KR820002112B1 - Process for preparing cis-hexahydrodibenzo-pyranones - Google Patents

Abstract

Title compds. I(R=C5-10 alkyl, alkenyl, C5-8 cycloalkyl, cycloalkenyl; the configuration of H on the position of 6a and 10a carbon is cis), intermediates for prepg. central nervous system-treating medicine 6a,10a-trans isomer, were prepd. Thus, 5-substituted resorcinol (III) was reacted with 4(1-hydroxy-1-methylethyl)-3-cyclohexen-1-one in inactive org. solvent at 30-100≰C in the presence of boron trifluoride or stannic chloride for 0.5-10min to give 3,4,5,6-tetrahydro-2H-1-benzoxocine (II) or for 0.5-8hr to give 6a,10a-cis-hexahydro dibenzo[b,d pyran-9-one(I).

Description

Method for preparing cis-hexa hydrodibenzopyranone

Reaction of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-l-one with 5-substituted resorcinol in the presence of a catalyst results in 2, 7-dihydroxy-5-iso depending on the reaction time. Furopylidene-9-substituted-2, 6-methano-3, 4, 5, 6-tetrahydro-2H-1-benzoxosine or 6a, 10a-cis-1-hydroxy-3-substituted-6 , 6-dimethyl-6, 6a, 7, 8, 10, 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one.

Naviron 6a, 10a-trans-1-hydroxy-3- (1, 1-dimethylheptyl) -6, 6-dimethyl-6, 6a, 7, 8, 10, 10a-hexahydro-9H-dibenzo [b, d] Pyran is the common name given to 9-one.

Naviron is one of a group of Tris-hexahydro dibenzopyranones that have recently been found to be particularly useful for the treatment of tension, depression and related central nervous system disorders. Reference: United States Patents 3, 928, 598, 3, 944, 673 and 3, 953, 603, Naviron and its related clinical efficacy of dibenzoparanone, in finding a personalized method for the preparation of such compounds. Much effort has been spent.

The conventional method of 6a, 10a-trans-hexahydrodi benzopyranone requires a number of steps, yields are low, and a mixture of 6a, 10a-cis and 6a, 10a-trans isomers is obtained which is substantially difficult to separate. Reference: US Patent Nos. 3, 507, 885.

Recently, a relatively simple one-step legal process for 6a, 10a-cis-hexahydrodibenzopyranone has been discovered and described by Archer et al. In J. Org. chem. 42, 2277 (1977).

However, a one-step synthesis of 6a, 10a-trans-hexahydro dibenzopyrans from relatively simple and inexpensive starting materials has not yet been found and conveniently converts 6a, 10a-cis isomers to the corresponding 6a, 10a-trans isomers. The way is possible. Reference: U.S. Patent Nos. 4, 054, 582.

Benzonoxinsine provided by the present invention is readily converted to 6a, 10a-trans-hexahydro dibenzopyranone. Reference: US Patent Nos. 4, 054, 582.

It is an object of the present invention to provide another method for preparing benzoxine and 6a, 10a-cis-hexahydric dibenzopyrazone, which compounds are biologically more active 6a, 10a-trans isomers, ie butterflies It is an intermediate in the manufacture of ron.

The present invention provides a process for preparing 6a, 10a-cis-hexahydrodibenzo [b, d] pyran-9-one having the following structural formula (I) or 3, 4, 5, 6-tetra having the following structural formula (II) Provided is a method for preparing hydro-2H-1-benzoxocine.

Wherein R is alkyl having 5 to 10 carbon atoms, alkenyl having 5 to 10 carbon atoms, cycloalkyl having 5 to 8 carbon atoms or cycloalkenyl having 5 to 8 carbon atoms, wherein the hydrogen atoms bonded to the 6a and 10a positions are cised together .

This method was carried out by the 5-substituted resorcinol of the following formula (III) with 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one having the following formula (IV) for 0.5 to 10 minutes. During the reaction in the presence of boron trifluoride or stanchloride in a non-reactive organic solvent at a temperature between about -30 ° C. and about 100 ° C. to obtain the compound of formula II and the compound of formula I for 0.5-8 hours. It is characterized by obtaining.

A preferred method according to the invention is to react 4- (1-hydroxy-1-methyl-ethyl) -3-cyclohexen-1-one in dichloromethane in the presence of stanchloride.

