KR790001321B1 - Process for preparation of dibenzopyrans - Google Patents

Abstract

Title compds. [I; Q = H -c ˜ DR or c=O, R = H or C1-5 alkanoyl, R1 = H, C1-5 alkanoyl or -co-(CH2)p-NR2R3, P = O or 1-4, R2,R3 = H or C1-4 alkyl, R4,R5 = H, meOH, EtOH, Z = (a)C1-9 alkylene, (b)-(alk1)m-x-(alk2)n(alk1),(alk2)=C1-9, m,n = 0 or 1, V = O,S,SO or So2, W= MeOH, Phenyl, P-chlorophenyl, P-fluorophenyl, pyridyl, piperidyl, C3-7 cycloalkyl or mono substituted cycloalkyl were prepd. by reduction of compd [II or comp. [III .

Description

Manufacturing method of dibenzo pyranes

The present invention relates to novel dibenzo pyranes, in particular in the 3 position (1) having an alkyl group (W) in which said position is aryl or cyclolinked by alkylene; (2) the positions are connected by (a) 0, S, S0 or SO ₂ ; Or (b) linked by an alkylene group interrupted by 0, S, S0 or S0 ₂ ; (c) linked by an alkylene group attached to the alkyl group by a cycle interrupted by said 3-position or the following methyl, aryl or O, S, S0 or S0 ₂ ; 1,9-dihydroxy-hexahydrodibenzopyran having a methyl, aryl, cycloalkyl group; And intermediates and derivatives thereof in the preparation thereof; And benzopyranes and their derivatives in analgesic, blood pressure, hypotensive, secretory and anti-anxiety and immunosuppressive and antistatic agents.

Although many analgesics have conventionally been available, the exploration of new and improved formulations has continued to focus on the suppression of pain to broad levels and the absence of useful formulations with minimal side effects. It is well known that aspirin, the most widely used agent, has no real value in suppressing severe pain and has many side effects. Also, more potent analgesics, such as d-propoxyphene, codeine and morphine, have an addiction tendency. Thus, the need for improved and high titer analgesics became evident.

Other cannabinoids, such as 9-nor-9β-hydroxyhexahydrocanna scales and Δ ⁸ -tetrahydrocanna scales (Δ ⁸ -THC) and their primary metabolites, 11-hydroxy-Δ ⁸ -THC The analgesic action of the structure is known.

A variety of 1-hydroxy-3-alkyl-6H-dibenzo [b, d] pyranes with substitutions such as oxo, hydrocarbyl and hydroxy or chloro, hydrocarbylidene at position 9 Products are known.

It is known that tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives having ω-dialkylaminoalkoxy groups in the 1-position are active as psychotherapeutic agents.

1,9-dihydroxy-hexahydrodibenzo [b, d] pyranes and their 1-acyl derivatives having alkyl or alkenyl groups at the 3-position have been known as blood pressure lowering, psychotropic, calming and analgesics .

In their preparation, hexahydro-9H-dibenzo [b, d] pyran-9-one was used as a precursor and it was reported to have similar utility as the corresponding 9-hydroxy compound.

It is known that 1-hydroxy-6,6,9-trimethyl-hexahydrodibenzo [b, d] pyran derivatives and their intermediates have aralkyl, (substituted aralkyl) or pyridyl alkyl groups in the 3-position. Is true. They are useful as analgesics and antidepressants.

(-) Trans-6a, 7, 8, 10a-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, better known as (-)-Δ ¹ -tetrahydro cannabinol d] Stereoselective synthesis of pyran-1-ol, reported by Razdan et al. (J. Am. Chem. Soc., 96, 5860-5, 1974).

This process is a one-step process in which cis / trans-(+)-P-menta-2,8-dien-1-ol is dissolved in 0 ° C. methylene chloride in the presence of 1% borontrifluoride etherate and manganese sulfate. Reaction with olilol. The resulting tetrahydro compound is converted to the corresponding 9-ketohexahydro compound using the method of Wildes et al. This process involves methylating the 1-hydroxy-tetrahydro compound with its methyl ether, followed by reacting zinc chloride and hydrochloric acid with chloroform at 0 ° C. to form a hydrogen chloride addition compound.

The additional compound is reacted with potassium tricyclopentylcarbinorate to dehydrogenize to yield the corresponding 6a, 7,8,9,10,10a-hexahydro-3-pentyl-6,6-dimethyl-9-methylene-6H- Dibenzo [b, d] pyran-1- is obtained as methyl ether.

The 9-methylene group is oxidized with potassium permanganate-potassium peroxoate to obtain 9-ketone. Methyl ether is demethylated with pyridinium chloride or other acid reagent to obtain an alcohol.

3-position pentyl group of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol is alkoxy (butoxy, pentoxy , Hexoxy and octoxy) have been found to deactivate this compound biochemically.

It has been reported that this hexoxy derivative exhibits slightly Indian cannabis activity at 10-20 mg / kg. The remaining ethers do not show activity at doses up to 20 mg / kg.

Recently, 3-substituted fractions of 7,8,9,10-tetrahydro-3-substituted 6,6,9-triethyl-6H-dibenzo [b, d] pyran-1-ol are each -OCH (CH ₃ ) ₃ C ₅ H ₁₁ ; A comparison with -CH ₂ CH (CH ₃ ) C ₅ H ₁₁ or CH (CH ₃ ) C ₅ H ₁₁ has been reported. Compounds containing ether side chains have a central nervous system activity of 50% lower than compounds attached directly to aromatic rings without intervening alkyl side chains with oxygen; It is five times more active than a compound substituted with methylene for oxygen.

Now compounds have been found that are effective as analgesics, lowering blood pressure, suppressing secretion and anti-anxiety and immunosuppressants and tablets; Namely, 1,9-dihydroxydibenzo [b, d] pyran (formula 1), a non-narcotic, non-addictive agent.

Also found are derivatives of these compounds that can be used as intermediates (formulas II and III) and formulations (formula I, R ≠ hydrogen) useful in preparing the compounds. The structural formula of the compounds is as follows.

Wherein R is selected from the group consisting of hydrogen and the group consisting of alkanoyls having C ₁ -C ₅ ;

R ₁ is selected from the group consisting of hydrogen, an alkanoyl group having C ₁ -C ₅ , and —CO— (CH ₂ ) p-NR ₂ R ₃ , where p is 0 or 1-4 integer; When R ₂ and R ₃ are each it is selected from the group having an alkyl group which is hydrogen or C ₁ -C ₄ . ; When R ₂ and R ₃ are bonded to nitrogen to form a 5- or 6-membered heterocyclic compound, N-alkylpyri, wherein piperidino, pyrrolo, pyrrolidino, morpholino and alkyl groups are C ₁ -C ₄ Is selected from the group consisting of ferrazino;

R ₄ and R ₅ are each selected from the group consisting of hydrogen, methyl and ethyl;

R ₀ is selected from the group consisting of oxo and alkylenedioxy that is C ₂ -C ₄ ;

Z is (a) alkylene which is C ₁ -C ₉ ;

(b)-(alk ₁ ) _m -X- (alk ₂ ) _n ; Wherein (alk ₁ ) and (alk ₂ ) are each C ₁ -C ₉ , provided that the sum of (alk ₁ ) and (alk ₂ ) does not exceed 9 and m and n are each 0 or 1; X is selected from the group consisting of 0, S, S0 and S0 ₂ .

(여기서 W은 수소, 불소, 염소로 구성된 군으로부터 선택된다), 및

(W₂는 수소 및

으로 구성된 군으로부터 선택되며 a는 1-5이고, b는 0 또는 1-5이며, a와 b의 합이 5를 넘지 않아야 한다)로 구성된 군으로부터 선택된다(a와 b는 정수).W is methyl, pyridyl, piperidyl,

Wherein W is selected from the group consisting of hydrogen, fluorine, chlorine, and

(W ₂ is hydrogen and

And a is 1-5, b is 0 or 1-5, and the sum of a and b must not exceed 5) (a and b are integers).

Provided that when W is methyl, Z is-(alk ₁ ) _m -X- (alk ₂ ) _n- .

Compounds having this structure have asymmetric centers at the 6a- and / or 10a-positions. There may also be asymmetric centers at the 3 or 6- and 9-positions with substitutions (-Z-W).

Diastereomers with 9β-coordination are generally advantageous because they have greater biological activity (quantitative) than 9α-isomers and trans (6a, 10a) diastereomers are more advantageous than cis (6a, 10a) diastereomers.

는 9- 및 6a,10a-위치에 부분적 입체 이성체를 나타냄을 뜻한다.In the above structural formula

Denotes partial stereoisomers at the 9- and 6a, 10a-positions.

In general, like natural cannabinol, enantiomers having optical activity containing absolute coordination at the 6a and 10-a positions are advantageous because of their high biological activity.

Racemic forms of these compounds can be used because they contain at least 50% of the active enantiomers. The usefulness of the racemic and diastereomeric mixtures as well as the pure enantiomers and diastereoisomers was determined by the biological method described below.

Although compounds of formula II have been described herein as intermediates of compounds of formula I, many of these, especially those with C-9 substitutions of oxo (= 0), also exhibit analgesic and affective action.

It is preferred that the OR group at the C-9 position in the compound of formula I has a β-configuration.

Such compounds have greater titers and effects than the corresponding α-compounds.

Some of the variables of significant significance among the compounds of formula I are shown in Table A below.

TABLE A

Particularly advantageous are the Z-W, ie, C-3, substitutions in Table A in the compounds of formula I, as indicated in Table B below because of their titers.

TABLE B

9 and t in the table are 1-4 and m and n are 0-1, respectively; Provided that either m or n is 0 (where t, m and n are integers).

In addition intermediates of the compounds (Tables A and B), in particular 6a-7-dihydro-6H-dibenzo [b, d] pyran-9 (8H) -oz and 6a, 7,10,10a, of formulas II and III Tetrahydro-6H-dibenzo [b, d] pyran-9 (8H) -one is a preferred intermediate because it is related to the precursors of the compounds of Tables A and B above.

The compounds of the invention of formula Ⅲ is suitable 5-OR ₁ -3- hydroxy-methylene _{-2-R 4 R 5 -7- (} ZW) -4- chromanone, for example an alkali metal hydroxide or alkoxide or an ethylene amine, such as tree 4 Ring annelation with methylvinylketone in the presence of a class organic base gives Michaeladdition, followed by treatment with bases such as alkali metal hydroxides or alkoxides (sodium hydroxide or potassium hydroxide, ethoxide or methoxide) Complete aldol cylization.

The resulting 6a, 7-dihydro-1-OR ₁ -6,6-R ₄ , R ₅ -3- (ZW) -6H-dibenzo [b, d] pyran-9 (8H) -one Birch reduction converts to the corresponding 6aβ, 7,10,10aα-tetrahydro compound (formula II, R ₀ = oxo). It is convenient to use lithium as metal during reduction. Sodium or potassium can also be used. The reaction is carried out at about -35 ° C to -80 ° C. Depletion reduction is advantageous as it provides stereoselectivity to produce the preferred trans-ketone of formula II.

Compounds of formula II wherein R ₀ is oxo are suitable alkylene glycols which are C ₂ -C ₄ in the presence of dehydrating agents such as P-toluenesulfonic acid or acids used in ketalization (oxalic, adipic) Treatment with, eliminates the corresponding corruption.

Reduction of the 9-oxo group of the compounds of formulas II and III (R ₀ = oxo) with metal hydrides yields the compounds of formula I (R = H). Representative metal hydrides useful for such conversion include lithium aluminum hydride, lithium borohydride and sodium borohydride.

Sodium borohydride is preferred as a reducing agent in this step because it not only provides a satisfactory yield of the desired product, but also reacts slowly with hydroxylated solvents (methanol, ethanol, water) to make them available as solvents. The temperature is generally used at about O-30 ° C. Lower temperatures, even below about 70 ° C., may be used to increase the selectivity of the reduction.

High temperatures cause the reaction of sodium borohydride with the hydroxyl solvent. If high temperatures are desired for reduction, dimethyl ether of isopropyl alcohol or diethylene glycol is used as the solvent.

Reagents such as lithium borohydride or lithium aluminum hydride must be anhydrous and non-hydroxy solvents (1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of diethylene glycol) should be used.

Isomers 9α- and 9β-hydroxy compounds are produced in this process. The reaction is summarized below.

The required 5-OR ₁ -3- hydroxy-methylene _{-2-R 4 R 5 -7- (} ZW) - claw Manon (Ⅳ) is prepared through the following summary of the process from the 3,5-dihydroxy benzoic acid.

The starting material 3,5-dihydroxybenzoic acid (V) is converted to the compound of formula (VI) by the method described in the literature. Wherein Y ₂ represents an alkoxy group, for ease of manufacture, methoxy or ethoxy is preferred, and Y ₁ is a hydroxyl protecting group.

When Z is alkylene, Y ₁ is preferably C ₁ -C ₄ alkyl or benzyl. Y ₁ function is to protect hydroxyl groups during the next reaction. It is its ability to perform special functions, that is, its function is to protect the hydroxyl groups rather than its structure.

The selection and differentiation of suitable protection groups is readily performed by those skilled in the art. The suitability and effectiveness of this group as a hydroxyl protecting group is determined by using such a group in the reactions described above. Therefore, this group should be easily removed to recover the hydroxyl.

Methyl is preferred as a protective alkyl group because it is easily removed by treating it with pyridine hydrochloride. If a benzyl group is used as a protective group, it is removed by catalytic or acid hydrolysis.

When Z is-(alk ₁ ) _m -X- (alk ₂ ) _n- , Y ₁ is preferably benzyl or substituted benzyl which can be removed without damaging the subgroup.

The double protected benzoic acid derivative (VI) is then converted to the compound of formula VII by known methods.

In one process VI is hydrolyzed with the corresponding acid (Y ₂ = OH) or lithium salt and reacted with the appropriate alkyllithium to produce an alkyl double substituted phenylketone (Y ₂ = alkyl).

The acetophenone derivatives produced when methyllithium was used are treated with Grignard Reagent (W-Z'-MgBr). The intermediate addition hydrolyzes the compound with the corresponding alcohol and hydrolyzes the alcohol to replace the hydroxyl group with hydrogen. This method is particularly useful in compounds where Z is alkylene.

Ether groups can be reacted with pyridine hydrochloride (Y ₁ = methyl), catalytic hydrogenolysis (Y ₁ = benzyl) or with acids such as trifluoroacetic acid, hydrochloric acid, hydroboric acid, sulfuric acid or pyridine hydrochloride, etc. Deblock using an appropriate method. Of course debenzylated acids are used when the -ZW group contains sulfur.

The process for converting a compound of formula VI to a compound of formula VII involves a suitable triphenyl phosphonium bromide derivative [(C ₆ H ₅ ) _{3 in the} presence of a base (eg sodium hydride) in the ketone of formula VI (Y ₂ = alkyl). It is made to react with P ⁺ -ZW] Br. This reaction is then proceeded by alkenes which are catalytically reduced to the corresponding alkanes (ZW) which are deblocked to yield the dihydroxy compounds.

Of course, benzyl ether is cleaved by catalytic reduction when -Z- is (alk ₁ ) _m -X- (alk ₂ ) _n and Y is benzyl.

In addition, the conversion of the compound of formula VI to the formula VII takes place in a chain from VI → Ⅶ → Ⅷ.

Here, the double protected benzamide (VI, Y ₂ = NH ₂ ) is reacted with a suitable Grignard reagent (BrMg-Z'-W) to convert to a ketone followed by reaction with methyl or ethyl-magnesium halide. To yield the corresponding carbinol. Carbinol is dehydrogenated with, for example, P-toluene sulfonic acid to give the corresponding alkenes which are subject to catalytic reduction (pd / c) to give alkanes. The ether group is deblocked (converted to hydroxyl) as described above.

Chlorone was reacted with crotonic acid or an acid of the formula R ₄ R ₅ -C = CH-COOH at about 20 ° -125 ° C. in the presence of boron trifluoride etherate. Switch to) (Ⅸ). In addition to the structural VII product, a tertiary product is also produced which is an isomer of VII (7-hydroxy-2,2-R ₄ R ₅ -5-ZW-4-chromanone). At this time, 4-chromanone of formula (VIII) is reacted with ethyl homomate and sodium hydride to convert to hydroxy methylene derivative of formula (IV).

The compound of formula V is obtained by: Wherein -ZW is -alkylene-W or-(alk ₁ ) -X '-(alk ₂ ) _n -W (alk ₁ ), (alk ₂ ); W and n are as described above and X 'is O or S.

The selection of the appropriate reactants in the first step of the process (Witich, wittig reaction) offers the opportunity to generate compounds with straight or branched alkylene groups.

In the above description, when the R 'value is methyl or ethyl, a compound having an alkyl substitution on the carbon atom (α) adjacent to the phenyl group can be produced.

For example, when substituting a methyl or ethyl group to another part, such as β-carbon atom of an alkylene group, suitable carboalkoxy alkylidene triphenyl such as (C ₆ H ₅ ) ₃ P = C (R ')-COOC ₂ H ₅ This can be done by selecting a phosphoran.

