CS203015B2 - Process for preparing 5-isopropyliden-2,7-dihydroxy-9-subst.-2,6-methano-3,4,5,6-tetrahydro-2h-1-benzoxocines - Google Patents

Abstract

A process for preparing 5-isopropylidene-2,7- dihydroxy-9-substituted-2,6- methano-3,4,5,6- tetrahydro-2H-1-benzoxocins of the formula <IMAGE> in which R1 is C5-C10 alkyl, C5-C10 alkenyl, C5-C8 cycloalkyl, or C5-C8 cycloalkenyl; which process is characterized by reacting a 1-alkoxy-4-(1- hydroxy-1-methylethyl)-1, 4-cyclohexadiene of the formula <IMAGE> wherein R3 is C1-C4 alkyl, with a 5-substituted resorcinol of the formula <IMAGE> in an organic solvent in the presence of stannic chloride for from 1 to 15 minutes at a temperature from -40 DEG C. to ambient temperature. The benzoxocins prepared are useful intermediates in the production of dibenzo [b,d] pyran-9- ores which are anti-anxiety, analgesic and anti-depressant drugs.

Description

The present invention discloses a process for the preparation of 5-isopropylidene-2,7-dihydropyls-9-substituted-2, bmethano-3,4,5,6-ethoxy-2H-1-benzoxscins by reacting 5- (substituted) ressrcins with 4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in the presence of tin tetrachloride for 1 to 15 minutes. Benzoxocin derivatives are useful for the synthesis of certain dibenzo [b, dlp: ran-9-ones _> valuable as anti-anxiety drugs for a team of states, analgesics and antidepressants.

As already mentioned, the present invention relates to 5-isopropylidene-2,7-dihydric-9-substituted- _β- 2,6-methano-3,4,5,6-trimethyl-2H-1-benzoxysine. Certain benzoxocin derivatives are known in the art. 2-Methyl-5-isopropyl-7-hydroxy-9-n-pentel-2,6-methano-3,4,5,6-tetrhydrohydro-2H-1-benzoxocin was prepared by reacting bostriflusride tetrahydrate with 2 - ( 3-methyl ^- 6-isopropylene-1,2-cyclohexyl-5-l-octylresorcinol, known under the trivial name klnaabidis [see Gaoni and Mechoulam, Tetrahedron, 22, 1481 (1966) and J. Am. Chem. Soc., 93, 217 (19711). Razdan and Zitko have described that the above isopropell-1-belsxocin derivative can be converted to the corresponding isopropllidene-benzsxocin derivative by reaction with p-eselsulphonic acid.

These authors further suggest that 2-methyl-5-isopropylspinyl-7-nitro-9-n-pentyl-2, 6-methalo-4,5,6-tetrahydro-2H-1-benzenesulfon is can be converted under acidic conditions to 1-hydroxy-3-l-Otltyl 6,6,9-trimethyl-6a, 7,8,1Ooltetrlhydrodibelzs [b, dlplran [see Tetrahedron Letters 56, 4 947 (1969)].

Recently, Razdan et al. describes the preparation of 2-methyl-5-isoprsollidyl-7-hydroxy-4-n-pentyl-4,6-methano-3,4,5,6-tetrahydro-2H-1-benzoxoxine by reacting 5-methylthio-5-methylsulfonyl 1-hydrosyl-1-meteo-4-isopropene-2-glycol acetone [see J. Am. Chem ·. Soo., 96,560 (197431.

The compounds of formula (I) below have been previously described, as in Belgian 203015.

203015 ´ patent δ. It is disclosed in this patent that the compounds corresponding to formula (I) are useful as intermediates for the preparation of dibenzo [d] pypyran-4-ones, which are now known to be very important as. antidepressants and as anti-anxiety drugs. The present invention offers a particularly fast and efficient process for the production of these intermediate benzoxocins.