According to the process of the present invention, 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one is condensed with about equimolar moles of 5-substituted resorcinol of formula (III) in the presence of a catalyst. In the above formula, R is defined as 5 to 10 alkyl, alkenyl having 5 to 10 carbon atoms, cycloalkyl having 5 to 8 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms.

Examples of the alkyl group having 5 to 10 carbon atoms include n-pentyl, 1, 1-dimethylpentyl, n-hexyl, 1-ethylhexyl, 1, 2-dimethylheptyl, 1-ethyl-2-methylhexyl, 1, 2, 3 -Trimethyl heptyl, n-octyl, 1-methylnonyl and n-decyl. Similarly, typical alkenyl groups having 5 to 10 carbon atoms are 3-methyl-2-butenyl, 1-pentenyl, 1, 2-dimethyl-1-hexenyl, 2-heptenyl, 1-ethyl-2-heptenyl, 1, 1-dimethyl-2-octenyl, 3-nonenyl, 1,2-dimethyl-1-heptenyl and 1-methyl-1-nodenyl. In addition, R is a cycloalkyl group having 5 to 8 carbon atoms such as cyclohexyl, cycloheptyl and cyclooctyl and having 5 to 8 carbon atoms such as 1-cyclopantenyl, 1-cyclo hexenyl, 2-cycloheptenyl and 3-cyclooctenyl Is a cyclo alkenyl group.

Typical 5-substituted resorcinols commonly used in the process of the invention include 5- (n-pentyl) resorcinol, 5- (1, 2-dimethyl-heptyl) resorcinol, 5- (1-ethyl-2 -Methylbutyl) resorcinol, 5- (n-octyl) resorcinol, 5- (1-hepsenyl) resorcinol, 5- (1, 2-dimethyl-1-heptenyl) resorcinol, 5 -(1-octenyl) resorcinol, 5-cyclopentyl resorcinol, 5-cycloheptilesolcinol, 5- (l-cyclohexenyl) resorcinol, 5- (2-cyclooctenyl) Resorcinol and the like.

The present invention prepares a process for preparing d 1 -cis-hexahydrodibenzo [b, d] -pyran-9-one of formula (I).

As used herein, the term “cis” relates to the mutually related direction of hydrogen atoms bonded at positions 6a and 10a of the dibenzopyranone compound. The compound represented by "cis" is therefore dibenzopyranone of formula (I) in which the hydrogen atom molecules bonded to 6a and 10a are placed in the same direction on a plane. The term "cis" indicates that there are at least two isomers. In particular, both 6a hydrogen atoms and 10a hydrogen atoms can be placed on the plane of the molecule, in which case their complete atomic arrangement is represented by 6aβ and 10aβ. Alternatively, both 6a hydrogen atoms and 10a hydrogen atoms can be placed under the plane of the molecule, in which case they are represented by 6aα and 10aα.

The complete atomic arrangement of the 6a-hydrogen and 10a-hydrogen atoms is not indicated hereafter, but the indication "cis" includes not only the separated enantiomers of the compounds having the above alban structure, but also mixtures of such enantiomers.

For example, 6a, 10a-cis compounds prepared by the process of the present invention are meant to include 6aβ, 10aβ-isomers, plus 6aα, 10aα isomers, or mixtures of these mirror images. Mixtures of such enantiomers are represented in the same way as d1-mixtures and are common products of the process.

The process according to the invention comprises 5-substituted resorcinol and 4- (1-hydroxy-1-methyl ethyl) of formula (III) in the presence of a catalyst selected from boron trifluoride and stan chloride in an unreactive organic solvent. It is carried out by mixing -3-cyclohexen-1-one at about equimolar. Non-reactive solvents commonly used in this reaction are dichloromethane, chloroform, 1-2-dibromoethane, 1-bromo-2-chloroethane, 1,1-dibromoethane, 2-chloro furophane, 1 Halogenated hydrocarbons such as iodofurophane, chlorobenzene, bromobenzene and 1,2-dichlorobenzene; aromatic solvents such as benzene, toluene, xylene: diethyl ether, dimethyl ether, dimethyl ether and diisofurophyll ether; It contains the same ether. Preferred non-reactive organic solvents are halogenated hydrocarbons and aromatic solvents.

Preferred catalyst for the reaction is stan chloride. When boron trifluoride is used as a condensation catalyst, a commercially available dimethyl ether complex is used. Generally, the amount of catalyst in the process is from about equimolar to about 0.1 to about 5 molar excess relative to the resorcinol and cyclohexenone reactants.