The resulting unsaturated ester is reacted with lithium aluminum hydride in the presence of a small amount of aluminum chloride to reduce it to the corresponding saturated alcohol. In addition, when Y ₁ is other than benzyl (such as methyl), palladium-carbon is used to catalyze the unsaturated ester and then the resulting saturated ester is treated with aluminum hydride lithium to produce an alcohol. The alcohol is converted to the corresponding tosylate or mesylate, followed by alkylation of the tosylate or mesylate with the alkali metal salt of the appropriate HX '-(alk ₂ ) -W reactant, and finally removal of the protecting group (Y ₁ ) Shinol is obtained. When X 'is sulfur, the protecting group is methyl.

Variations of the process include bromination rather than converting alcohol to tosylate or mesylate. The bromine derivative is reacted with the appropriate HX '-(alk ₂ ) -W in the presence of a suitable base (Williamson reaction).

Bromine compounds also act as important intermediates in the process to increase the chain length of the alkylene moiety to form compounds in which Z is -alkylene-W.

This method consists in treating the bromine derivative with triphenylphosphine to produce the corresponding triphenylphosphonium bromide. Triphenylphosphonium bromide is reacted with a suitable aldehyde or ketone in the presence of a base such as sodium hydroxide or R-butyllithium to obtain an unsaturated derivative which is catalytically oxidized to obtain the corresponding foam compound.

In the present invention, the value of the selected protecting group Y ₁ depends in particular on the following procedure. When the vertical binding sequence on the right side is used, it is preferable to use benzyl group as the protecting group because of the contact reduction step. As the left vertical binding sequence, the protecting group is preferably ethyl because it is convenient to remove by treatment with acid as described above.

The compound of formula II wherein -ZW is-(alk ₁ ) _m -X- (alk ₂ ) _n -W and X is -S0- or -SO ₂ -is obtained by oxidizing the corresponding compound where X is -SS. Hydrogen peroxide is a convenient reagent for oxidizing thioether to sulfoxide. Oxidation of the thioether to the corresponding sulfone can be conveniently carried out by peracids such as perbenzoic acid, perphthalic acid or m-chlorobenzoic acid. m-chlorobenzoic acid is particularly useful because the by-product m-chlorobenzoic acid is easily removed.

The compounds of the present invention may also be prepared according to the method described by Fahrenholtz et al.

The method consists of condensing a suitable Z-W substituted 3,5-di hydroxy benzene with diethyl-α-acetogjutarate in the presence of Von Pechmann in the presence of oxychloride phosphate.

The resulting ethyl-5-hydroxy-7- (ZW) -coumarin-3-propionic acid was reacted with sodium hydride in dimethyl sulfoxide to give 7,10-dihydro-1-hydroxy-3- (ZW) -6H-dibenzo [b, d] pyran-6,9 (8H) -dione is cyclic. The resulting dibenzo [b, d] pyrans are then reacted with ethylene glycol and P-toluene sulfonic acid to convert to the corresponding 9-ketal derivatives.

Treat the ketal with a suitable alkylmagnesium iodine and hydrolyze with acid to dl-6α, 7-dihydro-1-hydroxy-6,6-dialkyl-3- (ZW) -6H-dibenzo [b, d] Obtain pyran-9 (8H) -one. The resulting dihydro compound is subjected to Birch reduction to yield the corresponding tetrahydro compound which is converted to the 1,9-dihydroxy compound of formula I by reaction with sodium borohydride as described above.

Another method of making a compound of formula III wherein ZW is (alk ₁ ) -X- (alk ₂ ) -W is a suitable 3,5- (double-protected hydroxyl) styrene oxide with an alcohol or its alkali metal (sodium or Potassium is preferred) and react with thioalcohol HX- (alk ₂ -W) such as salt.

Methyl is preferred as a protecting group for 3,5-dihydroxy styrene oxide because it is easy to remove. The resulting 3,5- (di-protected hydroxyl) phenyl hydroxyalkyl ether compound (formula VII-A) was treated with oxyphosphate phosphate and the resulting chloro derivatives were dehalogenated with hydrogen on the palladium. To the corresponding alkyl ether (formula VIII-B). As described above, the protecting group is removed to obtain the desired compound. The chain reaction is shown below (alkyl with Y ₁ = benzyl, C ₁ -C ₄ ; X ′ is 0, S; R ′ = hydrogen, methyl, ethyl and may be the same or different).

Esters of compounds of formulas II and III wherein R ¹ is alkanoyl or —CO— (CH ₂ ) _p —NR ₂ NR ₃ are suitable for the use of alkanoic acid in the presence of a condensation reagent such as dicyclohexylcarbodiimide. Or by reacting with the structural formula HOOC- (CH ₂ ) _p -NR ₂ NR ₃ . It is also prepared by reacting a compound of formula II or III with a suitable alkanoic acid chloride or anhydrides such as acetyl chloride and acetic anhydride in the presence of a base such as pyridine.

Esters of the compound of formula I, wherein the R and R ₂ groups are each esterified, are prepared by acylating according to the method described above. Compounds in which only 9-hydroxyl groups are acylated are obtained by weakly hydrolyzing the corresponding 1,9-diacyl derivatives and have the advantage that hydrolysis of phenolic acyl groups is made very easy. Formula I compounds in which only 1-hydroxyl group is esterified are obtained by reducing the corresponding structural II ketones in which the 1-position is esterified with boron hydride.

De-esterification of Structural Formula I with 1- and 9-positioned ester groups by acylating the resulting compound of Structural Formula I with 1-acyl-9-hydroxyl substitution or 1-hydroxyl-9-acyl substituent with another acylating agent To produce a compound.

The analgesic effect of the present invention is examined using a nociceptive stimulant.

Testing with Thermal Nociceptive Stimuli

(a) Mouse hot plate analgesia test

The method used is an improvement of the law of Wolfe and MacDonald. Place the mouse on an l / 8 "thick aluminum plate and apply a controlled hot stimulant to the foot of the mouse. Place a 250-watt refractive medium infrared heating lamp on the bottom of the aluminum plate. Connect the heat regulator to the electrothermal regulator on the plate surface and heat The lamp is kept at a constant temperature of 57 ° C. Each mouse is placed in a glass cylinder (6 1/2 ”radius) placed on a hot plate and starts to time when the animal's foot touches the plate. After treatment with the test compound, the first one or both legs bounce or observe at 0.5 and 2 hours until no such movement for 10 seconds. MPE ₅₀ of morphine is 4-5.6 mg / kg (SC).

(b) Mouse Tailing Pain Relief Test

The tailing test in mice is an improvement on the D'Amour and Smith method.

Controlled high intensity heat is applied to the tail. Place each mouse in a comfortable metal cylinder and extend its tail through one end. Align this cylinder and lay its tail flat on the hidden heating lamp. At the start of the test, the aluminum groups are removed from the lamp and the photoelectrics pass through the slits to focus on the tail tip. At the same time, start the timer. Potential sudden tailings are identified. Untreated mice generally act within 3-4 seconds after exposure to light. The end point of protection is examined every 0.5 seconds at 0.5 and 2 hours after treatment with morphine and test compound, respectively. MPE ₅₀ of morphine is 3.2-5.6 mg / kg (SC).

(c) tail immersion

This method is an improvement on the socket method developed by Benbasset. Weigh and distinguish male males (19-21 g) of the Charles-River CD-1 strain.

Five dogs are used as drug treatment groups and their controls. In general, for screening, the new compound is first applied intraperitoneally or subcutaneously at a dose of 56 mg / kg (10 ml / kg).

Animals are placed in cylinders prior to drug treatment and 0.5 and 2 hours after drug treatment, respectively. Each cylinder has a hole for proper ventilation and is closed with a round nylon stopper to allow the animal's tail to emerge.

Place the cylinder upright and immerse the tail completely in a constant temperature water bath (56 ° C). The end point is when a strong gap or convulsion of the tail is connected to the reaction motor. In some cases the endpoint is less active after drug treatment.

To prevent unreasonable tissue damage, the tail is removed from the bath in 10 seconds to complete the reaction. The latent response is recorded up to 0.5 seconds. Intermediate controls and standards of known titer should be tested simultaneously with the sample. If the activity of the test compound does not return to baseline in the 2 hour test, the latent response is measured at 4 and 6 hours. Final measurements are made at 24 hours if activity is also observed on the last day of the test.

Testing with Chemical Receptor Stimulants

Inhibition of spasms induced by phenyl benzoquinone stimulants

Groups of 5-Carworth Farmhouse-CF-1 mice are pretreated subcutaneously or orally using salt, morphine, codeine or test compounds. After 20 minutes (subcutaneously) or 50 minutes (orally), intraperitoneal injection of phenyl benzoquinone, known to cause abdominal contractions in each group, is administered.

After injecting a stimulant into the mouse, observe for five minutes whether the convulsions appear or not.

In elimination of convulsions, MPE ₅₀ 's of pretreatment drugs are identified.

Inspection with pressure receptor stimulant

Effect by Haffner tail pinch method

An improvement of the Haffner method is used to confirm the effect of test compounds on seizure reactions caused by stimulants causing tail pain. Rat males (50-6Ob) of Spraque-Dawley CD strains are used. At 0.5, 1, 2 and 3 hours after treatment, Johns Hopkins 2.5 inch "bulldog" forceps are placed near the tail of the rat. The end point is identified as a clear seizure or biting act on the stimulant and the potential time of the seizure is recorded in seconds. The forceps are removed within 30 seconds if the seizure has not yet occurred and the potential response is recorded as 30 seconds. Morphine is effective at 17.8 mg / kg (i.p.).

Examination Using Electroreceptor Stimulants

"Flinch-Jump" Test

It is an improvement of Tenen's Furinch-Jump method as a measure of the pain threshold.

Rat males of the Charles River (Spraque Dawley) CD strain were used.

Before dosing the drug, each rat's foot is soaked in 20% glycerol / saline. Animals are placed in the pancreas (chamber) and given 1 sec-shank with increasing intensity every 30 seconds.

These intensities are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal's behavior is judged by (a) fliching (b) squeaking and (c) running or moving quickly when the shank is applied. The strength of the shank is marked at 0.5, 2.4 and 24 hours after drug administration immediately prior to each rat.

The results of the test are reported as% highest possible effect (% MPE). The% MPE of each group is statistically compared with the standard% MPE and pre-drug control.

% MPE is calculated as follows.

The compound of the present invention exhibits active analgesic action by oral and parenteral administration, and can be conveniently administered in combination. Such combinations contain a carrier of the drug selected based on the route of administration and standard drug experiments. For example, they may be administered in the form of tablets, pills, powders, granules containing excipients such as starch, lactose, certain clay forms and the like. They may also be administered as oral suspensions, solutions, emulsions, syrups and elixirs and may contain flavoring and coloring agents.

For oral administration of the therapeutic agents of the invention, tablets or capsules containing about 0.01-100 mg are most suitable for application.

Doctors can determine the dosage that is most appropriate for an individual patient, depending on age, weight, the specific patient's response and route of administration. In general, however, an adult's initial analgesic dose may be used once or in a single dose of 0.01-500 mg per day. In many instances it is not necessary to exceed 100 mg per day. Preferred doses are about 0.01-300 mg / day and more preferably about 0.10-50 mg / day. Preferred parenteral dosages are about 0.01-100 mg / day and more preferably about 0.01-20 mg / day.

The analgesic activity of several compounds of the present invention and known compounds was measured by this method. The data reported the highest possible effect.

This is summarized in the table below.

PBQ = phenyl benzoquinone-induced cramps;

TF = flick;

HP = hotplate;

RTC = rat tail tongs;

FJ = flinch jump;

And Tl = tail immersion test

TABLE 1

Vibration Effect (ED ₅₀ -mg / kg)

(a) Component A of Example 5, fifth compound.

(b) Component B of Example 5, and the fifth compound.

TABLE 2

(b) a mixture of two diastereomers

Their usefulness is determined by the statistically significant ability to lower blood pressure when orally administered the above doses to rats or dogs that have purposely raised blood pressure.

Their euphoria is expressed by unconsciously reduced motor capacity when orally administered to rats at a dose of about 0.01-50 mg / kg.

In addition to analgesic, hypotension, and euphoric activity, the compounds of formula I are also useful as immunosuppressants and secretory inhibitors.

Even in pouch dogs (Heidenhain) their gastric secretion inhibitory effect is measured by the following method.

The secretion of gastric juice secretion is examined using Hetanhain pouch dogs fasted from day to night using pentagastrin, histamine or foods that produce acid. Pentagastrin or histamine is administered by continuous infusion into the surface leg vein at a dose (already measured) that stimulates the highest acid yield from the gastric capsule.

For irritating foods, use Ken-L-Ration half cans (approx. 220 g) per 1 dog weighing 9-12.5 kg. Collect at intervals.

A total of 10 gastric juices are collected for each dog during the experiment. When the third gastric fluid is collected, the drug is orally administered at 0.01-50 mg / kg. The amount of all samples was recorded and the acid concentration was determined by titrating the sample aliquots (1.0 ml) to 0.1 N-NaOH to pH 7.4 using a pH meter or autoburette. The medicine is orally administered in gelatin capsules.

Immunosuppressive action is measured by a mixed lymphocyte culture effect assay. This effect assay is determined by the effect of the test compound on antigen-stimulated lymphocyte proliferation. Spleen lymphocytes from BALB / C and C57BL / 6 mice, 8 × 10 ⁶ cells from each strain, are suspended in 2.Oml of desorption medium containing the test compound and incubated at 37 ° C. in 10% CO ₂ atmosphere. Culture conditions and techniques are known.

Injection of H ³ -TdR into desoxyribonurea acid (24 hour pulse) is determined by assessment of radioactivity in trichloroacetic acid precipitation and dextrination counter of desoxribonucleic acid. . Inhibition rate is determined by comparing each test compound-treated mixed culture with the control mixed culture.

Example 1

dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chroma

A mixture of 2- (3,5-dihydroxyphenyl) -5-phenylpentane (9.6 g) and 3-methylchromonic acid (4.5 g) was heated to 125 ° C. in the presence of nitrogen and boron trifluoride etherate (8.7 ml). )

After refluxing for 1 hour, the reaction solution was cooled, water (10 ml) was added, and 6N-sodium hydroxide (40 ml) was added thereto. The reaction mixture is heated for 5 minutes in a steam bath, cooled and acidified with 6N hydrochloric acid. The aqueous layer is extracted with ether (3 × 100 ml) and the combined ether extracts are washed with 10% sodium bicarbonate (1 × 25 ml) and water (1 × 25 ml). The organic layer was dried over sodium sulfate, concentrated in vacuo to give 1.27 g of impure oil, and purified by silica gel chromatography to give a colorless oil, dl-5-hydroxy-2,2-dimethyl-7- (1-meth). Tyl-4-phenylbutyl) -4-chromanon is obtained in a yield of 5.0 g.

IR: (CHCl ₃ ) C = 0 1635 cm ^-1

1-1.7(M,7,α-메틸, 에틸렌), 1.5(S,6, 젬(gem) 디메틸), 2.3-2.9(M,3, 젠질성-메틸렌) 메티닐), 2.65(S,2,α-메틸렌), 6.1-6.35(M,2, 방향족), 6.9-7.4(M,5, 방향족), 11.53, 11.63(d,1, 하이드록실).NMR:

1-1.7 (M, 7, α-methyl, ethylene), 1.5 (S, 6, gem dimethyl), 2.3-2.9 (M, 3, zenith-methylene) methynyl), 2.65 (S, 2 , α-methylene), 6.1-6.35 (M, 2, aromatic), 6.9-7.4 (M, 5, aromatic), 11.53, 11.63 (d, 1, hydroxyl).

In a similar manner, 2- (3,5-dihydroxyphenyl) -6-phenylhexane was converted into dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-5-phenylpental) -4-chroma. Switch to paddy (oil);

1.2(d,3,α-메틸, J =7cps), 1.4(S,6, 젬 디메틸), 1.0-1.9[M,6,

-CH₂-(CH₃)-C(CH₃)-Ar], 2.3-2.8(M,3, 벤질성-메틸렌, 메티닐), 2.7(S,2,α-메틸렌), 6.2-6.4(M,2, 방향족), 7.1-7.3(M,5, 방향족), 11.6(S,1, 하이드록실);NMR:

1.2 (d, 3, α-methyl, J = 7cps), 1.4 (S, 6, gem dimethyl), 1.0-1.9 [M, 6,

-CH _2- (CH ₃ ) -C (CH ₃ ) -Ar], 2.3-2.8 (M, 3, benzyl-methylene, methynyl), 2.7 (S, 2, α-methylene), 6.2-6.4 ( M, 2, aromatic), 7.1-7.3 (M, 5, aromatic), 11.6 (S, 1, hydroxyl);

1- (3,5-dihydroxyphenyl) -2-phenylethanol 5-hydroxy-2,2-dimethyl-7- (2-phenylethyl) -4-chromenone (oil);

IR: (CHCl ₃ ) C = 0,645 cm ^-1

1.45(S,6, 젬 디메틸), 2.65(S,2,α-메틸렌), 2.85(S,4, 에틸렌), 6.25, 6.3(2d,2, 방향족), 7.2(S,5, 방향족), 11.6(S,1, 하이드록시-D₂O 오버레이(overlay)).NMR:

1.45 (S, 6, gem dimethyl), 2.65 (S, 2, α-methylene), 2.85 (S, 4, ethylene), 6.25, 6.3 (2d, 2, aromatic), 7.2 (S, 5, aromatic), 11.6 (S, 1, hydroxy-D ₂ O overlay).

