

AA

i

LiAlH „, l ΓΊ N- (CH) CH-ΑΛ

---- 4-} AAXN -Ά A

30 Z

jr

L

(II, M = CHOH)

(VI) F

li 35 63830

When acylating a compound of formula (I) to give compounds of formula (VI), acids of formula (V) or their acid chlorides or acid bromides may be used.

When acids of formula (V) are used in the acylation, about equimolar amounts of said acid and compound of formula (I) are reacted in the presence of a reaction-inert solvent and a condensation reagent known in the art to form peptide bonds. Such reagents include e.g.

Carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and alkoxyacetylenes such as methoxyacetylene and ethoxyacetylene. Dicyclohexylcarbodiimide is the preferred condensing reagent. Useful solvents 15 include. dichloromethane, chloroform, tetrahydrofuran, ethyl ether and benzene. Although the reaction can be carried out with satisfactory results at a temperature of -10 to 50 ° C, it is preferable to use a temperature of 0 to 30 ° C. At this temperature, the reaction usually takes place in a few 20 hours. The product of formula (VI) can be isolated, e.g. by filtering off insoluble material and evaporating the solvent. The residue is usually pure enough to be used in the next step.

The compound of formula VI is then reacted with lithium aluminum hydride to give a compound of formula II wherein M is CHOH.

When compounds of formula (II) wherein M is CHOH are oxidized using reagents and methods known to be capable of selectively converting secondary alcohols to the corresponding ketones, compounds of formula (II) wherein M is C = O are obtained. Suitable oxidants for this reaction include, for example, potassium permanganate, potassium dichromate and chromium trioxide, of which it is preferred to use chromium trioxide in the presence of pyridine. When this reaction is carried out with a preferred reagent, in a reaction-inert solvent such as dichloromethane, chloroform or benzene, the alcohol of formula (II) is added to a mixture of up to 10 molar excess of chromium trioxide and up to 10 molar excess of pyridine. , and the resulting mixture is usually stirred at 5 room temperature until the reaction is complete. Usually 15 minutes - one hour is enough. The product can be isolated, for example, by filtering off the insoluble matter, extracting the filtrate with a dilute base such as sodium hydroxide solution, drying the organic layer and evaporating to dryness. If desired, the product obtained as a residue can be purified, for example, by column chromatography.

The d-isomer of the compound of formula I is obtained by resolution of the corresponding racemic compound. The decomposition is carried out with a salt of a compound of formula I and an optically active acid. Although several acids useful in the resolution of amines are known in the art, the preferred acids are the optical isomers (D- and L-) of N-carbamoylphenylalanine. The latter is obtained by reacting isomeric phenylalanines with sodium cyanate in a manner known per se. The decomposition is carried out by reacting one of the isomeric N-carbamoylphenylalanines, e.g. the L-isomer, with a racemic compound of formula (I) in equimolar amounts in the presence of a suitable inert solvent to give a homogeneous solution of the salts. After cooling, the salt of the second optical isomer of the compound of formula I is obtained as a solid crystalline substance which can be further purified if desired. The mother liquors containing mainly the salt of the second isomer are evaporated to dryness, the salt is decomposed with an aqueous solution of a base such as sodium carbonate, potassium hydroxide or calcium carbonate, the free base is extracted with water-immiscible solvent, dried (usually ethyl acetate) and is enriched. This residue is then dissolved in an inert solvent and treated with an equimolar

II

7,63830 of the second isomer of N-carboxylphenylalamine, e.g. the D-isomer, and the solution is cooled to precipitate crystals of the N-carbamoylphenylalanine salt of the second isomer of the compound of formula (I).

The compound of formula I may form acid addition salts. The compounds are converted to acid addition salts by contacting the base with an acid in either an aqueous or non-aqueous medium. Similarly, an acid addition salt may be converted to the free base when the acid addition salt is treated in the same manner with an equivalent amount of an aqueous solution of a base such as alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate or an equivalent amount of a cation forming an insoluble precipitate with an acid ion.