Accordingly, the present invention provides a process for the manufacture of -9-tubyl-2,6-oethano-3,4,5,6-tetrahyart-2H-1-beizoxocirils

/ СНэ НэС — c OH 1? ^ 48 (3 CM AND 1 ⁰ 10 OH

5-isvorvoyliaen-2 _I 7-di-yrarvxyobecného- formula I (I) wherein, R represents an alkyl group having 5-10 carbon atoms with 5 to alkenylovou'skupinu JO uilíku atoms, cycloalkyl having 5-8 C atoms or a C 5 -C 8 cycloalkenyl group, characterized in that 1-alkoxy-4- (1-lyaroxy-1-oethoxyethyl) -1,4-cyclohexaaiene of formula III '-

(III) in which:

R @ 1 represents an alkyl group reacted with 5-Ciž-Ciž-C sub, alkyl having the formula II

in which

R 1 is as defined above, in an organic solvent in the presence of tin (II) chloride, for a period of from 1 to 15 minutes at a temperature of from -40 ° C to room temperature.

To this condensation reaction. it is possible to use a series of 5-tubed resorcinols of the general formula (II) in which the 5 'position in the 5 position corresponds to the radical R as defined above

Examples of C 5 -C 10 -alkyl groups include i-oertyl, n-hexyl, 1-oetl-trichloro-1-yl, isoheptyl, 1,1-aioethylheptyl, 1,2,3-trimethyl-isothecyl, isodecyl. , 1-ethylheptyl, 1,1-allylpolyityl and 1,2-aioethyltctyl groups. .

Examples of C5-C10 alkenyl groups include S-PEG, 3-hexenyl, 1,2-aioethyl-1-isothiyl, 4-cyclohexyl, 1,1-aioethyl-1H-2-heothiyl, 1-Ethyl-2-oetlyl-2-pentylyl, 1,2,3-trifluoromethyl-isopropyl ^{, a} group and related groups.

Typical C 5 -C 8 cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Similarly, typical cycloalkenyl groups having 5 to 8 carbon atoms include 1-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl and 1-cyclooctenyl.

Examples of 5-substituted resorcinols of formula (II) which are conventionally reacted with the aforementioned 1-alkoxy-4- (1-hydroxy-1-meethlethyl) -1,4-cyclohexadiene to give compounds of formula (I) include: :

5-n-pentylresoocinol;

5- (1, 1 -dieet h ^r ^ Cl ^le ptyC) resorcinol _J.

5- (1,2-dieethhC - ^ "h ^e ettnyllresorcinol, 5- (1-ethllheχl.) Reslrcinol, '.

5- (3-hexermllresorcimol 5-cyklohéétylresorcinol _{5-cyklooOtylгesorcinol>} 5- (1-clkllhexenyllгesoгcinol,.

5- (2-chlorophenyl) glycine and related resins.

In accordance with the present invention, a roughly equimolar amount of 5-substituted resorcinol and 1-alkose (1-hydroxy-1-ethyl-ethyl) -1,1-cyclohexane is mixed in tin (II) chloride in an organic solvent at room temperature. moving from -40 ° C to room temperature. ·, '. The organic solvents used in the reaction described above for the preparation of the compounds of the formula (I) are suitably halogenated organic solvents, for example halogenated hydrocarbons such as dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, bromomethyl 1,2-dibromoethane, 1-bromo-4-chloroethane, 1-bromopropane, 1,1-dibromoethane, 2-chloropropam, 1-indopropam, 1-bromo-2-chloroetham, bromobenzene, and 1,2-dichlorobehenate. However, the reaction can also be carried out in other organic solvents such as aromatic hydrocarbons, for example benzene, chlorobenzene, toluene and xylene.

The presence of a small amount of water in the reaction mixture leads to a better reaction and thus the addition of water is a preferred measure. The preferred amount of water is about 1 mole per mole of product to be prepared.

The reaction of the invention is completed in a very short time ranging from 1 to 15 minutes. The preferred reaction time is 1 to 10 minutes. As is clear from the examples below, it is desirable to carry out the entire process very quickly and to stop the reaction once all the addition of the comminutes is complete.