MS: (molecule, ion) 296

2- (3,5-dihydroxy phenyl) -4-phenylbutane to dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-3-phenylpropyl) -4-chromenone (oil ).

1.3(d,3, 메틸), 1.45(S,6, 젬 디메틸), 1.55-2.1(M,2, 메틸렌), 2.25-2.75(M,3, 벤질성-메틸렌, 메티닐), 6.15(d,2, 방향족), 7.1(S,5, 방향족), 11.6(S,1, 하이드록실-D₂O 오버레이).NMR:

1.3 (d, 3, methyl), 1.45 (S, 6, gem dimethyl), 1.55-2.1 (M, 2, methylene), 2.25-2.75 (M, 3, benzyl-methylene, methynyl), 6.15 (d , 2, aromatic), 7.1 (S, 5, aromatic), 11.6 (S, 1, hydroxyl-D ₂ O overlay).

MS: (molecule, ion) 324

2- (3,5-dihydroxy phenyl) -5-phenylpentane (5.27 g) was mixed with crotonic acid (freshly distilled 2.08 g) and boron trifluoride ether (4.81 ml) instead of 3-methylcrotonic acid. Reaction to convert dl-5-hydroxy-2-methyl-7- (1-methyl-4-phenylbutyl) -4-chromenone;

1.1(D,3,α-메틸, J=7Hz), 1.4(D,3,2-메틸, J=7Hz), 1.3-1.8(M,4-에틸렌), 2.2-2.9(M,5,α-메틸렌, 벤질성-메틸, 메티닐), 4.5(M,1, 메티닐 에테르), 6.1, 6.2(2D,2, 방향족, J =1Hz), 6.9-7.4(M,5, 방향족), 11.7(S,1, 렌놀성 OH).NMR:

1.1 (D, 3, α-methyl, J = 7 Hz), 1.4 (D, 3,2-methyl, J = 7 Hz), 1.3-1.8 (M, 4-ethylene), 2.2-2.9 (M, 5, α Methylene, benzyl-methyl, methynyl), 4.5 (M, 1, methynyl ether), 6.1, 6.2 (2D, 2, aromatic, J = 1 Hz), 6.9-7.4 (M, 5, aromatic), 11.7 (S, 1, lennolic OH).

4- (3,5-Dihydroxyphenyl) -1-phenoxypentane to light yellow oil dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenoxybutyl)- Conversion to 4-chromonone;

MS: (molecule. Ion) 354

Rf = 0.61 (silica gel, 18-benzene; 1-ethyl acetate)

Analyzes: Theoretic of C ₂₂ H ₂₆ 0 ₄ : C, 74.55; H, 7.39% found. C, 74.56. H, 7.36%

4- (3,5-Dihydroxyphenyl) -1- (4-pyridyl) pentane is oiled in dl-5-hydroxy-2,2-dimethyl-7- [1-methyl-4- (4 -Pyridyl) butyl] -4-chromenone.

Rf = 0.39 (silica gel, 1-benzene: 1-ethyl acetate)

1-1.90(M,13-H, 메틸렌, 1.20에서 메틸 더블렛트, J =7Hz, 및 젬 디메틸 싱글렛트); 2.43-2.86(M, 5-H, 메틸렌, 메티닐, 함유 싱글렛트(2C-3H'S at 2.71); 6.26(b,d,S,1-H,1방향족); 6.33(b,d,S,1-H, 방향족); 7.00-7.20(b,d,S,2-H, 피리딘 방향족); 7.25(b,d,S,1-H, 하이드록시), 8.41-8.61(b,d,S,2-H, 피리딘 방향족).NMR:

1-1.90 (M, 13-H, methylene, methyl doublet at 1.20, J = 7 Hz, and gem dimethyl singlet); 2.43-2.86 (M, 5-H, methylene, methynyl, containing singlet (2C-3H'S at 2.71); 6.26 (b, d, S, 1-H, monoaromatic); 6.33 (b, d, S, 1-H, aromatic); 7.00-7.20 (b, d, S, 2-H, pyridine aromatic); 7.25 (b, d, S, 1-H, hydroxy), 8.41-8.61 (b, d, S , 2-H, pyridine aromatic).

dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-3-phenoxypropyl) -4-chromanone is 3- (3,5-dihydroxyphenyl) -1-phen as an oil It is prepared from oxybutane.

Rf = 0.7 (silica gel, 18-benzene; 1-ethyl acetate)

MS: (molecule, ion) 340

Analyzes: Theoretical value of C ₂₁ H ₂₄ O ₄ : C, 74.09; H, 7.11%, found: C, 74.04, H, 7.19%

dl-2- (3,5-dihydroxyphenyl) -1- (2-phenylethoxy) propane was added as dl-2,2-dimethyl-5-hydroxy-7- [1-methyl-2- (2 -Phenyl ethoxy) ethyl] -4-chromenone (oil).

1.21(d,J=7Hz, 메틸), 1.48(S, 젬 디메틸), 2.73(S,C-3 메틸렌), 2.86(+, J=7Hz, CH₂Ph), 2.9(m, 메틴), 3.50(d, J=7Hz, -CH₂O-), 3.65(t, J=7Hz, -OCH₂-), 6.31(d,J=1Hz, ArH), 6.38(d, J=1Hz, ArH), 7.26(S,Ph) 및 13.33(S, 페놀).NMR:

1.21 (d, J = 7 Hz, methyl), 1.48 (S, gem dimethyl), 2.73 (S, C-3 methylene), 2.86 (+, J = 7 Hz, CH ₂ Ph), 2.9 (m, methine), 3.50 (d, J = 7 Hz, -CH ₂ O-), 3.65 (t, J = 7 Hz, -OCH _2- ), 6.31 (d, J = 1 Hz, ArH), 6.38 (d, J = 1 Hz, ArH), 7.26 (S, Ph) and 13.33 (S, phenol).

Example 2

dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromenone

Sodium hydride obtained by washing with 50% sodium hydride (6.67 g) pentane dissolved in mineral oil dispersion over 30 minutes, dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutyl ) -4-chromanone (4.7 g) and ethyl hormone (23.1 g) are added dropwise. The reaction mixture is cooled to room temperature and ether (350 ml) is added. The resulting mixture is refluxed for 18 hours, cooled to room temperature and acidified with 1N hydrochloric acid. The combined ether extracts were dried over sodium sulfate and concentrated in vacuo to give dl-5-hydroxy-3-hydroxy-methylene-2,2-dimethyl-7- (1-methyl-4-phenylbutyl)-in oil state. 4-chromanone) is obtained in a yield of 5.7 g.

1.05-1.8(M,13, 젬 디메틸, α-메틸, 에틸렌), 2.45(M,3, 벤질성 메틸렌, 메티닐), 6.2-6.5(M,2, 방향족), 7.0-7.6(M,6, 방향족, 메티닐에테르), 11.3, 11.36(2bd,S,1, 페놀성 수산), 13.3, 13.5(2bd,S,1, 하이드록시).NMR:

1.05-1.8 (M, 13, gem dimethyl, α-methyl, ethylene), 2.45 (M, 3, benzyl methylene, methynyl), 6.2-6.5 (M, 2, aromatic), 7.0-7.6 (M, 6 , Aromatic, methynyl ether), 11.3, 11.36 (2bd, S, 1, phenolic hydroxyl), 13.3, 13.5 (2bd, S, 1, hydroxy).

IR: (CHCl ₃ ) C = 0 1625 cm ^-1

In a similar manner, the product of Example 1 is converted:

dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-5-phenylpentyl) -4-chromanon is obtained.

1.2(D,3,α-메틸, J=7cps), 1.6(S,6, 젬 디메틸), 1.0-2.0[M,6,

CH₂-(CH₂)₃-CH(CH₃)Ar], 2.3-2.8(M,3, 벤질성 메틸렌, 메티닐), 6.2-6.4(M,2, 방향족), 7.1-7.4(M,6, 방향족, 비닐성), 11.4(bd, S,1 페놀성 수산);NMR:

1.2 (D, 3, α-methyl, J = 7cps), 1.6 (S, 6, gem dimethyl), 1.0-2.0 [M, 6,

CH _2- (CH ₂ ) ₃ -CH (CH ₃ ) Ar], 2.3-2.8 (M, 3, benzyl methylene, methynyl), 6.2-6.4 (M, 2, aromatic), 7.1-7.4 (M, 6, aromatic, vinyl), 11.4 (bd, S, 1 phenolic hydroxyl);

5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-phenylethyl) -4-chromenone (oil);

IR: (CHCl ₃ ) C = 0 1625 cm ^-1

1.5(S,6, 젬 디메틸), 2.85(S,4, 에틸렌), 6.2, 6.3(d,2, 방향족), 7.0-7.5(M,6, 방향족, 메티닐); 11.35(S,1, 하이드록실-D₂O 오버레이), 13.4, 13.6(d,1, 하이드록실-C₂O 오버레이).NMR:

1.5 (S, 6, gem dimethyl), 2.85 (S, 4, ethylene), 6.2, 6.3 (d, 2, aromatic), 7.0-7.5 (M, 6, aromatic, methynyl); 11.35 (S, 1, hydroxyl-D ₂ O overlay), 13.4, 13.6 (d, 1, hydroxyl-C ₂ O overlay).

MS: (molecule. Ion) 324

dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-3-phenyl-propyl) -4-chromenone (oil);

1.15(d,3, 메틸), 1.5(S,6, 젬 디메틸), 1.65-2.1(M,2, 메틸렌), 2.25-2.75(M,3, 벤질성-메틸렌, 에티닐), 6.15, 6.3(2d,2, 방향족), 7.1(M,6, 방향족, 올레핀성 프로톤), 11.3(S,1, 하이드록실-D₂O 오버레이), 13.3, 13.8(d,1, 하이드록실-D₂O 오버레이).NMR:

1.15 (d, 3, methyl), 1.5 (S, 6, gem dimethyl), 1.65-2.1 (M, 2, methylene), 2.25-2.75 (M, 3, benzyl-methylene, ethynyl), 6.15, 6.3 (2d, 2, aromatic), 7.1 (M, 6, aromatic, olefinic protons), 11.3 (S, 1, hydroxyl-D ₂ O overlay), 13.3, 13.8 (d, 1, hydroxyl-D ₂ O Overlay).

MS: (molecule. Ion) 352

dl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (1-methyl-4-phenyl-butyl) -4-chromenone;

1.1(D,3,α-메틸, J=7Hz), 1.5(D,3,2-메틸, J-7Hz), 1.3-1.8(M,4-에틸렌), 2.3-2.9(M,3, 벤질성), 4.9(M,1, 메티닐 에테르, J =5Hz), 6.2, 6.3(2D,2, 방향성, J=1Hz), 6.9-7.4(M,6, 방향족, 비닐성), 11.2(bd,S,1, 페놀성 OH).NMR:

1.1 (D, 3, α-methyl, J = 7 Hz), 1.5 (D, 3,2-methyl, J-7 Hz), 1.3-1.8 (M, 4-ethylene), 2.3-2.9 (M, 3, benzyl Gender), 4.9 (M, 1, methynyl ether, J = 5 Hz), 6.2, 6.3 (2D, 2, aromatic, J = 1 Hz), 6.9-7.4 (M, 6, aromatic, vinyl), 11.2 (bd , S, 1, phenolic OH).

dl-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenoxybutyl) -4-chromanone d, 1-5-hydroxy-3-hydroxymethylene-2,2-dimethyl -7- (1-methyl-4-phenoxybutyl) -4-chromenone; Rf = 0.44 [silica gel, 18-benzene; 1-ethyl acetate].

MS: (molecule, ion) 382

dl-5-hydroxy-2,2-dimethyl-7- [1-methyl-4- (4-pyridyl) butyl] -4-chromanone with viscous oil d, 1-5-hydroxy-3 -Hydromethylene-2,2-dimethyl-7- [1-methyl-4- (4-pyridyl) butyl] -4-chromenone.

Rf = 0.15 (silica gel, 1-benzene; 1-ethyl acetate)

dl-2,2-dimethyl-5-hydroxy-7- [1-methyl-2- (2-phenylethoxy) ethyl] -4-chromenone dl-2,2-dimethyl-3-hydroxy methylene Convert to -5-hydroxy-7- [1-methyl-2- (2-phenylethoxy) ethyl] -4-chromenone (oil).

Rf = 0.35 (silica gel, 1: 1 pentane: ether)

Example 3

dL-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyne) -6H-dibenzo- [b, d] pyran-9 (8H)- On

5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromanone (0.916 g) was added to methanol (4 ml) and methyl vinyl ketone (0.037 ml). ), Triethylamine (0.09 ml) is added.

The reaction is stirred at rt for 16 h and diluted with ether (50 ml). The resulting ether solution is extracted with 10% sodium carbonate solution (4 x 5 ml), dried over sodium sulfate and concentrated in vacuo to yield a 1.09 g solution. The residue is refluxed with ethanol (7.3 ml) for 16 hours. The reaction solution is then cooled, acidified with 6N hydrochloric acid and extracted with dichloromethane (3 x 20 ml). The organic phase was dried over sodium sulfate, evaporated and crystallized from ether: hexane (1: 1) to obtain 0.99 g of oil, and crystallized from isopropyl ether to 0.49 g of dℓ-6a having a melting point of 145 ° -148 ° C. 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one is obtained.

1-2.35(M, 10,α-메틸렌, 에틸렌, 잔류 양성자), 1.55(S,6, 젬 디메틸), 2.35-3.0(M, 5, α-메틸렌, 벤질성-메틸렌, 메티닐), 6.1-6.7(M,2, 방향족), 7-7.35(M, 5, 방향족), 7.9-8.2(bd, S, 1, 올 레핀성 양성자), 10.8(S, 1, 페놀성 OH).NMR:

1-2.35 (M, 10, α-methylene, ethylene, residual protons), 1.55 (S, 6, gem dimethyl), 2.35-3.0 (M, 5, α-methylene, benzyl-methylene, methynyl), 6.1 -6.7 (M, 2, aromatic), 7-7.35 (M, 5, aromatic), 7.9-8.2 (bd, S, 1, olefinic protons), 10.8 (S, 1, phenolic OH).

IR: (CHCl ₃ ) C = 0 1,600cm ^-1

Analyzes: Theoretic of C ₂₆ H ₃₀ 0 ₃ : C, 79.97; H, 7.74%

Found: C, 79.91; H, 7.78%

MS: (molecular ion) 390

In a similar manner, dL-6a-7-dihydro-1-hydroxy from 5-hydroxy-3-hydroxy methylene-2,2-dimethyl-7- (1-methyl-5-phenylpentyl) -4-chromanone Prepare oxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-9 (8H) -one. Melting Point is 204 ° -208 ℃

1.1, 1.5(2S, 6, 젬 디메틸), 1.0-3.0[M, 17, α-메틸,

CH₃(CH₂)₃-CH(CH₃)-Ar, 벤질성, 잔류 양성자 6.2, 6.5(2D, 2, 방향족 양성자, J=2CPS), 7.0-7.4(M, 5, 방향족), 8.05(D, 1, 비닐성, J=2CPS), 7.0-7.4(M, 5, 방향족), 8.05(D, 1, 비닐성, J=2CPS), 10.8(S, 1, 페놀성 하이드록실)NMR:

1.1, 1.5 (2S, 6, gem dimethyl), 1.0-3.0 [M, 17, α-methyl,

CH ₃ (CH ₂ ) ₃ —CH (CH ₃ ) —Ar, benzyl, residual protons 6.2, 6.5 (2D, 2, aromatic protons, J = 2CPS), 7.0-7.4 (M, 5, aromatic), 8.05 ( D, 1, vinylic, J = 2CPS), 7.0-7.4 (M, 5, aromatic), 8.05 (D, 1, vinylic, J = 2CPS), 10.8 (S, 1, phenolic hydroxyl)

IR: (KBr) C = 0 1613cm ^-1

Analyzes: C ₂₇ H ₃₂ O ₃ Theory: C, 80.16, H, 7.97%

Found: C, 8.OO, H, 8.29%

dL-6a, 7-dihydro-1, -hydroxy-6,6-dimethyl-3- (2-phenylethyl) -6H-dibenzo [b, d] pyran-9: 8H) -one-5 Prepared from -hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-phenylethyl) -4-chromanone. Melting Point 233 ° -235 ℃

1.0-1.4(M,3,6a-메티닐, 7-메틸렌), 1.5(S, 6, 젬 디메틸), 2.35-2.85(M, 2,8-α-메틸렌), 2.9(S, 4, 에틸렌), 6.3, 6.55(2d, 2, 방향족), 7.3(S, 5, 방향족), 7.95(d, 1,10-올레핀성 양성자), 10.5(S, 1, 하이드록실-D₂O 오버레이).NMR:

1.0-1.4 (M, 3,6a-methynyl, 7-methylene), 1.5 (S, 6, gem dimethyl), 2.35-2.85 (M, 2,8-α-methylene), 2.9 (S, 4, ethylene ), 6.3, 6.55 (2d, 2, aromatic), 7.3 (S, 5, aromatic), 7.95 (d, 1,10-olefinic protons), 10.5 (S, 1, hydroxyl-D ₂ O overlay).