The process of the present invention may be carried out in a temperature range of about -30 ° C to about 100 ° C. Most conveniently in the temperature range of about −25 ° C. to + 4 ° C., especially at −25 ° C. to + 25 ° C. As in the example, resorcinol, such as 5- (n-pentyl) resorcinol, is added to the equimolar amount or slightly excess of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one 0.1-0.5 molar excess) and in a solvent such as benzene. A catalyst such as boron trifluoride diethyl etherate is added in about 0.1 amount-about 5 molar excess. The reaction proceeds in the range of -25 [deg.] C.-50 [deg.] C. and is completed in substantially about 0.5- about 8 hours to obtain 3-n-pentyl hexahydro dibenzopyranone of formula (I).

Longer reaction times are not detrimental but can be used if desired. The reaction is terminated after a reaction time of 0.5-10 minutes and the product is n-pentyl benzoxosin of formula (II).

When 5-substituted resorcinol and the cyclohexenone derivatives are reacted according to the above reaction conditions, the product d1-cis-1-hydroxy-3-substituted-6, 6-dimethyl-6,6a, 7, 8 , 10, 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, if desired and the reaction product can be separated by simple washing with a water soluble acid or a water soluble base, or two in turn and the reaction mixture with water can do. The organic solvent layer is separated and the solvent is removed by evaporation. Typically, the water-soluble acids used for washing the reaction mixtures are water-soluble hydrochloric acid and rare water-soluble sulfuric acid, for example, 0.5-6N water-soluble acid. Commonly used bases include 0.1-1.0 N sodium hydroxide as well as the included sodium bicarbonate solution.

Once the reaction product is separated by removing the reaction solvent, no further purification is required, but if desired the product can be recrystallized from a solvent such as n-hexane or cyclohexane.

The product produced by the process of the present invention was substantially prepared with 1-hydroxy-3-substituted-6, 6-dimethyl-6, 6a, 7, 8, 10, 10a-hexahydro-9H-dibenzo [b, d Only the d1-cis isomer of pyran-9-one, but the corresponding d1-trans isomer can be detected in an amount of about 5-15% by weight.

Purification of such mixtures is not necessary to remove existing trans isomers. This is because the main product, ie dibenzo pyranone of d1-cis-hexa hydro structure (I), is converted to pure d1-trans isomers by treatment with aluminum halides as mentioned in more detail below. Such a conversion can be carried out if so desired, thereby eliminating the need for separation of the compound of formula (I).

Cis-hexahydro dibenzo [b, d] pyranones prepared according to the present invention are prepared when the reaction of resorcinol with cyclohexanone is continued for about 0.5 to about 8 hours. When the reaction is stopped after 0.5 to 10 minutes, benzoxine is produced. For example, 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one in 5- (1,2-dimethylheptyl) for 2 minutes in the presence of stan chloride in a solvent such as benzene When reacted with resorcinol, such as resorcinol, benzoxine, i.e., 2,7-dihydroxy-5-isopuropylidene-9- (1,2-dimethyl heptyl) -2 of formula (II) , 6-methano-3, 4, 5, 6-tetrahydro-2H-1-benzoxosocin is obtained. When the reaction is stopped by diluting the reaction mixture with water or ice easily, the product can be easily extracted and separated with benzene and each water-miscible solvent.

Benzoxosine derivatives that can be prepared are described in US Pat. No. 4, 054, 583, which are also converted to 6a, lOa-trans-hexahydrodibenzopyranone by reacting such benzoxosocin derivatives with aluminum halides. It is described. It is apparent that the benz oxosine derivatives are also converted to the corresponding 6a, 10a-cis-hexahydro dibenzopyranone by reaction with a catalyst such as stane chloride and such benzoxosine is first formed by the process of the invention. Such intermediates can be separated if desired and later purified for conversion to cis or trans-hexahydrodibenzopyranone, but simply preparing the cis-hexahydrodibenzopyranone of formula (I) according to the present invention It is preferred to convert such cis isomers to the corresponding trans isomers as described in US Pat. No. 4, 054, 582.

The d1-cis-hexahydrodibenzopyranone produced by the present invention is reacted with an aluminum halide such as aluminum bromide or aluminum chloride in dichloromethane in a halogenated hydrocarbon solvent to epimerize the whole, and the corresponding d1-trans-nucleus Hydro-dibenzopyranone is obtained exclusively.