A preferred embodiment of the process according to the invention is that the compounds of formulas II and III are mixed, the reaction mixture is cooled to a relatively low temperature at the lower limit of the above-mentioned size, and then added to the mixture within a few minutes. tin (II) chloride is added in a gentle stream or dropwise while the reaction mixture is allowed to warm somewhat during the addition.

Of course, the reaction starts when all the reactants, i.e. the compounds of formulas II and III, and the catalyst are present in the reaction mixture. Accordingly, the order of addition of the most reactive components may be arbitrary, provided that the temperature is controlled during the addition of the last reactant and that the reaction is interrupted in a pruritic manner, so that the time for which all the necessary reactants are in the reaction system. The direct flow does not exceed the above mentioned time range. .

Upon completion of the reaction, the benzoxocith derivative is normally isolated in a simple manner, such as by reaction. a mixture of water and a dilute aqueous base solution, evaporation of the reaction solvent and crystallization of the residue from conventional, relatively non-polar solvents such as _? from hexane or methylcyclohexane.

1- Alkooy-4- (1H-1-hhdrooy niethyleehhl) -1 _l 4-cyclohexadiene, .potřebné as starting materials for the preparation · benzoxocinových derivatives according to the invention can be easily obtained by reduction of p-alkoxy-.alpha> ilfa-dmnetl-) of benzene-alcohols. The reduction is usually carried out by reacting the benzyl alcohol derivatives with a metal such as alcohol in the presence of liquid ammonia and a proton source such as ethyl alcohol. This reaction is carried out under standard Birch reduction conditions. In this regard, it is possible to refer to Belgian Patent No. 856,409. They are readily available [see, e.g., Adams Spoo., J. Am ^л. Chem. Soc., £ 0, 664 (1948)].

The benzoxocin derivatives of formula (I ') are useful as intermediates for the synthesis of hixah-drodibenzs (pyrans). The compounds of formula (I) can be converted to the following dl-trans-1-tyrosine-3-desiccans by treatment with an aluminum halide such as aluminum chloride. & Gt _; 6-Dimethyl-1H (66a, 7,8,10,10a-hexal-6-to-9H-benzene-b, dd-pyran-9-ones).

For example, by reacting 2-hydroxybenzoxocin according to the invention, such as 2 _with 7-ditydrxy-5-isopropylspiridene-9- (1,2-dimethyletheptyl) -2,6-octano-3,4,5,6-tetramethyl- dlso-2H-1'-benzoxysine, with about a two to four molar excess of aluminum chloride in a solvent such as dichloromethane, rearrangements to give dl-trans-1-thsilyl-3- (1,2-dimethylethyl); hteey -) - 6,6-dimeeth -) - 6,6a, 7,8,10,10a-hixalh ^г DDO-9H-dibeenoSb, d] pyran-9-one. Such dl-trns (heext-ydodibnnoopyranones) are useful in the treatment of anxiety states and depression, as well as sedatives and analgesics.

The 2-hydroxybenzoxocins of formula (I) can also be converted to the corresponding 1-cis-tert-hydrodibenzopyridines by further treatment with tin (II) chloride. For example, the reaction of 5-issprsp Liden-2,7ddt yroo-T9-enyl NN- _e "2., 6-methano-3,4,5,6-tetat ydoo22H-1 · s -benzoxscinu approx .ekvimolárním the amount or excess of tin (II) chloride in the solvent, such as benzene, rearranges to give dl-cis-1nh-ddose-n-pentyl-6,6-methylethyl (6a, 7,8) -. 1,10,10a-hexal-1 H -dibenzene-9b, dlpyran-9-one.

However, these cis-hexetrans-benzylspyransins, although also larmacologically effective in the treatment of anxiety and depression, are nevertheless somewhat less effective than transdermal trans-socme. . ry. However, treatment of these cis-texrth (dibisopyranes) with aluminum halide, such as aluminum chloride, leads to epimerization to produce the corresponding, largely effective, trans-hexas-dibenzopyranes.

For example, the reaction of dl-cis-1-tyгdrsx- · (3-N-6,6-eentyl dimeith ^r --6,6r, 7,8,10,10a-hexalh- <DDO-9H-ddbennzSb according The gamma-9-dream with aluminum chloride in dichloromethane is epimerized to give the corresponding d-taas-teeati-diboodibenzopyran.