MS: (molecular ion) 348

And dL-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenyl-propyl) -6H-dibenzo [b, d] pyran-9 (8H) -One is prepared from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-3-phenylpropyl) -4-chromenone. Melting point 181 ℃

1.2, 1.3(d, 2, 메틸), 1.55(S, 6, 젬 디메틸), 1.6-3.1(M, 8, 잔류 양성자), 6.3, 6.55(2d, 2, 방향족), 7.2, 7.25(2S, 6, 방향족, 하이드록시-D₂O 오버레이), 8.05(d, 1, 올레핀성 양성자).NMR:

1.2, 1.3 (d, 2, methyl), 1.55 (S, 6, gem dimethyl), 1.6-3.1 (M, 8, residual protons), 6.3, 6.55 (2d, 2, aromatic), 7.2, 7.25 (2S, 6, aromatic, hydroxy-D ₂ O overlay), 8.05 (d, 1, olefinic proton).

MS: (molecular ion) 376

dL-6aα-7-Dihydro-1-hydroxy-6α from dL-5-hydroxy-3-hydroxymethylene-2-methyl-7- (1-methyl-4-phenylbutyl) -4-chromanone Prepare -methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one. Melting Point 195 ° -197 ℃

1.2(D, 3,α-메틸, J=7Hz), 1.4(D, 3,6-메틸, J=7Hz), 1.3-1.8(M, 6, 7-메틸렌, 알릴성), 3.8(M, 1, 메티닐 에테르, Jvicinal=11Hz), 7.0-7.4(M, 5, 방향족), 7.9(D, 1, 비닐성, J=1Hz), 9.6(S, 1, 페놀성 0H)NMR:

1.2 (D, 3, α-methyl, J = 7 Hz), 1.4 (D, 3,6-methyl, J = 7 Hz), 1.3-1.8 (M, 6, 7-methylene, allylic), 3.8 (M, 1, methynyl ether, Jvicinal = 11 Hz, 7.0-7.4 (M, 5, aromatic), 7.9 (D, 1, vinylic, J = 1 Hz), 9.6 (S, 1, phenolic 0H)

IR: (KBr) C = O 1,639cm ^-1

Analyzes: Theoretical C of C ₂₅ H ₂₈ 0 ₃ , 79.75; H, 7.50%

Found: C, 79.96; H, 8.33%

=226(ε=14,400), 324(ε=26,000),UV:

= 226 (ε = 14,400), 324 (ε = 26,000),

MS: (molecular ion) 376

DL-6a, 7-dihydroxy-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenoxybutyl) -6H-dibenzo from the corresponding 3-hydroxy-methylene derivative [b, d] Prepares pyran-9 (8H) -one. Melting point 165 ° -175 ° C.

MS: (molecular ion) 406

Rf = 0.31 (silica gel, 18-benzene: 3-ethyl acetate

Analyzes: Theoretic of C ₂₆ H ₃₀ O ₄ : C, 76.82; H, 7.44%

Found: C, 76.80, H, 7.57%

DL-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl)-, which is a vitreous solid from the corresponding 3-hydroxymethylene derivative Butyl] -6H-dibenzo [b, d] pyran-9 (8H) -one is prepared.

MS: (molecular ion) 391

Assay: Theoretic of C ₂₅ H ₂₉ NO ₃ H ₂ O: C, 73.32; H, 7.62: N, 3.42%

Found: C, 73.22; H, 7.47; N, 3.25%

dℓ-2,2-dimethyl-3-hydroxymethylene-5-hydroxy-7- [1-methyl-2- (2-phenylethoxy) ethyl] -4-chromenone from dℓ-6a, 7- Dihydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy) ethyl] -6H-dibenzo- [b, d] pyran-9 (8H)- Prepare the on. Melting point 185 ° -187 ° C.

IR: (CHCl ₃ ) C = 0 1613 cm ^-1

1.15(S, 젬 디메틸 중 메틸하나), 1.20(d, J=7Hz, 메틸), 1.48(S, 젬 디메틸중 메틸하나), 2.0-3.1(m), 2.85(t, J=7Hz, CH₂Ph), 3.4-3.8(m, -CH₂OCH₂-), 6.35(bs,ArH), 6.63(bs, ArH), 7.30(S, Ph), 8.10(d, J=2Hz, C-1OH) 및 12.3(S, 페놀)NMR:

1.15 (S, methyl one in gem dimethyl), 1.20 (d, J = 7 Hz, methyl), 1.48 (S, methyl one in gem dimethyl), 2.0-3.1 (m), 2.85 (t, J = 7 Hz, CH ₂ Ph), 3.4-3.8 (m, -CH ₂ OCH _2- ), 6.35 (bs, ArH), 6.63 (bs, ArH), 7.30 (S, Ph), 8.10 (d, J = 2 Hz, C-1OH) And 12.3 (S, phenol)

), 391, 376, 363, 315, 302(100%), 287, 285 및 272.MS: m / e 406 (M

), 391, 376, 363, 315, 302 (100%), 287, 285 and 272.

Example 4

dL-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 ( 8H) -on

DL-6a, 7-dihydro-1-hydroxy-6, dissolved in tetrahydrofuran (7 ml) in a lithium (0.1 g) solution dissolved in a rapidly stirred ammonia solution (35 ml) (distilled through potassium hydroxide ferret). , 6-Dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran 1-9 (8H) -one (0.976 g) was added thereto.

The reaction is stirred for 15 minutes and solid ammonium chloride is added until the color disappears. Excess ammonia is evaporated and the residue is diluted with water and acidified with concentrated hydrochloric acid.

The aqueous solution was extracted with dichloromethane (3 × 25 ml) and the dichloromethane extract was dried over sodium sulfate and evaporated to yield 0.98 g of a mixture of trans and cis-6a, 10a, and diastereomers in an impure oil state. This product was purified by column chromatography on silica gel to obtain the trans-diastereomer and then the cis-diastereomer in the fraction.

Thus the following materials are obtained:

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 ( 8H) -one, 0.393 g, melting point 200 ° -205 ° C.

1-2.35(M, 11, α-메틸, 에틸렌, 잔류양성자), 1.55(S, 6, 젬 디메틸), 2.35-3.0(M, 7, α-메틸렌류, 벤질성, 메틸렌, 메티닐), 6.2-6.45(M, 2, 방향족), 7-7.35(M, 5, 방향족), 7.8(bd, S, 1, 하이드록시-D₂O 오버레이)NMR:

1-2.35 (M, 11, α-methyl, ethylene, residual protons), 1.55 (S, 6, gem dimethyl), 2.35-3.0 (M, 7, α-methylenes, benzyl, methylene, methynyl), 6.2-6.45 (M, 2, aromatic), 7-7.35 (M, 5, aromatic), 7.8 (bd, S, 1, hydroxy-D ₂ O overlay)

IR: (CHCl ₃ ) C = 0 1,600cm ^-1

And dL-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d in solid foam state ] Pyran-9 (8H) -on.

IR: (CHCl ₃ ) C = 0,690 cm ^-1 , OH 3,275 cm ^-1

0.95-2.12(M, 11, α-메틸렌류, 벤질성 메틸렌, 메티닐), 6.1-6.35(M, 2, 방향족), 7.1(bd, S, 1, 하이드록실), 7.25(S, 5, 방향족).NMR:

0.95-2.12 (M, 11, α-methylenes, benzyl methylene, methynyl), 6.1-6.35 (M, 2, aromatic), 7.1 (bd, S, 1, hydroxyl), 7.25 (S, 5, Aromatic).

The following compound was obtained by repeating the above procedure except using the product of Example 3 as the reactant.

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-9 ( 8H) -on, melting point 159 ° -163 ° C. :

1.1, 1.5(2S, 6, 젬 디메틸), 0.9-3.1[M, 19, α-메틸,

-CH₂-(CH₂)₃=CH(CH₃)-Ar, 벤질성류, 잔류 양성자], 3.9-4.4(bd, D, 1, α-카르보닐), 6.2(M, 2, 방향족), 7.0-7.4(M, 5, 방향족), 7.8(S, 1, 페놀성 하이드록실).NMR:

1.1, 1.5 (2S, 6, gem dimethyl), 0.9-3.1 [M, 19, α-methyl,

-CH _2- (CH ₂ ) ₃ = CH (CH ₃ ) -Ar, benzyl, residual proton], 3.9-4.4 (bd, D, 1, α-carbonyl), 6.2 (M, 2, aromatic), 7.0-7.4 (M, 5, aromatic), 7.8 (S, 1, phenolic hydroxyl).

IR: (KBr) C = 0 1,695cm ^-1

Analyzes: Theoretic of C ₂₇ H ₃₄ 0 ₃ : C, 79.76; H, 8.43%

Found: C, 79.49; H, 8.43%

And corresponding cis-diastereomers;

dL-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-9 (8H) -one; Melting point 91 ° -130 ° C.

IR: (KBr) C = 0,709cm ^-1

MS: (molecular ion) 406.

dL-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-phenylethyl) -6H-dibenzo [b, d] pyran-9 (8H) -one Melting point 206 ° -209 ° C:

IR: (KBr) OH 3,260cm ^-1 , C = 0 1710cm ^-1

1.05-1.45(2S, 6, 젬 디메틸), 2.75(bs, 4, 에틸렌), 1.1-3.1(M, 7, 잔류양성자), 3.75, 4.0(2d,1,10aα양성자), 6.2(d, 2, 방향족), 7.15(S, 5, 방향족), 8.8(S, 1, 하이드록실-D₂O 오버레이).NMR:

1.05-1.45 (2S, 6, gem dimethyl), 2.75 (bs, 4, ethylene), 1.1-3.1 (M, 7, residual protons), 3.75, 4.0 (2d, 1,10aα protons), 6.2 (d, 2 , Aromatic), 7.15 (S, 5, aromatic), 8.8 (S, 1, hydroxyl-D ₂ O overlay).

MS: (molecular ion) 350

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropyl) -6H-dibenzo [b, d] pyran-9 ( 8H) -one, melting point 165 캜;

IR (KBr) OH 3,175cm ^-1 , C = 0 1,695cm ^-1

And dL-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl) -3- (1-methyl-3-phenylpropyl) -6H-dibenzo [b, in solid foam state; d] pyran-9 (8H) -one;

IR: (CHCl ₃ ) C = 0 1,685cm ^-1 , OH ^- 3,250cm ^-1

1.35, 1.45(2S, 6, 젬 디메틸), 2.8(bd, S, 4, 에틸렌), 1.75-3.6(M, 8, 잔류양성자), 6.3(M, 2, 방향족), 7.25(M, 6, 방향족, 하이드록실).NMR:

1.35, 1.45 (2S, 6, gem dimethyl), 2.8 (bd, S, 4, ethylene), 1.75-3.6 (M, 8, residual protons), 6.3 (M, 2, aromatic), 7.25 (M, 6, Aromatic, hydroxyl).

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4phenoxybutyl) -6H-dibenzo [b, d] pyran-9 ( 8H) -one; Melting point 160 ° -175 ° C.

MS: (molecular ion) 408

Rf = 0.53 (silica gel, 8-benzene; 2-ethyl acetate)

7.41-6.67(멀티프레이트, 6, 페놀성 OH, C₆H₅); 6.3(S, 2, 방향족 H₂+H₄); 4.33-1.50(Ms, 15, 잔류 메틸렌 및 메틴 양성자); 1.47(S, 3, CH₃); 1.27 및 1.17(D, 3, Me); 1.12(S, 3, CH₃) :NMR:

7.41-6.67 (multiplates, 6, phenolic OH, C ₆ H ₅ ); 6.3 (S, 2, aromatic H ₂ + H ₄ ); 4.33-1.50 (Ms, 15, residual methylene and methine protons); 1.47 (S, 3, CH ₃ ); 1.27 and 1.17 (D, 3, Me); 1.12 (S, 3, CH ₃ ):

Analyzes: Theoretic of C ₂₆ H ₃₂ 0 ₄ : C, 76.44; H, 7.89%

Found: C, 76.61; H, 7.90%

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl) butyl] -6H-dibenzo [b, d Pyran-9 (8H) -one;

Melting Point: 60 ° -70 ℃

Rf = 0.4 (silica gel, ethyl acetate)

MS: (molecular ion) 393

1.2(D,3,6-메틸, J =7Hz), 1.4(-1.8(M, 3,6-메틸), 3.1-4.0-(2M, 메티닐 에테르, J=8 및 14Hz), 6.2-6.4(M, 2, 방향족), 6.8-7.4(M, 6, 방향족, 페놀성), 1.2-2,6(M, 15, 잔류양성자).NMR:

1.2 (D, 3,6-methyl, J = 7 Hz), 1.4 (-1.8 (M, 3,6-methyl), 3.1-4.0- (2M, methynyl ether, J = 8 and 14 Hz), 6.2-6.4 (M, 2, aromatic), 6.8-7.4 (M, 6, aromatic, phenolic), 1.2-2, 6 (M, 15, residual protons).

IR: (KBr) C = 0 1709cm ^-1

Analyzes: Theoretic of C ₂₅ H ₃₀ 0 ₃ : C, 79.33; H, 7.99%

Found: C, 79.43; H, 8.03%

MS: (molecular ion) 378

dL-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxyethyl] -6H-dibenzo [b, d Pyran-9 (8H) -one (solid glassy);

1.13(S, 젬 디메틸 중 메틸하나), 1.24(d, J=7Hz, 메틸), 1.50(S, 젬 디메틸 중 메틸하나), 1.6-3.2(M), 3.2-3.8(M), 4.05(M, 양성자 하나), 4.30(M, 양성자 하나), 6.33(S, 두개의 ArH), 7.30(S, Ph) 및 7.70(5, 페놀).NMR:

1.13 (S, methyl one in gem dimethyl), 1.24 (d, J = 7 Hz, methyl), 1.50 (S, methyl one in gem dimethyl), 1.6-3.2 (M), 3.2-3.8 (M), 4.05 (M , One proton), 4.30 (M, one proton), 6.33 (S, two ArH), 7.30 (S, Ph) and 7.70 (5, phenol).

, 100%), 392, 375, 304, 287, 286, 274 및 273.MS: (molecular ion) 408 (M

, 100%), 392, 375, 304, 287, 286, 274 and 273.

Rf = 0.57 (silica gel, ether) and corresponding cis-isomers;

dL-6aβ, 7,10,10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (phenylethoxy) ethyl] -6H-dibenzo [b, d] Pyran-9 (8H) -one, melting point 127 ° -130 ° C;

1.20(d, J =7Hz, 메틸), 1.32 및 1.39(S, 젬 디메틸), 1.6-3.8(M), 6.25(S, ArH 2개), 7.07(S, 페놀) 및 7.28(S, Ph).NMR:

1.20 (d, J = 7 Hz, methyl), 1.32 and 1.39 (S, gem dimethyl), 1.6-3.8 (M), 6.25 (S, 2 ArH), 7.07 (S, phenol) and 7.28 (S, Ph) .

, 100%), 393, 391, 325, 316, 304, 287, 286, 274, 273 및 245.MS: (molecular ion) 408 (M

, 100%), 393, 391, 325, 316, 304, 287, 286, 274, 273 and 245.

Rf = 0.50 (silica gel, ether)

Example 5

dL-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] Pyran-9β-ol

Sodium borohydride (0.5 g) was dissolved in ethanol (200 ml) stirred at room temperature in the presence of nitrogen, dℓ-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1- To a methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one (0.25 g) solution.

The reaction was stirred for 30 minutes, acidified with 6N hydrochloric acid, diluted with water (50 ml) and extracted with ether (3 × 50 ml).

The combined ether extracts are dried over sodium sulfate and concentrated in vacuo to give 9-OH α- and β-isomers in 0.25 g yield. Column chromatography (silica gel) gave 0.087 g of dL-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9β-ol, is obtained, which is then recrystallized from ether: hexane (1: 2). Melting point 156 ° -158 ° C.

