CS200183B2 - Process for preparing 9-formyl-9,10-dihydro-9,10-methanoanthracene - Google Patents

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE INVENTION FOR PATENT 200183 (11) (B2) (51) Int. Cl, 3 C 07 C 47/52 - (22) Registered 15 12 75 (21) (PV 406-77) (32) (31) (33) Priority from 13 12 74 (143734) Japan (40) Published 30 11 79 OFFICE AND DISCOVERY OFFICE (45) Issued 15 07 83 172}

Author of the Invention (73)

Patent holder SUNAGAWA MAKOTO, HAYO HIROMI, KATSUBE JUNKI AΥΑΥΑΥ HISAO, OSAKA (Japan) SUMITOMO CHEMICAL COMPANY, LIMITED, OSAKA (Japan) (54) Method of preparation 9-formyl-9,10-dihydro-9, H0-niethanoaiittiracene 1

The present invention relates to a novel organic tricyclic compound 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula I,

which is useful as a key intermediate in the production of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of general formula II,

R 1 (A 1 where A represents a C 1 -C 6 alkylene- or C 1 -C 6 alkenyl group and each of the 2 symbols

R 1 and R 2 are hydrogen, C 1 -C 6 alkyl, C 3 -C 4 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl (C 1 -C 3) -alkyl-, ar (C 1 -C 3) alkyl or polyhalo (C 2 (C 4) alkyl group or

R 1 and R 2 together with the adjacent nitrogen atom represent a nitrogen-containing 5- to 7-membered heterocyclic ring which optionally contains an additional hetero atom and non-toxic pharmaceutically acceptable salts thereof. The compounds of formula (II) exhibit various pharmacological effects, particularly on the central nervous system and the autonomic nervous system, and are particularly useful as anti-irritant drugs such as antidepressants, potent tranquilizers, anti-histamines, antiallergics, and the like.

According to the invention, 9-formyl-9,10-dihydro-9,10-methanoanthracene (I) is prepared by shifting 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene of formula A.

2. (A) 200183 200183 The rearrangement of amine derivatives and α-aminoalicylic acids with nitrous acid is known as Dem-Genoa rearrangement and Tiffeneu-Demjanov's rearrangement [Organic Reactions, Vol. 11, p. 157, John Wiley and Sons, Inc.]. This type of rearrangement has been used in most published ring propagation-related reactions and few cases have been reported where this rearrangement has been used to reduce the circle. The rearrangement of the 9,10-ethanoanthracene derivative to 9-formyl-9, -10-dihydro-9,10-methanoanthracene has not yet been reported and therefore represents a novel process for 9-formyl-9,10-dihydro- 9,10-meethanoanthene. The rearrangement of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene to 9-formyl-9,10-dihydro-9,10-methanoanthracene can be accomplished by the action of nitrous acid. 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene is treated with nitrous acid or a metal nitrite such as sodium nitrite or potassium nitrite in an acidic medium such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid. , sulfuric acid or a bulk solution of these acids. The reaction may optionally be carried out in an inert solvent such as water, methanol, ethanol, acetone, benzene, toluene, chloroform, dichloroethane, dichloromethane, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, dimethylsulfoxide or dimethylformamide or The temperature of the reaction may in this case vary from the temperature given by the ice cooling bath to the reflux temperature of the reaction system. The 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula (II) thus obtained can be conveniently recovered from the reaction mixture and purified.

Compound A (i.e., 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene can be prepared from a compound of formula (B))

wherein R represents hydrogen or a hydroxy protecting group, such as acetyl, benzoyl or tetrahydropyranyl, by rearrangement, such as Curti reaction or Hofmann rearrangement and hydrolysis. The shear can be carried out, for example, by the general Curti reaction (Organic Reacts, Vol. 3, p. 337, John Wiley and Sons, Inc.) And hydrolysis can be carried out under conventional hydrolysis conditions of urethane or isocyanate derivatives.

Intermediates for the synthesis of the 9-aminoalkyl-methanoanthracene compounds of general formula II can be prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene of general formula II using conventional reactions such as oxidation, reduction, hydrolysis, reaction of i. -and with the expansion of the carbon chain (substitution, Wittig reaction, Reformat re-action, Grignard reaction, etc.). Some typical examples of these conversions are listed below:

Scheme I

where

Ts is p-toluenesulfonyloxy, i.e. 1. 9-formyl-9,10-dihydro-9,10-methanoanthracene is oxidized to 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid by treatment with an oxidizing agent such as chromium oxide or silver oxide in i-nert solvent; 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene was prepared from 9-formyl-9,10-dihydro- 9,10-methanoanthracene acting as a reducing agent such as sodium borohydride or lithium aluminum hydride in an inert solvent; 3. 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from 9-hydroxymethyl-9,10-dihydro-9, 10-methanoanthracene treatment of p-toluenesulfonyl chloride in the presence of a base in an inert solvent; 4. 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid is converted to the corresponding acid chloride by reaction with thionyl chloride 200183

With 8ide, optionally in the presence of an inert solvent and an acid chloride, 9,10-dihydro-9,10-methanoanthracene-9-carboxamide is converted by a conventional reaction with an α-monoacetate, 5. dehydration of 9,10-dihydro-9,10- of methano-anthracene-9-carboxamide to 9,10-dihydro-9,10-methanoanthracene-9-carbonitrile is carried out using phosphorus oxychloride, optionally in the presence of an inert solvent.