The invention is illustrated by the following Examples. stern-. in any direction. ·

P Ex. 1 et al. ♦ '

2,7-Dihydroxy-55-pyridyl-9- (1,1-dimethyl-1Heptyl) -2,6-methanesulfonyl-4,5,6-thetyrrole-1H-1-benzoxscin

A solution of 11.8 g of 5- (1,1-dimethoxy-heptopyridine), 12.0 g of-ethoxy-4- (1-h-dtoxy-1-meethylene) -1, N-cyclohexadiene and 0.9 ml of water in 100 ml of dichloromethane stabilized with cyclohexane (i.e. commercially pure dichloromethane) are cooled to -20 DEG C. in a solid carbon dioxide / acetone cooling bath with stirring. stirring rapidly dropwise over 3 minutes to 13 ml of TiCl4.

During the dropwise addition, the temperature of the reaction mixture rose to -11 ° C. Immediately after completion of the addition of tin (II) chloride, the reaction mixture is poured onto 200 g of ice and 50 ml of water are added, the organic layer is separated, washed twice with 200 ml of 1 K sodium hydroxide each and then 250 ml of water, dried and the solvent was evaporated under reduced pressure. 20.5 g of solid product are obtained which, after recrystallization from n-hexane, yields 16.2 g (yield 87%) of 2,7-dihydroxy-55-isopropplide (en-9- (1,1-dimethylylheptyl) -6-methano-4-carboxylic acid. 148 DEG-152 DEG C., 6-Eetralyr-2H-1-benzoxocin.

Example 1 and d 2.

- 7ilidy0roxy-5sΓPO0Popylt0i9i9- (1, 1-dimethylheptyl) -2 ', _{6'-methano-3,4,5-5'} 6-tttrsyyro - 2H-1-benzoxocin

A mixture of 11.8 g of 5- (1,1-dimethylheppyresorcinol), 12.0 g of 1-methoxy-4 - (- 1-hydroxy-1-methylethyl) -1,4-cycloheyadiene, 0.9 ml of water and 100 ml of dichloromethane was added to the mixture. ochladi.na 0 ° C and maintaining the temperature between 0 and 10 ° C · thereto dropwise over 10 minutes 13 ml of stannic chloride »hydroxyli5isoppooplidep-II 1 1 ilimePhllhlpPyl) i-, 6"_{methιrooгЗ>} 4,5 _ϊ 6- 145 DEG-148 DEG C. (yield 83%).

Example 1 'and d 3.

2,7-β-γ-γ-γ 5 - i spprpyylidene-9- (1, 1-dimethoxyphenyl) -1,6,6-methylenedi-3,4,5,6-piperidin-2H-1-benzoxocin -.

The procedure of Example 2 was repeated except that the initial temperature of the reaction mixture was -20 ° C and tin tetrachloride was added over 2 to 3 minutes while allowing the reaction mixture to warm to 9 ° C. By analogous treatment of the resulting mixture as in Example 1, 16.0 g (87% yield) of - 7-hydroxy-5-isopropylphenilen-9i (1,1-ethylheppyl) τ2,6-methyl-6-methyl- is obtained.

3.4.5.6-PgP-ahydrp-2H-1-benzoxocin, m.p. 151-153 ° C.

Pří.k laď. 4 -.

7,7-Dipyldigyl-5-isopropylidene-9- (1,1-dimethyl-hepPyl) -, 6-methano-3,4,5,6-tetrlyl-2- (1-benzoxocin).

In this example, the procedure of Example 2 and 3 was followed except that the initial temperature of the reaction mixture was -40 ° C. The tin (II) chloride is added over 1 minute while the temperature rises to -11 ° C. Workup of the reaction mixture as described above afforded 14.2 g (78% yield) of 7,7-lilyl-4-pyrrolidin-5-ylpyridine-9- (1,1-dimethyl-4'-pyrrolidin-1-yl) -1,6-mePhano-3,4,5,6-tetraethyl-1H-1-benzogyocine. mp 153-155 ° C.