MS: (molecular ion) 394

Analyzes: Theoretic of C ₂₆ H ₃₄ 0 ₃ : C, 79.15; H, 8.69%

Found: C, 78.94; H, 8.79%

The following compounds are prepared from the appropriate reactants of Example 4 according to the methods described above.

dL, 6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] Pyran-9β-ol;

1.0, 1.4(2S, 6, 젬 디메틸), 1.2(D, 3,α-메틸, J =7cps), 0.8-4.0(M, 18, 잔류양성자), 4.1-4.7(M, 2, 페놀성 0H 및 알콜성 OH), 6.1, 6.2(2D, 방향족, J=3cps), 7.0-7.3(M, 5, 방향족),NMR:

1.0, 1.4 (2S, 6, gem dimethyl), 1.2 (D, 3, α-methyl, J = 7 cps), 0.8-4.0 (M, 18, residual protons), 4.1-4.7 (M, 2, phenolic 0H And alcoholic OH), 6.1, 6.2 (2D, aromatic, J = 3cps), 7.0-7.3 (M, 5, aromatic),

Analyzes: Theoretic of C ₂₇ H ₃₆ 0 ₃ : C, 79.37; H, 8.88%

Found: C, 79.58; H, 8.92%

dl-6a, 7, 8, 9, 10,10a-hexahydro-1-hydroxy-6,6-dimethyl-3- (2-phenyl-ethyl) -6H-dibenzo [b, d] pyran-9 -Ol; Melting point 213 ° -215 ° C;

IR: (KBr) OH 3,367cm ^-1 , 3125cm ^-1

1.0, 1.35(2S, 6, 젬 디메틸), 2.85(S, 4, 에틸렌), 3.85(bs, 1, 하이드록시-D₂O 오버레이), 3.6(M, 1, 10aα 양성자), 0.8-3.6(M, 8, 잔류 양성자), 6.2(2D, 2, 방향족), 7.2(S, 5, 방향족), 8.75(S, 1, 하이드록실-D₂O 오버레이)NMR:

1.0, 1.35 (2S, 6, gem dimethyl), 2.85 (S, 4, ethylene), 3.85 (bs, 1, hydroxy-D ₂ O overlay), 3.6 (M, 1, 10aα proton), 0.8-3.6 ( M, 8, residual protons), 6.2 (2D, 2, aromatic), 7.2 (S, 5, aromatic), 8.75 (S, 1, hydroxyl-D ₂ O overlay)

MS: (molecular ion) 352

dl-6aβ, 7, 8, 9, 10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropyl) -6H-dibenzo [b, d Pyran-9β-ol, melting point 171 ° -172 ° C;

1.35, 1.25(d, 3, 메틸), 1.35(S, 6, 젬 디메틸), 1.6-1.95(M, 2, 메틸렌), 2.15-2.7(M, 3, 벤질성-메티닐 및 메틸렌), 1.0-3.8(M, 10, 잔류 양성자 및 하이드록실), 6.1, 6.25(2d,2,방향족), 7.2(S, 5, 방향족)NMR:

1.35, 1.25 (d, 3, methyl), 1.35 (S, 6, gem dimethyl), 1.6-1.95 (M, 2, methylene), 2.15-2.7 (M, 3, benzyl-methynyl and methylene), 1.0 -3.8 (M, 10, residual protons and hydroxyl), 6.1, 6.25 (2d, 2, aromatic), 7.2 (S, 5, aromatic)

Analyzes: Theoretic of C ₂₅ H ₃₂ 0 ₃ : C, 78.91; H, 8.47%

Found: C, 78.57; H, 8.50%

dl-6aα-7, 8, 9, 10, 10a-hexahydro-1-hydroxy-6α-methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran- 9β-ol, this product is obtained as a mixture of diastereomeric alcohols. This foamy mixture is separated into two materials by layer chromatography on a silica gel plate using 5% methanol in chloroform as the elution solvent.

Diastereomeric mixtures exhibit maximums at infrared 3,827 and 3333 cm ⁻¹ (0H) (in chloroform).

10 mg of component A is separated from 60 mg of foam;

R _f = 0.65. Its NMR spectrum is as follows.

7.0-7.5(M, 5, 방향족), 6.2, 6.3(2D, 2, 방향족), 1.2(D, 3, α-메틸, J=7Hz), 0.8-4.5(M, 22, 잔류양성자)NMR:

7.0-7.5 (M, 5, aromatic), 6.2, 6.3 (2D, 2, aromatic), 1.2 (D, 3, α-methyl, J = 7 Hz), 0.8-4.5 (M, 22, residual protons)

Component B, 42 mg, R _f = 0.75 are similarly isolated. Its NMR spectrum is as follows.

7.0-7.5(M, 5, 방향족), 6.1-6.3(2D, 2, 방향족), 1.2(D, 3, α-메틸, J=7Hz), 0.8-4.5(M, 22, 잔류양성자)NMR:

7.0-7.5 (M, 5, aromatic), 6.1-6.3 (2D, 2, aromatic), 1.2 (D, 3, α-methyl, J = 7 Hz), 0.8-4.5 (M, 22, residual protons)

dl-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenoxybutyl) -6H-dibenzo [b, d Pyran-9β-ol, welding 144 ° -146 ° C.

R _f = 0.31 (silica gel, 9-ether; 1-hexane)

Analyzes: Theoretic of C ₂₈ H ₃₄ 0 ₄ : C, 76.06; H, 8.35%

Found: C, 75.85; H, 8.22%

6.75(M, 6, 페놀성 OH+C₆H₅); 7.95 및 7.80(BS, 2, 방향족 H₂+H₄); 4.17-1.00(M, 26, 1.42[S, Me]를 함유한 비방향족, 1.28및 1.17[D, Me], 1.10(S, CH₃), 메틸렌, 메틴 및 하이드록실).NMR:

6.75 (M, 6, phenolic OH + C ₆ H ₅ ); 7.95 and 7.80 (BS, 2, aromatic H ₂ + H ₄ ); 4.17-1.00 (non-aromatic containing M, 26, 1.42 [S, Me], 1.28 and 1.17 [D, Me], 1.10 (S, CH ₃ ), methylene, methine and hydroxyl).

Dl- (6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenoxybutyl) -6H-dibenzo in oil state [b, d] pyran-6α-ol,

R _f = 0.37 (silica gel, 9-ether: 1-hexane)

MS: (molecular ion) 410

dl-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl) butyl-6H-dibenzo [ b, d] pyran-9β-ol;

Melting Point: 170 ° -190 ℃

R _f = 0.19 (silica gel, 9-benzene: 1-methanol)

8.50-8.45(D, 2, 피리딘 방향족), 6.26(BS, 1, 벤젠 방향족), 6.10(BS, 1, 벤젠 방향족), 4.60-3.30(M, 3, 메틴+0H[싱글렛 3.83]), ; 2.80-0.80(M, 26, 알킬, 1.44[Me]에서 싱글렛을 함유하며, 더블렛 1.24-1.17([CH₃], 싱글렛 1.12[CH₃]) 및 잔류 메틸렌 및 메틴흡수)NMR:

8.50-8.45 (D, 2, pyridine aromatic), 6.26 (BS, 1, benzene aromatic), 6.10 (BS, 1, benzene aromatic), 4.60-3.30 (M, 3, methine + 0H [Single 3.83]), ; 2.80-0.80 (M, 26, alkyl, containing singlet at 1.44 [Me], doublet 1.24-1.17 ([CH ₃ ], singlet 1.12 [CH ₃ ]) and residual methylene and methine absorption)

dl-6aβ, 7, 10, aα-tetrahydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy) ethyl) -6H-dibenzo [b, d] pyran- 9 (8H) -one was added as dl-6aβ-7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy ) Methyl] -6H-dibenzo [b, d] pyran-9β-ol (solid).

IR: (CHCl ₃ ) OH 3,597 and 3333 cm ^-1

1.02(S, 젬 디메틸 중 메틸 하나), 1.20(d, J=7Hz, 메틸), 1.37(S, 젬 디메틸 중 메틸 하나), 1.6-4.2(M), 6.19(bs, ArH), 6.30(bs, ArH), 및 7.27(s, Ph).NMR:

1.02 (S, one methyl in gem dimethyl), 1.20 (d, J = 7 Hz, methyl), 1.37 (S, one methyl in gem dimethyl), 1.6-4.2 (M), 6.19 (bs, ArH), 6.30 (bs , ArH), and 7.27 (s, Ph).

dl-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylmethoxy) ethyl] -6H-dibenzo [b, d] pyran-9 (8H) -olol

dl-6aβ, 7, 8, 9, 10, 10aβ-hexahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy) -ethyl) -6H- Dibenzo [b, d] pyran-9β-ol is converted to a melting point of 90 ° -105 ° C.

IR: (CHCl ₃ ) OH 3,534 and 3,279 cm ^-1

1.12(M, 3메틸), 1.73(M), 2.32(M), 2.82(t, J =7Hz, CH₂Ph), 3.0-4.1(M), 6.13(d, J=2Hz, ArH), 6.30(d, J=2Hz, ArH), 6.90(bs, 페놀) 및 7.25(s, Ph).NMR:

1.12 (M, 3 methyl), 1.73 (M), 2.32 (M), 2.82 (t, J = 7 Hz, CH ₂ Ph), 3.0-4.1 (M), 6.13 (d, J = 2 Hz, ArH), 6.30 (d, J = 2 Hz, ArH), 6.90 (bs, phenol) and 7.25 (s, Ph).

) 및 105.MS: (molecular ion) 410 (M

And 105.

Example 6

dl-5-hydroxy-2,2-dimethyl-7- (2-heptyloxy) -4-chromenone

While stirring 2-bromoheptane (15.77 g, 88.OmM), 5.7-dihydroxy-2,2-dimethyl-4-chromanone (18.5 g, 8.71 mM) and potassium hydroxide (2.44 g, 43.5 mM) were added. It is added to a solution dissolved in N, N-dimethylformamide (58 ml).

The mixture is heated at 100 ° C. for 4 days, cooled to room temperature and then added to a mixture of sodium hydroxide liquid (110 ml, 1N), water (45 ml) and chloroform (150 ml). The mixture is shaken and the chloroform layer is separated. The aqueous layer is extracted with more chloroform (150 ml). The combined layers of chloroform are washed with 1N-sodium hydroxide (2 x 100 ml), dried over sodium sulphate and concentrated in oil.

Unreacted brheptane is removed by distillation and the residue is purified by silica gel chromatography to give 5.90 g (22.1%) of the title product as an oil.

NMR (CDCl ₃ ) δ-12.4 (one proton singlet, hydroxyl), 5.7 and 6.0 (two, one proton doublet J = 3 Hz, aromatic protons), 4.1-4.7 (one proton multifret, ethermethine), 2.7 (2 proton singlet, C-3 methylene), 0.7-2.0 (22 proton multiplets for residual-protons, gem dimethyl appearing as singlet at 1.5).

In a similar manner, dl-5-hydroxy-2,2-dimethyl-7- [2- (5-phenyl) pentyl-oxy]-using 2-bromo-5-phenylpental instead of 2-bromoheptane. Prepare 4-chromanones:

Melting point 83 ° -84 ℃

IR (KBr) C = 0 1,639 cm ^-1

1.3(D, 3, α-메틸, J =7Hz), 1.3-2.0(M, 4, 에틸렌), 1.5(S, 6, 젬 디메틸), 2.7(S, 2, α-메틸렌), 2.5-2.9(M, 2, 벤질성 메틸렌), 4.1-4.7(M, 1, 메틴), 5.9-6.1(M, 2, 방향족), 7.1-7.5(M, 5, 방향족), 12.2(S, 1, 페놀성).NMR:

1.3 (D, 3, α-methyl, J = 7 Hz), 1.3-2.0 (M, 4, ethylene), 1.5 (S, 6, gem dimethyl), 2.7 (S, 2, α-methylene), 2.5-2.9 (M, 2, benzyl methylene), 4.1-4.7 (M, 1, methine), 5.9-6.1 (M, 2, aromatic), 7.1-7.5 (M, 5, aromatic), 12.2 (S, 1, phenol castle).

MS: (molecular ion) 354

Analyzes: Theoretic of C ₂₂ H ₂₆ 0 ₄ : C, 74.55; H, 7.39%

Found: C, 74.68; H, 7.46%

Dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-3-phenylpropoxy) -4-chromenone in oil state is prepared from 2-bromo-4-phenylbutane;

1.25, 1.35(d, 3, 메틸), 1.4(S, 6, 젬 디메틸), 1.6-2.4(M, 2, 메틸렌), 2.6(S, 2, 벤질성 메틸렌), 2.85(S, 2, 3α-메틸렌), 4.05-4.7(M, 1, 메티닐), 5.9(6d, 2, 방향족), 7.25(S, 5, 방향족).NMR:

1.25, 1.35 (d, 3, methyl), 1.4 (S, 6, gem dimethyl), 1.6-2.4 (M, 2, methylene), 2.6 (S, 2, benzyl methylene), 2.85 (S, 2, 3α Methylene), 4.05-4.7 (M, 1, methynyl), 5.9 (6d, 2, aromatic), 7.25 (S, 5, aromatic).

Dl-5-hydroxy-2,2-dimethyl-7-cyclohexyloxy-4-chromenone is prepared from bromo cyclohexane.

Melting Point 72 ° -75 ℃

IR (KBr) C = 0,626cm ^-1 : 3390cm ^-1

MS: (molecular ion) 290

1-2.1(M, 10, C₅H₁₀-싸이클로헥실), 1.4(S, 6, 젬 디메틸), 2.65(S,2, α-메틸렌), 4.0-4.45(M, 1, 싸이클로헥실메티닐), 5.85-6.05(M, 2, 방향족), 11.9(S, 하이드록실, D₂O 오버레이).NMR:

1-2.1 (M, 10, C ₅ H ₁₀ -cyclohexyl), 1.4 (S, 6, gem dimethyl), 2.65 (S, 2, α-methylene), 4.0-4.45 (M, 1, cyclohexylmethynyl ), 5.85-6.05 (M, 2, aromatic), 11.9 (S, hydroxyl, D ₂ O overlay).

Example 7

4.dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4-chromenone

9.23 g (192 μm) of 50% sodium hydride dissolved in mineral oil dispersion was washed with pentane, and then dl-5-hydroxy-2,2-dimethyl-7- (2-heptyloxy) -4-chromanone ( 5.90 g, 19.2 mM) and ethyl hormone (34.9 ml, 432 mM) were added dropwise over 30 minutes. After the addition is complete, ether (475 ml) is added and the resulting mixture is refluxed. After 18 hours, the reaction mixture is cooled to room temperature and acidified with 1N hydrochloric acid. The organic layer is separated and the aqueous layer is further extracted with ether (3 x 125 ml). The combined ether extracts were dried over sodium sulfate and concentrated in vacuo to give dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4-chromenone in oil form 6.41 g (> 100%) is obtained.

13.4(하나의 넓은 싱글렛 양성자, 하이드록실성), 11.8(하나의 양성의 싱글렛, 페놀성 하이드록실성), 7.4(하나의 넓은 양성자 싱글렛, 비닐), 6.1, 6.0(2 하나의 양성자 더블렛, J=3Hz, 방향족), 4.8-4.2(하나의 양성자 멀티플렛, 메틴), 2.1-0.7(잔류 양성자를 위한 20 프로톤 멀티프렛)NMR:

13.4 (one wide singlet proton, hydroxyl), 11.8 (one positive singlet, phenolic hydroxyl), 7.4 (one wide proton singlet, vinyl), 6.1, 6.0 (2 one proton Doublet, J = 3 Hz, aromatic), 4.8-4.2 (one proton multiplet, methine), 2.1-0.7 (20 proton multiplet for residual protons)

In a similar manner, the appropriate reactants of Example 6 were converted to afford the following materials; dl-5-hydroxy-3-methylene-2,2-dimethyl-7- [2- (5-phenyl) pentyloxy] -4-chromenone, oil;

1.3(D, 3, α-메틸, J-7Hz), 1.3-2.0(M, 4, 에틸렌), 1.4(S, 6, 젬 디메틸), 2.3-2.8(bd, T, 2-벤질성 메틸렌),4.1-4.7(M, 1, 메틴), 5.8-6.0(M, 2, 방향족), 7.0-7.4(M, 6, 방향족 및 비닐성), 10.0(S, 1, 페놀성), 13.3(bd, S, 1, 하이드록실성)NMR:

1.3 (D, 3, α-methyl, J-7 Hz), 1.3-2.0 (M, 4, ethylene), 1.4 (S, 6, gem dimethyl), 2.3-2.8 (bd, T, 2-benzyl methylene) , 4.1-4.7 (M, 1, methine), 5.8-6.0 (M, 2, aromatic), 7.0-7.4 (M, 6, aromatic and vinylic), 10.0 (S, 1, phenolic), 13.3 (bd , S, 1, hydroxyl)

dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- [2- (4-phenyl) -butyloxy] -4-chromenone, oil;

dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-cyclohexyloxy-4-chromenone;

IR (KBr) C = 0 0620 cm ⁻¹ ; OH 3,420 cm ^-1

MS: (molecular ion) 318

1.1-2.3(M, 10,C₅H₁₀-싸이클로헥실), 1.55(S, 6, 젬 디메틸), 4.1-4.5(M, 1-싸이클로헥실-메티닐), 5.9-6.1(M, 2, 방향족), 7.1-7.5(d, 1, 메티 닐), 11.6(S, 1, 하이드록실, D₂O 오버레이).NMR:

1.1-2.3 (M, 10, C ₅ H ₁₀ -cyclohexyl), 1.55 (S, 6, gem dimethyl), 4.1-4.5 (M, 1-cyclohexyl-methynyl), 5.9-6.1 (M, 2, Aromatic), 7.1-7.5 (d, 1, methynyl), 11.6 (S, 1, hydroxyl, D ₂ O overlay).

dl-5-hydroxy-3-hydroxy methylene-2,2-dimethyl-7- (1-methyl-3-phenoxypropyl) -4-chromenone, oil (from the reactant of Example 1);

R _f = 0.42 (silica gel, 18-benzene: 1-ethyl acetate)

MS: (molecular ion) 368

Example 8

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo- [b, d] pyran-9 (8H) -one

Dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -3-chromanone (5.17 g, 15.4 mM) dissolved in methanol (23 ml) and methyl vinyl ketone ( 2.27 ml, 27.9 ml) is added to triethylamine (0.54 ml). The reaction solution is stirred for 16 hours at room temperature and diluted with ether (250 ml). The resulting ether solution is extracted with 10% sodium carbonate (6 x 30 ml), dried over sodium sulphate and concentrated in vacuo to yield 6.11 g of oil.