For example d1-cis-1-hydroxy-3- (1, 1-dimethylheptyl) -6, 6-dimethyl-6, 6a, 7, 8, prepared by about 80- about 85% by the process of the present invention. 10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is reacted exclusively with d1-trans- by reacting with about 3-4 molar excess of aluminum chloride in dichloromethane at a temperature of about 25 ° C. 1-hydroxy-3- (1, 1-dimethyl heptyl) -6, 6-dimethyl-6, 6a, 7, 8, 10, l0a-hexahydro-9H-dibenzo [b, d] pyran-9- On, that is, get the butterfly. As mentioned earlier, such trans-hexahydro dibenzopyranones are particularly useful for the treatment of tension and depression.

The following detailed examples further illustrate the method of the present invention.

[Manufacturing Method 1]

4- (1-hydroxy-1-methylheptyl) -3-cyclohexene-l-one 4- (1-hydroxy-1-methylethyl) -1-methoxy-1 in 80 ml of a 2% aqueous acetic acid solution, A solution of 10 g of 4-cyclohexadiene is stirred at 25 ° C. for 2 hours.

The acidic solution is extracted with dichloromethane, organic extracts are collected, washed with water and dried. Under reduced pressure the solvent is removed by evaporation to afford 4- (1-hydroxy-1-methyl-ethyl) -3-cyclohexen-1-one.

NMR (CDCl ₃ ): §5, 8 (t, 1H): §1.9 (s, 1H, OH), §1, 33 (s, 6H): m / e: 154 (M ⁺ ).

Example 1

2,7-dihydroxy-5-isopuropylidene-9- (1, 1-dimethylheptyl) -2, 6-methano-3, 4, 5, 6-detrahydro-2H-1-benz Oxocin

A solution of 2.36 g of 5- (1, 1-dimethylheptyl) resorcinol in 50 ml of dichloromethane containing 1.85 g of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one Stir and cool to -22 ° C in anhydrous ice-methanol bath.

2.5 ml of stan chloride was added dropwise to the cooled stirred solution over 2 minutes. Immediately after the dropping, the reaction mixture is poured into 50 g of ice. The compound is warmed up to room temperature. The organic layer is separated, washed with 50 ml of sodium hydroxide, washed with water and dried. The solvent was evaporated to give a residue, washed with 25 ml of warmed hexane and dried to give 2, 7-dihydroxy-5-isopuropylidene-9- (1, 1-dimethyl heptyl) -2, 6-methano- Obtain 3, 4, 5, 6-tetrahydro-2H-1-benzoxosine. Melting Point 158-159 ℃

Example 2

d1-cis-1-hydroxy-3- (1, 1-dimethyl heptyl) -6, 6-dimethyl-6, 6a, 7, 8, 10, 10a-hexahydro-9H-dibenzo- [b, d Pyran-9-one.

Stir 2.36 g solution of 5- (1, 1-dimethylheptyl) risolcinol in 50 ml of dichloromethane containing 1.85 g of 4- (1-hydroxy-1-methyl heptyl) -3-cyclohexen-1-one And cooled to -22 ° C in an ice-ethanol bath. 2.5 ml of stanchloride was added dropwise to the cold stirring solution over 2 minutes. After the dropwise addition of the stan chloride, the reaction mixture is stirred at 10 ° C. for a time and then the reaction mixture is warmed to room temperature. The organic layer is then separated, washed with 50 ml of 1N sodium hydroxide, washed with water and dried. The solvent was evaporated off under reduced pressure to give d1-cis-1-hydroxy-3- (1, 1-dimethylheptyl) -6, 6-dimethyl-6, 6a, 7, 8, 10, 10a-hexahydro-9H- Obtain 3.18 (83%) of dibenzo [b, d] pyran-9-one. Thin layer chromatography analysis showed that the product contained about 10% of 6a and 10-trans isomers.

Claims (1)

5-substituted resorcinol of the following structural formula (III) was substituted with 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one of the following structural formula (IV) At a temperature in a non-reactive organic solvent in the presence of boron trifluoride or stan chloride for 0.5 to 10 minutes to obtain 3, 4, 5, 6-tetrahydro-2H-1-benzoxosine of the following formula (II) Reaction for 0.5 to 8 hours to prepare 6a, 10a-cis-hexahydro dibenzo [b, d] pyran-9-one of the following formula (I).

Wherein R is alkyl having 5-10 carbons, alkenyl having 5-10 carbons, cycloalkyl having 5-8 carbons. Or a hydrogen atom which is cyclo alkenyl having 5 to 8 carbon atoms and bonded at a position of 6a and 10a is in a cis position with each other.