The bases thus regenerated can be reconverted into the same or other acid addition salts.

The following examples illustrate the invention.

Preparation of intermediate according to the invention Example 1 Trans-dl-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole

To a clean glass-lined pressure vessel, 780 g of 5% palladium / carbon catalyst having a water content of 50% by weight, 1167 ml of water, 1556.5 g (3.77 mol) of trans-dl-2-benzyl-8 -fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,5-hexahydro-1H-pyrido [M, 3-b] indole hydrochloride and 86.1 L of methanol. The reactor was purged with nitrogen and then with hydrogen and finally fed with hydrogen at a pressure of 3.5 kg / cm 2 and hydrogenated at 25-41 ° C until hydrogen consumption was complete (about two hours). The vessel was depressurized and After washing with methanol, the filtrate and the washings were evaporated under reduced pressure, 28 l of methylene chloride and 87 liters of water containing 852 g of sodium hydroxide were added to the residue, and the resulting mixture was stirred for 12 minutes (pH 12). the layers were separated.

8 63830

The aqueous layer was extracted with a second portion (28 L) of methylene chloride and the organic layers were combined and washed with 26.5 liters of water. The organic extracts were dried over anhydrous magnesium sulfate and concentrated by the addition of 5 hexane (95 L) to displace methylene chloride. The resulting slurry was cooled to 8 ° C, filtered, washed with hexane and dried to give 1446 g (67%) of the desired product, m.p. 115-118 ° C.

Analysis: C H 5.63; N 9.79; F 13.27 Found: C71.25; H 5.50; N 9.76; F 13.28

Mass spectrum (m / e): 286 (100, m +), 257 (50), 256 (72), 243 (61), 242 (57), 148 (32), 135 (36), 57 (79).

Example 2 Decomposition of dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole A. Enantiomeric N- Decomposition of Carbamoylphenylalanine Salts 1. To one equivalent of dl-trans-8-fluoro-5-20 (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4,3-b7-indole one equivalent of L - (+) - N-carbamoyl-phenylalanine was added to the free base dissolved in a minimum amount of ethanol. The mixture was heated on a water bath with more ethanol until a homogeneous solution formed.

This was allowed to cool to room temperature and the precipitated white needles of the L - (+) - N-carbamoylphenylalanine salt of the free base (-) enantiomer were isolated by filtration and dried, m.p. 207 ° -209 ° C, 5.9 ° in methanol.

2. The mother liquor obtained above was evaporated to dryness, the residue was partitioned between aqueous sodium carbonate solution and ethyl acetate, the organic layer dried over magnesium sulphate, evaporated in vacuo to give an oily residue, the oil dissolved in a small amount of N ethanol and treated with 1 equivalent. -karbamoyylifenyylialaniinia. The mixture was heated on a water bath while adding more ethanol until complete dissolution. The solution was cooled and proceeded as above to give in 92% yield the crude D - (-) - N-carbamoylphenylalanine of the free base (+) enantiomer, which was recrystallized from ethanol (75 ml / g), total yield 65%, mp. 209 DEG-211 DEG C., [.alpha.] D @ 20 = + 6.6 DEG (in methanol).

B. Isolation of Hydrochloride Salts of the Enantiomeric Free Base 1. The enantiomeric N-carbamoyl-10-phenylalanine salt obtained in A1 was partitioned between aqueous sodium bicarbonate solution and ethyl acetate over 100 ml of water, the organic layer was dried over magnesium sulfate and evaporated to dryness. / g) and dry hydrogen chloride was passed over the surface of the solution and shaken to give a white precipitate. Excess hydrogen chloride and ether were removed by evaporation at ambient temperature to give (-) - trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4.3 -b_7-indole hydrochloride-20 in about 96% yield. This was recrystallized by dissolving in a minimum amount of boiling ethanol and ethyl ether was added until the solution became cloudy. The product was obtained as small white crystals, yield 75%, m.p. 258 ° -260 ° C, = (“) 40.9 ° (in methanol).