The residue is refluxed for 16 h with ethanol (45 ml) and 2N-potassium hydroxide (45 ml). The reaction solution is then cooled, acidified with 6N hydrochloric acid, and extracted with dichloromethane (3 × 100 ml). The organic layer is dried over sodium sulfate and evaporated to yield 6.3 g of a dark solid. The solid is triturated in hot ether to give 1.00 g of the title compound having a melting point of 185 ° -189 ° C. Silica gel chromatography gives 1.26 g more from liquid B. The total yield is 42.3%.

3Hz, 방향족 양성자), 4.6-4.0(하나의 양성자 멀티프렛 메틴 에테르), 3.0-0.6(25 양성자 멀티프렛, 잔류 양성자).NMR (CDCl ₃ ) δ-11.2 (one wide proton singlet, phenolic 0H), 7.9 (one wide proton singlet, vinyl), 6.2, 5.9 (two one proton doublet, J

3 Hz, aromatic protons), 4.6-4.0 (one proton multipret methine ether), 3.0-0.6 (25 proton multiplets, residual protons).

IR (KBr) C = 0 1600 cm ^-1

Analyzes: Theoretical value of C ₂₂ H ₃₀ 0 ₄ : C, 73.71; H, 8.44%

Found: C, 73.41; H, 8.37%

=342mμ(ε=26,800)UV

= 342 mμ (ε = 26,800)

In a similar manner, the following compounds are prepared from the appropriate reactants of Example 7.

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 (8H)- On; Melting point 140 ° -168 ° C;

1.3(D, 2, α-메틸, J=7Hz),1.1-2.3(M, 15, 잔류양성자),2.3-3.0(bd, T, 2, 벤질성 메틸렌), 4.1-4.7(M, 1, 메틴), 5.95(D, 1, 방향족, J=2Hz), 6.3(D, 1, 방향족, J =2Hz), 7.2-7.4(M, 5, 방향족), 8.0(D, 1, 비닐성, J=2Hz).NMR:

1.3 (D, 2, α-methyl, J = 7 Hz), 1.1-2.3 (M, 15, residual protons), 2.3-3.0 (bd, T, 2, benzyl methylene), 4.1-4.7 (M, 1, Methine), 5.95 (D, 1, aromatic, J = 2 Hz), 6.3 (D, 1, aromatic, J = 2 Hz), 7.2-7.4 (M, 5, aromatic), 8.0 (D, 1, vinyl, J = 2 Hz).

IR: (KBr) C = 0 1,563cm ^-1

Analyzes: Theoretic of C ₂₆ H ₃₀ O ₄ : C, 76.82; H, 7.44%

Found: C, 76.74; H, 7.48%

MS: (molecular ion) 406

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylbutoxy) -6H-dibenzo [b, d] pitan-9 (8H)- On;

Melting Point: 16 ℃

1.2, 1.3(d, 3, 메틸), 1.45(S, 6, 젬 디메틸), 1.65-2.2(M, 2, 메틸렌), 2.3-2.95(M, 4, 메틸렌, 벤질성 메틸렌), 4.1-4.6(M, 1, 메티닐), 5.9, 6.15(2d, 2, 방향족), 7.15(S, 6, 방향족, 하이드록실-D₂O 오 버레이), 7.95(6S, 1, 올레핀성 양성자).NMR:

1.2, 1.3 (d, 3, methyl), 1.45 (S, 6, gem dimethyl), 1.65-2.2 (M, 2, methylene), 2.3-2.95 (M, 4, methylene, benzyl methylene), 4.1-4.6 (M, 1, Methynyl), 5.9, 6.15 (2d, 2, aromatic), 7.15 (S, 6, aromatic, hydroxyl-D ₂ O overlay), 7.95 (6S, 1, olefinic proton).

MS: (molecular ion) 392

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3-cyclohexyl oxy-6H-dibenzo- [b, d] phytan-9 (8H) -one; Melting point. 259-254 ℃

IR (KBr) C = 0 1590 cm ⁻¹ ; OH 3,390cm ^-1

NMR: δ DMSO 1.05-3.0 (M, 15, C ₅ H ₁₀ -cyclohexyl, 6a-methynyl, 7-methylene, 8-α-methylene), 1.45 (S, 6, gem dimethyl), 4.0-4.4 (M , 1, methynyl), 5.8-6.1 (2d, 2, aromatic), 7.1-7.25 (d, 1, olefinic proton), 7.3 (S, 1, hydroxyl-D ₂ O overlay)

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibenzo [b, d] pyran-9 (8H)- Warm, light yellow solid;

Melting point: 203 ° -206 ° C.

MS: (molecular ion) 392

Analyzes: Theoretic of C ₂₅ H ₂₈ 0 ₄ : C, 76.50; H, 7.19%

Found: C, 76.33; H, 7.12%

Example 9

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one

dl-6aβ, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (2-heptyl-oxy) -6H-dibenzo [b, d] pyran-9 (8H) -one (1.2 g , 3.3 mM) in tetrahydrofuran (9 ml) was added dropwise to a lithium (25 mg) solution in ammonia solution (45 ml) rapidly stirred at -78 ° C.

Add 75 mg of lithium until you see blue. After further stirring for 15 minutes, solid ammonium chloride is added until it is blue. Excess ammonia is evaporated and the residue is diluted with water (45 ml) and acidified with 10% hydrochloric acid. The aqueous solution was extracted with dichloromethane (3 × 50 ml) and the dichloromethane extract was dried over sodium sulfate and evaporated to give 1.3 g of impure semisolid which was purified on silica gel column chromatography to yield product 0.614 (50.9%) which was then followed by chloroform / Recrystallize from hexane.

Melting Point: 155-158 ℃

NMR (CDCl ₃ ) δ-8.2 (one proton singlet, phenolic OH), 5.8-6.3 (two-pronged multifret, aromatic), 3.9-4.6 (two-proton multifret, methine ether and C-10 horizontal ), 0.3-3.2 (26 proton multifret, residual protons).

IR (KBr) C = 0 1,737 cm ^-1

MS (m / e) 360 (M < + >), 261 (M-99).

Analyzes: Theoretic of C ₂₂ H ₃₂ 0 ₄ : C, 73.30; H, 8.95%

Found: C, 73.05; H, 8.82%

And corresponding cis-isomers:

dl-60aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one , Melting point 141 ° -146 ° C. (From ether / hexane)

IR: (KBr) C = 0 1718 cm ^-1

MS (m / e) 360 (M +), 261 (M-99)

In a similar manner, the following compounds are prepared from the product of Example 8.

dl-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy-6H-dibenzo [b, d] pitane-9 ( 8H) -one, melting point 122 ° -125 ° C.

1.3(D, 3, α-메틸, J=7Hz), 1.1-3.0(M, 16, 잔류 양성자), 2.3-3.0(bd, T, 2, 벤질성 메틸렌), 4.1(bd, D, 1, C-10 수평방향, J =14Hz), 4.1-4.7(M, 1, 메틴), 5.95(D, 1, 방향족, J=2Hz), 6.1(D, 1, 방향족, J=2Hz), 7.2-7.4(M, 5, 방향족), 7.9(S, 1, 페놀성).NMR:

1.3 (D, 3, α-methyl, J = 7 Hz), 1.1-3.0 (M, 16, residual protons), 2.3-3.0 (bd, T, 2, benzyl methylene), 4.1 (bd, D, 1, C-10 horizontal, J = 14 Hz, 4.1-4.7 (M, 1, methine), 5.95 (D, 1, aromatic, J = 2 Hz), 6.1 (D, 1, aromatic, J = 2 Hz), 7.2- 7.4 (M, 5, aromatic), 7.9 (S, 1, phenolic).

IR: (KBr) C = 0 1709cm ^-1

Analyzes: Theoretic of C ₂₆ H ₃₂ 0 ₄ : C, 76.44; H, 7.90%

Found: C, 76.22; H, 7.79%

And corresponding cis-isomers;

dl-6aβ, 7, 10, 10aβ-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 (8H) -on, melting point 141 ° -142 ° C

IR: (KBr) C = 0 1,707cm ^-1

MS: (molecular ion) 408

Analyzes: Theoretic of C ₂₆ H ₃₂ 0 ₄ : C, 76.44; H, 7.90%

Found: C, 76.58; H, 7.92%

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropoxy) -6H-dibenzo [b, d] pyran-9 (8H) -one, melting point 160 ° C.

1.2, 1.3(d, 2,-메틸), 1.4(S, 6, 젬 디메틸), 1.65-2,9(M, 11, 잔류 양성자), 3.9 4.5(M, 2, 10aα-양성자, 메티닐), 5.9-6.1(2d, 2, 방향족), 7,2(S, 5, 방향족), 7.9(S, 1, 하이드록실-D₂O 오버래치).NMR:

1.2, 1.3 (d, 2, -methyl), 1.4 (S, 6, gem dimethyl), 1.65-2, 9 (M, 11, residual protons), 3.9 4.5 (M, 2, 10aα-proton, methynyl) , 5.9-6.1 (2d, 2, aromatic), 7,2 (S, 5, aromatic), 7.9 (S, 1, hydroxyl-D ₂ O overlatch).

MS: (molecular ion) 394

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo [b, d] pyran-9 (8H) -one, melting point 215 ° -218 ° C

IR (KBr): C = 0 169 5 cm ^-1 ; OH 3,225 cm ^-1

MS: (molecular ion) 344

1.0-3.2(M, 18, C₃H₁₀-싸이클로헥실, 6aβ, 7, 8, 10, 10aα-양성자), 1.5(S, 6, 젬 디메틸), 3.9-4.3(M, 1, 싸이클로헥실-메티닐), 5.9, 6.05(2d, 2, 방향족), 8.9(bs, 1, 하이드록실-D₂O 오버래이).NMR:

1.0-3.2 (M, 18, C ₃ H ₁₀ -cyclohexyl, 6aβ, 7, 8, 10, 10aα-proton), 1.5 (S, 6, gem dimethyl), 3.9-4.3 (M, 1, cyclohexyl- Methynyl), 5.9, 6.05 (2d, 2, aromatic), 8.9 (bs, 1, hydroxyl-D ₂ O overlay).

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibenzo [b, d] pyran- 9 (8H) -one;

Melting Point: 167 ° -170 ℃

MS: (molecular ion) 394

Analyzes: Theoretic of C ₂₅ H ₃₀ 0 ₄ : C, 76.11; H, 7.66%

Found: C, 75.93; H, 7.63%

7.87(S, 1, 페놀성 양성자), 7.42-6.67(M, 5, C₆H₅), 6.33(S, 2, 방향성 H₂+H₅), 4.42-1-1.00(M, 22, -CH₂-0- 에서 3.90에 중심을 둔 트리프렛을 함유한 비-방향족, CH₃에서 1.48에서 싱글렛), CH₃에서 1.27에 중심을 둔 더블렛, CH₃와 그외 메틸렌에서 1.13에서 싱글렛, 메틴 양성자).NMR:

7.87 (S, 1, phenolic proton), 7.42-6.67 (M, 5, C ₆ H ₅ ), 6.33 (S, 2, aromatic H ₂ + H ₅ ), 4.42-1-1.00 (M, 22,- CH ₂ containing a tree fret centered at 3.90 in the 0-non-aromatic, CH ₃ at 1.48 singlet), a double leg, centered on 1.27 in CH _3, CH ₃ and the other in the methylene singlet at 1.13 , Methine protons).

Example 10

dl-6aβ, 7, 8, 9, 10, 10-hexahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9β- Come

Dl-6aβ, 7, 10, 10-tetrahydro-1-hydroxy-6,6-dimethyl-3- (2- dissolved in sodium borohydride (275 mg) in ethanol (18 ml) with stirring at room temperature in the presence of nitrogen. Heptyloxy) -6-H-dibenzo [b, d] pyran 9 (8H) -one (0.60 g, 1.66 mH). The reaction solution is stirred for 30 minutes and poured into ice (35 ml), 10% hydrochloric acid (35 ml) and ether mixture. The ether layer is separated and the aqueous layer is extracted with more ether (2 × 100 ml). The combined ether extracts are dried over sodium sulfate and evaporated to give an oil. Crystallization from hexane gave 305 mg (50.3%) of product having a melting point of 102 ° -104 ° C.

-7.6-6.7(하나의 넓은 양성자 싱글렛, (하이드록실성), 6.1-5.8(두개의 넓은 양성자, 싱글렛, 방향족), 4.5-0.5(31 양성자 멀티프렛, 잔류 양성자).NMR:

-7.6-6.7 (one broad proton singlet, (hydroxyl), 6.1-5.8 (two broad protons, singlet, aromatic), 4.5-0.5 (31 proton multi frets, residual protons).

IR (KBr) OH3,390cm ^-1

Analyzes: C ₂₂ H ₃₄ 0 ₄ Theory: C, 72.89: H, 9.45%

Found: C, 72.52: H, 9.18%

In a similar manner, the following materials are obtained from suitable tetrahydro compounds:

dl-6aβ, 7, 8, 9,10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d Pyran-9β-ol, amorphous solid

IR: (KBr) OH 3390cm ^-1

MS: (molecular ion) 410

1.3(P,3,α-메틸),1.0-4.5(H, 24, 잔류양성자), 5.8-6.0(M,2, 방향족), 6.8-7.3(M, 5, 방향족).NMR:

1.3 (P, 3, α-methyl), 1.0-4.5 (H, 24, residual protons), 5.8-6.0 (M, 2, aromatic), 6.8-7.3 (M, 5, aromatic).

dl-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropoxy) -6H-dibenzo [b, d Pyran-9β-ol, amorphous solid.

24, residual dredger), 5.8-6.0 (M, 2, aromatic), 6.

MS: (molecular ion) 396

dl-6aβ, 7, 8, 9, 10, 10aα-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo [b, d] pyran-9β-ol; Melting Point 214 ° -216 ℃

IR (KBr) OH 3365 cm ^-1 ; 3,125 cm ^-1

MS: (molecular ion) 346

1.0-3.0(M, 23, C₅H₁₀-싸이클로헥실, 젬 디메틸, 7, 8, 9α, 10 양성자), 3.5-4.15(M, 2, 6aβ, 10aα 양성자), 4.35-4.7(M, 1, 싸이클로헥실-메티닐), 4.85-5.05[bd, 1, 히이드록실-D₂0 오버레이), 6.1-6.45(M, 2, 방향족), 9.7(S, 1, 하이드록실-D₂O 오버레이).NMR:

1.0-3.0 (M, 23, C ₅ H ₁₀ -cyclohexyl, gem dimethyl, 7, 8, 9α, 10 protons), 3.5-4.15 (M, 2, 6aβ, 10aα protons), 4.35-4.7 (M, 1 , Cyclohexyl-methynyl), 4.85-5.05 (bd, 1, hydroxyl-D ₂ 0 overlay), 6.1-6.45 (M, 2, aromatic), 9.7 (S, 1, hydroxyl-D ₂ O overlay ).

dl-6aβ, 7,8,9,10, aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibenzo [b, d Pyran-9β-ol;

Melting Point: 151 ° -152 ℃

R _f = 0.25 (silica gel, 9-ether: 1-hexane)

MS: (molecular ion) 396

Analyzes: Theoretic of C ₂₅ H ₃₂ 0 ₄ : C, 75.72; H, 8.14%

Found: C, 75.79; H, 8.39%

dl-6aβ, 7, 8, 9, 10, 10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxy propyl) -6H-dibenzo [b, d Pyran-9α ol; Oil,

R _f = 0.35 (silica gel, 9-ether: 1-hexane)

MS: (molecular ion) 396

Example 11

The following compounds are prepared from the appropriate (3,5-dihydroxy) phenyl compounds of formula 3,5- (HO) ₂ C ₆ H ₃ -ZW and of suitable acids of formula R ₄ R ₅ C = CH-COOH. Prepared according to the method of -5.