where

Ts is as defined above. 9. 9,10-Dihydro-9,10-methano-9-anthrylacetic acid ethyl ester is obtained from 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid by conventional Arndt-Eister method 7. 9,10-Dihydro-9,10-methano-9-anthrylacetic acid is obtained from the corresponding ethyl ester by a conventional hydrolysis procedure. 9. 9- (3-Hydroxyethyl-9,10-dihydro-9), 10-methanoanthracene is obtained by reducing [9,10-dihydro-9,10-methano-9,10-methano-9-anthryl] acetic acid ethyl ester with a reducing agent such as lithium aluminum hydride or sodium aluminum diethyl dihydride in i-nert solvent 9. 9- (3-tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene) was obtained as above. 10. (9,10-Dihydro-9,10-methano-9-anthryl- acetaldehyde is obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wittig reaction with methoxymethyltriphenylphosphonium chloride followed by acid hydrolysis, 11. (9,10-dihydro-9,10-methano-9-anthryl) The acetonltril can be obtained from 9-tos loxymethyl-9,10-dihydro-9,10-methanoanthraceneureaction with metal cyanide in an inert solvent.

Scheme III

(12)

(1?)

(18)

Ψ

where

Ts is as defined above; 12. 3- (9,10-dihydro-9,10-methano-9-antipyralic acid is prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene) 200183

Wittig reaction with triethylphosphonoacetate by hydrolysis of ester function, 13. (S- (9,10-dihydro-9,10-methano-9-anthrylpropionic acid is prepared by the corresponding acrylic acid by conventional hydrogenation, 14. 9-phydroxypropyl-9, 10-Dihydro-9,10-methanoanthracene is prepared from [3- (9,10-dihydro-9,10-methano-9-anthryl) propionic acid by treatment with a reducing agent such as lithium aluminum hydride or sodium aluminum diethyl dihydride in an inert solvent. 15. A 9-y-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from the corresponding alcohol by the procedure described above. 9. 9-γ-Hydroxypropyl-9,10-dihydro-9, 10-methanoanthracene is oxidized to the corresponding aldehyde by treatment with an oxidizing agent such as chromium oxide-pyridine complex in an inert solvent, 17 and 18 S- (9,10-dihydro-9,10-methano-9-). the anthrylpropionic acid is converted to the N - (9,10-dihydro-9,10-methanoanthryl) propionitrile by the process described above, 19. (3- (9,10-Dihydro-9,10-methano-9-anthryl) acrylic acid aldehyde is prepared from 9-formyl-9,10-dihydro-9,10-methanoanthra-pr. Wittig reaction with formylmethylene- triphenylphosphorous.

Scheme IV

Claims (2)

200183 g 10 wherein Ts, R 1 and R 2 are as defined above. The following examples are for illustration only, but are not intended to limit the scope of the invention in any way. Přikladl. To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (3.0 g) in acetic acid (250 ml) was added a solution of nitrite of sodium (6.7 g) in water (120 ml). at 5 ° C and the resulting mixture was stirred at the same temperature for 1 hour and then at 95-105 ° C for 5 hours, diluted with water and extracted with benzene, washed with water, dried over sodium sulfate and evaporated to dryness. the crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthra-protein (2.8 g) were recrystallized to give colorless crystals (2.45 g) at 99-100 ° C. After further purification by crystallization, analytically pure 9-formyl-9,10-dihydro-9,10-methanoanthracene is obtained, m.p. 102.5 DEG C. EXAMPLE 2 To a 9-amino-12-hydroxy- 9,10-dihydro-9,10-ethanoanthracene (50 mg) in concentrated hydrochloric acid (2 mL) and water (2 mL) was added a solution of sodium nitrite (112 mg) in water (1.0 mL). ml) at 0 ° C The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness. SUBJECT v A process for preparing 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula I, The crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (35 mg) were obtained. Example 3 A solution of 12-acetoxy-9,10-dihydro-9,10-ethananthracene-9-carboxylic acid (1.0 g) in benzene (10.0 ml) and thionyl chloride (4.0 ml) was boiled for 4 hours After evaporation of excess thionyl chloride and benzene, 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid chloride was obtained, and the acid chloride was dissolved in dry acetone (25.0 mL). and cooling with ice, a solution of na-triumazide (0.63 g) in water (1.3 ml) was added thereto, followed by stirring for 2 hours under cooling and diluting with water and extracting with benzene. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, refluxed for 2 hours and evaporated to dryness to give 9-isocyanato-t-12-acetoxy-9,10-dihydro-9,10-ethano-anthracene. the compound was dissolved in ethanol (12.0 ml) and 20% aqueous sodium hydroxide (12.0 ml) and the resulting solution was refluxed for 6 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, the ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystalline 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (0.72 kg) is obtained, m.p. 181-181.5 ° C. Recrystallization from benzene gave analytically pure crystals of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene, m.p. 183.5 ° C. (A) characterized in that 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene of formula A is treated with nitrous acid or nitrite in an acidic medium. Severojrafl », n. P., Race 7, Most