2. In a similar manner, (+) - trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,5b-hexahydro-1H-pyrido [4,3-b] indole was obtained above. from the salt of A2, crude yield 96% and after recrystallization 75%, m.p. 260 ° -262 ° C, / c </ p0 = (+) 39.2 ° (in methanol).

30 Manufacture of finished products

Example I

of dl-trans-8-fluoro-5- (p-fluorophenyl) - (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido / 4,3-bJindoli hydrochloride 35 A. To a suspension of 554 mg (2.69 mmol) of dicyclohexylcarbodiimide and 479 mg (2.69 mmol) of 3-benzoylpropionic acid in 25 mL of dichloromethane at 0 ° C was added. 700 mg (2.44 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole 10 ml of the above solvent. The resulting mixture was stirred and the temperature was allowed to rise to room temperature over two 5 hours. After recooling to 0 ° C, the reaction mixture was filtered, washed with dichloromethane and the filtrate evaporated to give a residue which was dl-trans-8-fluoro-5- (p-fluorophenyl) -2-H3-benzoyl) propionyl / -2,3,4,4a, 5,9b-hexa-10 hydro-1H-pyrido / 4,3-byindole and used without purification in the next step.

B. The residue obtained above was dissolved in 25 ml of tetrahydrofuran and heated to reflux. A filtered solution of lithium aluminum hydride in the above solvent was added until gas evolution ceased (molar excess), and the resulting mixture was stirred at reflux for 5-10 minutes, followed by cooling. Anhydrous powdered sodium sulfate, 3a, was added and then 0.2 ml of water was added. The resulting mixture was stirred at room temperature for 30 minutes, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a column containing 35 g of silica gel, eluting with ethyl acetate / hexane (1: 1, v / v) to give the title compound as the free base after evaporation of the solvent. The free base was converted to the hydrochloride salt by dissolving it in ether, and adding a saturated solution of anhydrous hydrogen chloride until precipitation was complete, followed by filtration and drying to give 212 mg of the hydrochloride salt, 30 m.p. 220-223 ° C.

Example II

dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-methoxyphenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido] 4,3-b / indole.

35 A. To a suspension obtained by mixing 426 mg (2.07 mmol) of dicyclohexylcarbodiimide and 431 mg (2.07 mmol) of 3- (p-methoxybenzoyl) propionic acid in 25 ml of "68830 dichloromethane at 0 ° C, 540 mg (1.88 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b_7indole in 10 ml of the above-mentioned solvent The resulting mixture was stirred and the temperature was allowed to rise to room temperature over 2 hours.

After recooling to 0 ° C, the reaction mixture was filtered, washed with dichloromethane and the filtrate evaporated to give a residue which was dl-trans-8-fluoro-5- (pf-fluorophenyl) -2- (T (3- p-methoxybenzyl) -10-pionyl / -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and used without purification in the next step.

B. The residue obtained above was dissolved in 25 ml of tetrahydrofuran and heated to reflux. A filtered solution of lithium aluminum hydride in the above solvent was added until gas evolution ceased (molar excess), and the resulting mixture was stirred at reflux for 5-10 minutes, followed by cooling. Anhydrous powdered sodium sulfate, 3 g, was added and then 0.2 ml of water was added. The resulting mixture was stirred at room temperature for 30 minutes, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a column containing 35 g of silica gel eluting with ethyl acetate / hexane (2: 1, v / v) to give, after evaporation of the solvent, 272 mg of the title compound, m.p. 45 to 48.5 ° C.

Claims (2)

12,60830 Claim for the use of therapeutically useful 2-substituted dl- and d-trans-8-fluoro-5- (p-fluorophen-5-yl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4 Used in the preparation of 1,3-b / indoles dl- or d-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] b / indole of formula 10 H F. ^>, - T9b N H I 15 I! F 20 or an acid addition salt thereof.