Example 12

The following compounds are obtained according to the methods of Examples 1-4 from the appropriate reactants of formulas K and Y and from the appropriate acids with the formula R ₄ R ₅ C = CH-COOH (R ₄ and R ₅ = H, CH ₃ or C). ₂ H ₅ ):

The keto compound is reduced with sodium borohydride according to the method of Example 5 to obtain the corresponding 9-hydroxy compound (two isomers are formed: β-form dominant).

In a similar manner, the sulfoxide and sulfone compounds of Examples 15 and 16 are reduced to the corresponding 9-hydroxy compounds.

Example 13

dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutoxy) -4-chromenone

Under nitrogen atmosphere a mixture of 5-phenyl-2-pentanol (16.4 g, 100 mM), triethylamine (28 ml, 200 mM) and anhydrous tetrahydrofuran (80 ml) is cooled in ice / water weight. Methane sulfonyl chloride (8.5 ml, 110 mM) dissolved in anhydrous tetrahydrofuran (20 ml) is added dropwise at such a rate that the temperature can be kept constant. The mixture is warmed to room temperature and filtered to remove triethylamine hydrochloride. The filter cake is washed with anhydrous tetrahydrofuran and the combined washes and filtrate are evaporated under reduced pressure to give an oily product. The oil is dissolved in chloroform (100 ml), the solution is washed with water (2 x 100 ml), followed by saturated brine (1 x 20 ml), and the solvent is evaporated to 5-phenyl-2-pentanol methylsilate. Is obtained in a yield of 21.7 g (89.7%) and used in the next procedure without further purification.

Under a nitrogen atmosphere, 2,2-dimethyl-5,7-dihydroxy-4-chromanone (2.08 g., 10 mM), potassium carbonate (2.76 g., 20 mM), N, N-dimethyl-hormamide (10 ml) And 5-phenyl-2-pentanol methylsilate (2.64 g., 11 mM) are heated to 80-82 ° C. for 1.75 h under oil weight. The mixture is cooled to room temperature and poured into ice / water (100 ml). The aqueous solution is extracted with ethyl acetate (2 × 25 ml) and the combined extracts are washed with water (3 × 25 ml) followed by saturated brine (1 × 25 ml). The extract is dried (MgSO ₄ ), bleached with charcoal and evaporated to give an oily product which is recrystallized by inoculation with pure product. Melting point 83 ° -84 ° C. Yield = quantitative.

In a similar manner, the following compounds are produced from suitable 2,2-R ₄ R ₅ -5,7-dihydroxy-4-chromanone and suitable alkanols. Necessary alkanol reactants not introduced in the literature in the past are prepared from suitable aldehydes or ketones according to the Wittig reaction of Preparation G.

Example 14

The product of Example 13 is converted to the compound having the structure according to the method of Examples 1-5.

Example 15

dl-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylsulfinyl propyl) -6-dibenzo [b, d] pyran- 9 (8H) -on

m-chloroperbenzoic acid and dl-6aβ, 7.10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylthiopropyl) -6H-dibenzo- [b, d] The same molar amount of pyran-9 (8H) -one is reacted for 1 hour at room temperature in a mixture of chloroform and acetic acid.

The organic layer is washed with water, dried (MgSO ₄ ) and evaporated to dryness.

In a similar manner the thio compound of Example 12 is oxidized to the corresponding sulfoxide having the structure

Example 16

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylsulfonyl propyl) -6H-dibenzo [b, d] pyran- 9 (8H) -on

The procedure of Example 15 is repeated except that 2 equivalents of m-chloroper benzoic acid is used as oxidant per mole of thioether reactant. In a similar manner, the thioether of Example 12 is converted to the corresponding sulfonyl derivative having the structure

Example 17

(-1-trans 3- (1-methyl-4-phenylbutyl) -6a, 7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1- β-ol

(+) P-Menta-2,8-diene-1-ol (4.9 g., 0.0322 mol) and 5- (1-methyl-4-phenylbutyl) -resorcinol dissolved in anhydrous methylene chloride (200 ml) Anhydrous magnesium sulfate (4 g., 0.332 mol) is added to a stirred solution of 8.2 g., 0.032 mol). The mixture is stirred under nitrogen atmosphere and cooled to 0 ° C. Freshly distilled boron trifluoride etherate (2 ml., 0.016 mol) is added dropwise over 5 minutes. The reaction mixture is stirred at 0 ° C. for 1.5 hours and anhydrous sodium bicarbonate (10 g., 0.119 mol) is added. Continue stirring until dark color fades. The reaction mixture was filtered and evaporated to give 11.7 g (93.6%) of dendritic product.

Mixture of optically active diastereomers, purified by column chromatography on magnesium silicates (using MC & B Manufacturing Chemists, 2909 Highland Avenue, Cincinnati, Ohio). Obtain 3.4 g (27%) of the product in the state.

1.1(S,3,C₁-메틸), 1.3, 1.45(2S,6, 젬 디메틸), 1.75(S,3,C₉-메틸), 0.7-3.0(M, 12, 잔류양성자), 3.0-3.6(M,1, C_10a-양성자), 5.05(S,1, 하이드록실, D₂O오버레이), 6.1(S,1,C₄-양성자, 방향족), 6.4(M,2,C₂-양성자, 방향족, C₁₀-양성자,), 7.1-7.5(M,5, 방향족 양성자).NMR

1.1 (S, 3, C ₁ -methyl), 1.3, 1.45 (2S, 6, gem dimethyl), 1.75 (S, 3, C ₉ -methyl), 0.7-3.0 (M, 12, residual protons), 3.0- 3.6 (M, 1, C _10a -proton), 5.05 (S, 1, hydroxyl, D ₂ Ooverlay), 6.1 (S, 1, C ₄ -proton, aromatic), 6.4 (M, 2, C _2- Proton, aromatic, C ₁₀ -proton,), 7.1-7.5 (M, 5, aromatic protons).

MS: (molecular ion) 390

This is optically active 6aβ, 7,10,10aα-tetrahydro-1-hydroxy-3- (1-methyl-4-phenylbutyl) -6,6-dimethyl-6, according to Wildes' method. Conversion to H-dibenzo [b, d] pyran-9 (8H) -one diastereomer.

(C =1.OCHCl₃)= -100.8°

(C = 1.OCHCl ₃ ) = -100.8 °

Example 18

dl-6aβ, 7, 10, 10aα-tetrahydro-1- (4-morpholinebutyryloxy) -6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b , d] pyran-9 (8H) -one hydrochloride

Dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- dissolved in 4-morpholinobutyl hydrochloride (0.268 g., 1.28 mM) in anhydrous methylene chloride (25 ml) It is added to a stirred solution of (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one (0.25 g., 1.28 mM).

The mixture is stirred at room temperature under nitrogen atmosphere. 0.1M solution of dicyclohexyl carbodiimide dissolved in methylene chloride (12.8 ml., 1.28 mM) is added dropwise and the mixture is stirred for 24 hours. It is filtered and evaporated to afford the title product, which is purified by column chromatography on silica gel.

Example 19

Example 4,9 and Example 11, 12 and 14 prepared in a suitable way to the previous stage product material dl-6aβ, 7,10,10aα- tetrahydro _{-6,6-R 4 R 5 -3- (} ZW) Example 18 is repeated, except that -6H-dibenzo [b, d] pyran-9 (8H)-warms are used; Esters having the following structure are prepared using a suitable alkanoic acid or an acid of the structure HOOC- (CH ₂ ) _p -NR ₂ R ₃ .HCl.

Basic esters are obtained with their hydrochlorides. With attention, neutralize with sodium hydroxide to give free ester.

Example 20

dl-6aβ, 7,8,9,10,10aα-hexahydro-1- (4-morpholino butyryloxy) -6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H- Dibenzo [b, d] pyran-9β-ol hydrochloride

The title product of Example 5 is esterified according to the method of Example 18 to prepare such ester salts.

In a similar manner, the residual products of Examples 5 and 10-12 and 14 are converted to esters having the structure

Wherein R ₄ , R ₅ , Z and W are the same as in the above embodiment and R ₁ is as shown in the following table.

Example 21

dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one

A) dl-ethyl 5-hydroxy-4-methyl-7- (1-methyl-4-phenylbutyl) coumarin-3-propionate

2- (3,5-dihydroxyphenyl) -5-phenylpentane (33 g ,, 0.13 M), (Manufacturing C) Diethyl α-acetoglutarate (32.2 g., 0.14 M) and oxyphosphate oxychloride ( 20 g., 0.13 M) is stirred at room temperature while protecting from atmospheric moisture. After 10 days, the mixture is dissolved in chloroform, washed three times with water, dried (Na ₂ SO ₄ ) and evaporated. The residue was passed through silica gel chromatography (eluant-9benzene: 1 ether) to afford 22 g of the desired ester with a melting point of 58-70 ° C. (from hexanes). Recrystallization from ethyl acetate / hexanes once more gives analytical sample: melting point 78 ° -85 ° C.

Analyzes: Theoretic of C ₂₆ H ₃₀ O ₅ : C, 73.91; H, 7.16%

Found: C, 73.82; H, 7.13%

MS: (molecular ion) 422.

B) dl-7, 10-dihydro-1-hydroxy-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] -pyran-6, 9 (8H) -dione

To the sodium hydride powder obtained by washing 10.Og (0.21 mol) of 50% sodium hydride dissolved in mineral oil dispersion with anhydrous hexane, 20.6 g (0,049 mol) of the ester of Part A of the example was added and the two powders were thoroughly mixed. The reaction flask is cooled to 15 ° -17 ° C. and dimethyl sulfoxide (200 ml) is added directly into the reaction flask.

After stirring at 15 ° -17 ° C. during the addition, the reaction solution is left overnight in the refrigerator.

After warming to room temperature, the reaction mixture is poured into a mixture of 600 ml of rapidly stirred ice and water and 40 ml of concentrated hydrochloric acid. If necessary to cool the mixture, add more ice.

During the addition, the resulting slurry is stirred and the supernatant is poured off gently. The residual gum is heated with an excess of concentrated sodium bicarbonate solution in a steam bath and the final solid is filtered while continuing to warm. The filter cake is washed with bicarbonate and water and recrystallized from ethyl acetate / hexanes to give 4.5 g of cyclized product. Melting point 163 ° -164 ° C, further purification by recrystallization from methanol: Melting point: 166 ° -167 ° C.

Analyzes: Theoretic of C ₂₄ H ₂₄ 0 ₄ : C, 76.57; H, 6.43%

Found: C, 76.50; H, 6.56

MS: (molecular ion) 376

c) dl-7,8,9,10-tetrahydro-1-hydroxy-3- (1-methyl-4-phenylbutyl) spiro- [6H-dibenzo [b, d] pyran-9,2 ' -[1 ', 3'] dioxolane] -6-one

A solution obtained by dissolving 0.031 mol of the cyclization product of Part B of this example, containing ethylene glycol (10 ml) and P-toluene sulfonic acid (10 mg), in benzene was heated overnight under a Dean-stark trap. The solution is cooled, poured into water containing excess sodium bicarbonate, the organic layer is separated, dried (Na ₂ SO ₄ ) and evaporated to produce the desired ketal.

D) dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-pentylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -On

0.175 mole of the above-mentioned ketal was dissolved in ether (1.5 L) over 90 minutes, and magnesium (44.6 g., 1.84 g-atom) and methyl iodide (110 ml., 251 g., 1.77 mole) were added to ether (1.8). Is dissolved in a liter) and added to a Grignard reagent prepared. After refluxing for 2 days, the reaction was carefully reacted with 1N hydrochloric acid (200 ml) followed by 6N hydrochloric acid (74O ml).

The mixture is stirred vigorously for 1 hour and the ether layer is washed once with water and with 5% sodium bicarbonate. The ether layer is dried (Na ₂ SO ₄ ) and concentrated to produce the desired unsaturated ketone. Purify by recrystallization and / or column chromatography as desired (see Examples 3 and 8).

In a similar manner, the remaining 1- (ZW-substituted) -3,5-dihydroxy-benzenes of formula C and formulas D, E, K, M, Q, R and T have the corresponding dl-6a, 7- Dihydro-1-hydroxy-6,6-dimethyl-3- (ZW) -6H-dibenzo [b, d] pyran-9 (8H) -one is converted.

Example 22

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one, ethylene ketal

dl-6aβ, 7, 10, 10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyloxy) -6H-dibenzo [b, d] pyran-9 A liquid of crystals of (8H) -one (60 mg, 0.145 mM), ethylene glycol (0.5 ml), benzene (10 ml) and P-toluene sulfonic acid is heated under reflux for 3 hours.

The reaction mixture is cooled and concentrated.

The concentrate is shaken in chloroform and the chloroform phase is first washed with sodium bicarbonate and then with water. It is dried (MgSO ₄ ) and concentrated to give a light brown oily ketal (63 mg).

The method is repeated to obtain the corresponding ketal except that propylene glycol, trimethylene glycol and tetramethylene glycol are used instead of ethylene glycol.

According to the method the ketone products of Examples 3,4,8,9,11,12,14-16,18,19 and 21 are converted to the corresponding ethylene, triethylene and tetramethylene ketals.

Example 23

dl-5-hydroxy-2,2-dimethyl-7- (2-heptyl mercapto) -4-chromenone

5-hydroxy-7-mercapto-2,2-dimethyl-4-chromanone (19.7 g, 87.1 mM) and potassium hydroxide (2.44 g., 43.5 mM) were added to N, N-dimethylformamide (58 ml). To the melted solution, 2-bromoheptane (15.77 g, 88.OmM) was added with stirring.

The mixture is heated at 100 ° C. for 4 days, cooled to room temperature and added to a mixture of sodium hydroxide solution (110 ml, 1N), water (45 ml) and chloroform (150 ml). The mixture is shaken, the layers are separated and the aqueous layer is extracted with more chloroform (150 ml). The combined chloroform layers are washed with 1N sodium hydroxide (2 x 100 ml), dried over sodium sulfate and concentrated to an oil. Unreacted 2-bromo heptane is removed by distillation and the residue is purified by silica gel chromatography to give the title product.

The following compounds are prepared from suitable reactants of the formula Br- (alk ₂ ) _n -W from suitable 5-hydroxy-7-mercapto-2,2-R ₄ R ₅ -substituted-4-chromanones. .

Example 24

dl-6aβ, 7,10,10aα-tetrahydro-1-acetoxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 (8H) -on

Pyridine (15 ml), acetic anhydride (15 ml) and dl-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H -Dibenzo [b, d] -pyran-9 (8H) -one (4.06 g) is mixed at 0 ° C and the mixture is stirred at 0 ° C for 30 minutes. The reaction mixture is poured into ice / water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2 x 100 ml) and the combined extracts are washed with brine.

The extract is dried (MgSO ₄ ) and evaporated to give a colorless oil which crystallizes from ether-pentane. Yield = 1.69 g; Melting point 95 ° -96 ℃

Analyzes: Theoretic of C ₂₈ H ₃₄ 0 ₅ : C, 74.64; H, 7.61

Found: C, 74.55; H 7.59

The mother liquor is evaporated to give a secondary crystalline fraction which is immersed in hexane. Yield = 1.74 g; Melting point 94 ° -96 ℃

As reactants and a suitable embodiment 4,9,11,12 6,7,10,10aα- dl-tetrahydro -6,6-R of _{14 4, R 5 -3- (ZW} ) -6H- dibenzo [ b, d] pyranyloxy, butyryloxy and varyloxy esters thereof are obtained according to the present method except using pyran-9 (8H) -one and a suitable anhydrous alkanoic acid.

The 9-keto group of the resulting monoester is reduced according to the method of Example 5 to obtain the corresponding 9-hydroxy derivative. A mixture of 9α and 9β-isomers is prepared.

Example 25

dl-6aβ, 7,8, 9, 10, 10aα-hexahydro-1,9-diacetoxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b , d] pyran

Dl-6aβ, 7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-di dissolved in pyridine (20 ml) Benzo [b, d] pyran-9β-ol (2.Og) is treated with acetic anhydride (20 ml) at 10 ° C. and the mixture is stirred for 18 hours in the presence of nitrogen.

The reaction mixture is carried out according to the method of Example 24.

In a similar manner, the 1,9-dihydroxy compounds of Examples 5,10-12,14 and 15 are converted to their diacetoxy, dipropionyloxy, dibutylyloxy and divaleryloxy esters.

Example 26

dl-6aβ, 7, 10, 10aα-tetrahydro-1- (4-N-piperidyl-butyloxy) -6,6-dimethyl-3- [2- (5-phenyl) pentyloxy] -6H Dibenzo [b, d] pyran-9 (8H) one hydrochloride

Dl-6aβ, 7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3- [2- (5-phenyl) pentyloxy] -6H-di dissolved in anhydrous dichloromethane (3.5 ml) Benzo [b, d] pyran-9 (8H) -one (1.26 g, 3.08 m water), 4-N-piperidylbutyl hydrochloride (0.639, 3.08 m water) and dicyclohexyl carbodiimide (0.698 g , 3.39 mmol) is stirred at 20 ° C. for 18 hours.