Example 5

2,7'Di-4'o hroχliiiooopopopopopop--------,,,,,, ,eeeeeeeeeeeeeeeeeeeeeeeeeeeeee) )eeeeeeee )ee)) )eeee)))))))) H H

2.36 g of 5- (1,1-dimethyl-4-hydroxymethyl) -sulfonyl and 2.0 g of 1-methyl-4- (1-hydroxy-1-hydroxy-1,4-cyclohexyl-1,4-cyclohexyl) were combined in 25 ml of toluene and the solution was cooled. 0.18 ml of water was added thereto, followed by 2.6 ml of tin (II) chloride over 2 minutes while the temperature rose to -4 DEG C. The reaction mixture was briefly worked up as described in Example 1. There was thus obtained 1.47 g (40% yield) of 7,7-thiilydroxy-15-bisproppliden-9- (1,1-dimethyl-1-carboxy) -6-methyl-2-carboxylic acid.

13.4.5.6-tetrotro-2H-1-benzoyoci, m.p. 156-158 ° C.

203015,

EXAMPLE 6 dl-tran8-1-HydrO3x-3- (1,1-dimethyltheptyl) -6,6-dimethylthio-o, 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran -9-on ·

To a solution of 100 mg of 2,7-dihidroxy-5-isoproppliden-9- (1,1-dimethylheptyl) -2,6-methano-3

4,5,6-Ptlycol-22H-1-benzoxocin in 5 ml of dichloromethane is added in a single portion of 100 with stirring at about 24 ° C. mg of aluminum chloride. The reaction mixture was stirred at 24 ° C for 6 hours, then washed with 1N hydrochloric acid solution and water, and dried. The solid residue - evaporation of the solvent under reduced pressure gave - after recrystallization from hexane, dl-trans-lohydroxy-3- (1,1-dimethylethyl) -6,6-dimethyl-0666,7,8,10,10a-hexahidroo 9 H -dibenzoo [b] d) pirano9-one, m.p. 160-16 ° C.

Claims (2)

1 to 10 minutes to react with a compound of formula III wherein R 1 is as in 1. 3. The process of claim 2, wherein the reaction is carried out in the presence of water. 4. The process of claim 3, wherein the reaction is carried out at a temperature of from -20 to 10 ° C. 5. Method according to claim 1 for preparing 2,7-dihydrsxy --- issproppliden ^9-> (Ijl-dimethlheeiyD- 1. A process for the preparation of 5-isopropylidene-2,7-dihydroxy-19-oxo-2,6-methano-3,4,5,6-tetrahydro-2H-1-benzoxocines of formula I (I) wherein R is a C5-C10 alkyl group. , an alkenyl group having 5-10 carbon .mu.l ^{u k} u,, cycloalkyl having ^{5 and} 8 ate ^ uMíku or cycloalkyl-enyl group having from 5 to. 8 carbon atoms, Characterized in that 1-alkoxy-4- (1-hydroxy-1-methyl-1-methyl-1-yl) -1,4-cyclohexadiene of formula III OR ₃ Ф HO-C — CH3. I ³ . CH3 in which. R 1 represents an alkyl group having from 1 to 4 carbon atoms, reacted with a 54% tert-resorcinol of the formula II (III) in which (II), R 1 is as defined above, in a halogenated organic solvent in the presence of fluoride c (destroyed) for a period of from 1 to 15 minutes at -40 ° C to room temperature. 7. 203015 2. The process of item 1, for producing compounds of formula I wherein R 1 is. a (C 5 -C 10) alkyl group, characterized in that the compound of formula (II) wherein R 1 is a C 5 -C 10 alkyl group is left for a period of time -2,6-Ethano-3,4,5,6-tetrahydro-2H-1-benzenesulfonate, characterized in that 5- (1,1-dimethoxyphenyl) ressrciase is reacted for 1 to 10 minutes at from -20 to 9 ° C with 1-methoxy-4- (4-cyclohexadiene) -1,4-cyclohexadiene. .