The reaction is cooled to 0 ° C., stirred for 30 minutes and then filtered. The filtrate was evaporated to give an oil which was washed with ether (3x) and evaporated to yield 1.78 g (97%) of dl-6aβ, 7,10,10aα-tetrahydro-1- (4-N- as a white foamy solid. Piperidyl-butyloxy) -6,6-dimethyl-3- [2- (5-phenyl) pentyl-oxy] -6H-dibenzo [b, d] pyran-9 (8H) -one hydrochloride is obtained.

2,667, 2,564, C=0 1,779 및 1,730cm^-1 TR: (KBr) NH

2,667, 2,564, C = 0 1,779 and 1730 cm ^-1

-HCl), 407, 262, 247, 154, 98 및 91MS: (molecular ion) (M

-HCl), 407, 262, 247, 154, 98 and 91

[Preparation A]

2-bromo-5-phenylpentane

Bromine (9.Og) dissolved in methylene chloride (10 ml) was added to phosphorus tribromide (15.Og) dissolved in methylene chloride (15 ml) at 0 ° C, and dissolved in methylene chloride at 0 ° C in phosphorus pentabromide. -Phenyl-2-pentanol (8.2 g) is added.

The mixture is stirred at 0 ° C. for 2.5 hours and warmed up to room temperature. Water (50 ml) is added and the mixture is stirred for 1 hour before the methylene chloride layer is separated.

The extraction is repeated and the combined extracts are washed with water, saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The dried extract is concentrated to give 12.4 g of the title product as light yellow oil.

1.6(D,3, 메틸, J=7Hz), 1.6-2.0(M,4, 에틸렌), 2.3-3.0(bd, T,2, 벤질성 메틸렌), 3.7-4.2(M,1, 메틴), 6.9-7.4(M,5, 방향족).NMR:

1.6 (D, 3, methyl, J = 7 Hz), 1.6-2.0 (M, 4, ethylene), 2.3-3.0 (bd, T, 2, benzyl methylene), 3.7-4.2 (M, 1, methine), 6.9-7.4 (M, 5, aromatic).

[Production B]

2- (3,5-dimethoxyphenyl) -5-phenylpentane

A solution of 1-bromopropylbenzene (51.7 g) dissolved in ether (234 ml) was added to a refluxed magnesium (7.32 g) mixture dissolved in ether (78 ml) over 2 hours. The reaction mixture is refluxed for at least 30 minutes, and a solution of 3,5-dimethoxy-acetophenone (50 g) dissolved in ether (78 ml) is added dropwise, followed by heating for 1.5 hours. Saturated ammonium chloride (234 ml) is added to stop the reaction, the ether layer is separated and the aqueous layer is extracted with ether (3 x 200 ml).

The combined ether extracts are dried over magnesium sulfate and concentrated in vacuo to give 81 g of oil.

40 g of oil are hydrogenated in a mixture containing ethanol (300 ml), concentrated hydrochloric acid (2 ml) and 5% palladium on 5% carbon. The catalyst is filtered off and ethanol is removed under vacuum. The residue is distilled under vacuum to yield 28 g of 2- (3,5-dimethoxyphenyl) -5-phenylpentane (b.p. 0.125 mm., 154 ° -159 ° C.).

1.25(d,3,α-CH₃), 1.3-2.1(M,4, 에틸렌), 2.2-2.9(M,3, 벤질성 메틸렌, 메티닐), 5.43(S,6, 메톡실), 6.2-6.7(M,3, 방향족), 7.2(S,5, 방향족).NMR:

1.25 (d, 3, α-CH ₃ ), 1.3-2.1 (M, 4, ethylene), 2.2-2.9 (M, 3, benzyl methylene, methynyl), 5.43 (S, 6, methoxyl), 6.2 -6.7 (M, 3, aromatic), 7.2 (S, 5, aromatic).

[Manufacturing C]

2- (3,5-dihydroxy phenyl) -5-phenylpentane

Under nitrogen, a mixture of 2- (3,5-dimethoxyphenyl) -5-phenylpentane (22 g) and pyridine hydrochloride (94 g) is heated to 190 ° C. for 2 hours with vigorous stirring.

The reaction mixture is cooled, dissolved in 6N hydrochloric acid (200 ml) and diluted with water to 600 ml.

The aqueous solution is extracted with ethylene acetate (4 x 100 ml) and the ethyl acetate extract is dried over sodium sulfate and concentrated in vacuo to yield 24 g of impure product. The product is purified by silica gel chromatography to give 19.2 g of 2- (3,5-dihydroxyphenyl) -5-phenylpentane in oil state.

1.1(d,3,α-메틸), 1.35-1.65(M,4, 에틸렌), 2.2-2.8(M,3, 벤질성-메틸렌, 메티닐), 6.1-6.5(M,3, 방향족), 6.65(bd,S,2,하이드록실), 7-7.4(M,5, 방향족)NMR:

1.1 (d, 3, α-methyl), 1.35-1.65 (M, 4, ethylene), 2.2-2.8 (M, 3, benzyl-methylene, methynyl), 6.1-6.5 (M, 3, aromatic), 6.65 (bd, S, 2, hydroxyl), 7-7.4 (M, 5, aromatic)

The following compounds were prepared using suitable 1-bromoalkylbenzene instead of 1-bromopropylbenzyl according to Preparation Methods B and C;

1.1(D,3,α-메틸, J-7cps), 1.0-1.9[M,6,

CH₂(CH₂)₃-CH(CH₃)-Ar, 2.2-2.8(M,3, 벤질성메틸렌, 메티닐), 6.0(bd,S,2, 페놀성 OH), 6.2-6.4(M,3, 방향족), 7.1-7.4(M,5, 방향족).2- (3,5- (Dihydroxyphenyl) -6-phenylhexane-NMR:

1.1 (D, 3, α-methyl, J-7cps), 1.0-1.9 [M, 6,

CH ₂ (CH ₂ ) ₃ -CH (CH ₃ ) -Ar, 2.2-2.8 (M, 3, benzylmethylene, methynyl), 6.0 (bd, S, 2, phenolic OH), 6.2-6.4 (M , 3, aromatic), 7.1-7.4 (M, 5, aromatic).

1- (3,5-dihydroxyphenyl) -2-phenylethane-melting point: 76-77 ° C

1.1, 1.25(d,2, 메틸), 1.45-2.0(M, 2, 메틸렌), 2.15-2.7(M,3, 벤질성-메틸렌, 메티닐), 6.3(S,3, 방향족), 6.85(S,2, 하이드록실-D₂O오버레이), 7.1(S,5, 방향족).2- (3,5-Dihydroxyphenyl-4-phenylbutane (oil) -NMR:

1.1, 1.25 (d, 2, methyl), 1.45-2.0 (M, 2, methylene), 2.15-2.7 (M, 3, benzyl-methylene, methynyl), 6.3 (S, 3, aromatic), 6.85 ( S, 2, hydroxyl-D ₂ Ooverlay), 7.1 (S, 5, aromatic).

In a similar manner the following compounds are prepared from suitable alcohols and 3,5-dimethoxybenzaldehyde or 3,5-dimethoxyacetophenone according to the methods of Preparations A, B and C.

[Production D]

1- (3,5-dihydroxyphenyl) -2-methyl-4-phenylbutane

While stirring n-butyllithium (29ml, 2.2M) liquid, it was added dropwise to 3,5-dimethoxybenzyl triphenyl phosphonium bromide (31.5g) dissolved in tetrahydrofuran (200ml), and the resulting dark red liquid was added to 30 Stir for minutes. Benzene acetone (9.4 g) is added dropwise and the reaction mixture is stirred for 12 hours. Acetic acid is added to adjust the pH to 7 and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract is evaporated to give an oily impure 1- (3,5-dimethoxyphenyl) -2-methyl-4-phenyl-1-butene.

This was purified by chromatography on silica gel (400 g) using benzene as the eluent. Yield: 10 g (oil)

1.95(S,3), 2.3-3.1(M,4), 3.8(S,6), 6.15-6.6(M,3), 7.1-7.5δ(M,6)NMR:

1.95 (S, 3), 2.3-3.1 (M, 4), 3.8 (S, 6), 6.15-6.6 (M, 3), 7.1-7.5δ (M, 6)

The resulting 1- (3,5-dimethoxyphenyl) -2-methyl-4-phenyl-1-butene (9.4 g) was dissolved in ethanol (250 ml) and palladium on carbon (1 g, 10%) and concentrated hydrochloric acid ( 1 ml) and then contact reduction at 45 p.si.

Yield: 9.4 g of oily 1- (3,5-dimethoxyphenyl) -2-methyl-4-phenylbutane

0.9(d,3), 1.35-1.95(M,3), 2.2-2.9(M,4), 3.75(S,6), 6.35(S,3), 7.25δ(S,5).NMR:

0.9 (d, 3), 1.35-1.95 (M, 3), 2.2-2.9 (M, 4), 3.75 (S, 6), 6.35 (S, 3), 7.25δ (S, 5).

This is demethylated according to the method of Preparation C to give 1- (3,5-dihydroxyphenyl) -2-methyl-4-phenylbutane.

A mixture of 3,5-dimethoxy benzyl bromide (12 g) and triphenylphosphine (14.2 g) dissolved in acetonitrile (200 ml) was refluxed for 1 hour to prepare 3,5-dimethoxybenzyl triphenylphosphonium bromide. .

The reaction mixture is cooled and filtered to afford crystalline product, washed with ether and dried (20 g).

Melting Point 269 ° -270 ℃

[Production E]

2-methyl-2- (3,5-dihydroxyphenyl) -5-phenylpentane

A 2-methyl-2- (3,5-dimethoxyphenyl) propionitrile (2.75 g) solution dissolved in anhydrous ether (20 ml) was diluted with 2-phenylbromoethane (5.5 g), magnesium (0.8 g), and anhydrous ether. To Grignard reagent solution prepared from (60 ml).

The ether was distilled off and replaced with anhydrous ether (50 ml) and the mixture was refluxed for 48 hours.

This is carefully treated with dilute sulfuric acid to decompose and heated in a steam bath for 1 hour. The mixture is extracted with ether and the extract is dried (MgSO ₄ ) and concentrated to give an oil. The oil is distilled off in vacuo to yield 2-methyl-2- (3,5-dimethoxyphenyl) -5-phenyl-3-pentanone. Boiling Point 168 ℃ / 0.2mm (Yield: 2.32g., 60%)

The resulting pentanone (58 g) is dissolved in ethanol (400 ml) and treated with sodium borohydride (10 g) at room temperature. The reaction mixture is stirred for 12 hours, cooled and neutralized with 6N hydrochloric acid.

Ethanol is removed under reduced pressure and the residue is extracted with ether.

The extract is dried (MgSO ₄ ) and concentrated to give 2-methyl-2- (3,5-dimethoxyphenyl) -5-phenyl-3-pentanol in oil form (52 g, 88% yield).

Pentanol (16 g) is absorbed into ether (100 ml) and reacted with powdered potassium (2.5 g) in ether (200 ml). Carbon disulfide (potassium and animal) is added and the mixture is stirred for 30 minutes.

Methyl iodide (9.Og) is added and the reaction mixture is stirred for 6 hours. The resulting dispersion is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in ethanol (150 ml) and Ranickel (25 g) is added and the mixture is refluxed for 18 hours.

The alcohol is evaporated and the residue is distilled to give 2-methyl-2- (3,5-dimethoxyphenyl) -5-phenyl-3-pentene.

The pentene derivative is subjected to catalytic reduction according to Preparation D and the resulting 2-methyl-2- (3,5-dimethoxy-phenyl) -5-phenyl-3-pentane is demethylated according to Preparation C to give a product. .

[Manufacturing F]

3,5-dibenzyloxyacetophenone

Over 1.5 hours, methyl lithium (531 ml of 2 molar solution, 1.06 M) was dissolved in 3,5-dibenzyl in ether (250 ml) -tetrahydrofutane (1,400 ml), maintained at 15 ° -25 ° C. under nitrogen atmosphere. It is added to oxybenzoic acid (175 g., 0.532 M) liquid with rapid stirring. After stirring at 10-15 ° C. for 0.75 hours, water (600 ml) was slowly added while maintaining the reaction temperature below 20 ° C. The aqueous layer is separated and extracted with ether (3 x 250 ml). The combined organic layers are washed with saturated sodium chloride solution (4 x 300 ml), dried over sodium sulphate and concentrated in vacuo to give an oil which is slowly crystallized from isopropyl ether.

The impure product is recrystallized from ether-hexane to yield 104.7 g (59%) of product. Melting point 59 ° -61 ° C.

[Recipe G]

Ethyl 3- (3,5-dibenzyloxyphenyl) crotonate (Wittich reaction)

A mixture of 3,5-dibenzyloxyacetophenone (43.2 g., 0.13 mole) and carethoxymethylenetriphenylphosphorane (90.5 g., 0.26 mole) is heated at 170 ° C. under nitrogen atmosphere for 4 hours. The clear melt is cooled to room temperature, triturated with ether and filtered to remove triphenylphosphine oxide precipitation. The filtrate was concentrated in vacuo to give an oily residue, which was then chromatographed on silica gel (1,500 g) and the benzene: hexane solution was initially 40:60, gradually increasing the concentration of benzene to 100% benzene at the end. Elute. The appropriate fractions are concentrated to give an oily residue which is recrystallized from hexanes.

Yield: 40.2 g (77%); Melting point 73 ° -75 ° C.

Assay: C ₂₆ H ₂₆ 0 ₄ Theory: C, 77.58; H, 6.51%

Found: C, 77.72; H, 6.60%

In a similar manner, ethyl 3- (3,5-dimethoxyphenyl) crotonate is prepared from 3,5-dimethoxyacetophenone (51.7 g) and carbethoxymethylene triphenylphosphoran (200 g). Yield = 61.8 g, 86%, boiling point 146 ° -162 ° C. at 0.3 mm.

[Preparation H]

3- (3,5-dibenzyloxyphenyl) -1-butanol

A mixture of ethyl 3- (3,5-dibenzyloxyphenyl) chromate (24.1 g., 60 mM) and liquid dissolved in ether (250 ml) was mixed with lithium aluminum hydride (3.42 g., 90 mM) and ether (25O ml). Add to Aluminum chloride (0.18 g., 1.35 mM) is added and the mixture is refluxed for 12 hours and cooled. Water (3.4 ml), sodium hydroxide (3.4 ml of 6N) and (10 ml) are then added to the reaction mixture. The precipitated inorganic salts are filtered off and the filtrate is concentrated in vacuo to afford the desired oily alcohol (2.4 g) (98%).

R _f = 0.55 [silica gel: benzene (18): ethyl acetate (1)] MS (molecular ion) 362

Analyzes: Theoretic of C ₂₄ H ₂₆ 0 ₃ : C, 79.53; H, 7.23%

Found: C, 79.37; H, 7.11%

In a similar manner, ethyl 3- (3,5-dimethoxyphenyl) croronate (60.4 g) is reduced to 3- (3,5-dimethoxyphenyl) butanol (40.8 g., 90%).

[Preparation I]

3- (3,5-dibenzyloxyphenyl) butyl tosylate

Tosyl chloride (11.1 g., 58.1 mM) was added to 3- (3,5-dibenzyloxyphenyl) -1-butanol (2.7 g., 57) solution dissolved in pyridine (90 ml) at -45 ° C. . The reaction mixture is left at -35 ° C. for 18 hours, diluted with cold 2N hydrochloric acid (1,500 ml) and extracted with ether (5 × 250 ml). The combined extracts are washed with saturated sodium chloride solution (4 × 250 ml) and dried (Na ₂ SO ₄ ). The dried extract is concentrated to give an oily product.

It is crystallized by treatment with ether-hexane.

Yield 24.63 g (84%)

Analysis: C ₃₁ H ₃₂ 0 ₅ S Theoretical: C, 72.06; H, 6.24%

Found: C, 72.05: H, 6.29%

[Preparation J]

3- (3,5-dibenzyloxyphenyl) -1-phenoxybutane

A phenol (4.56 g., 48.6 mM) solution dissolved in dimethylformamide (40 ml) was dissolved in dimethyl formamide (70 ml) at 60 ° C. under nitrogen atmosphere, and sodium hydride (2.32 g. mM) is added to the dispersion. The reaction mixture was stirred at 60 ° -70 ° C. for 1 hour, and then 3- (3,5-dibenzyloxyphenyl) butyltosylate (23.93 g, 46.3 mM) solution dissolved in dimethylformamide (80 ml) was added. .

The reaction mixture is stirred at 80 ° C. for 30 minutes, cooled to room temperature, diluted with cold water (2,500 ml) and extracted with ether (4 × 400 ml). The combined extracts are washed with cold 2N hydrochloric acid (2 × 30 ml) and then with saturated sodium chloride solution (3 × 300 ml) and dried (Na ₂ SO ₄ ).

The solvent is removed under reduced pressure to give an oily product. The oily residue is dissolved in benzene and filtered through silica gel (100 g). The filtrate is concentrated under reduced pressure to give an oily product.

Yield: 14.86 g (73%).

R _f = 0.7 (silica gel, benzene)

MS: (molecular ion) 438

Analyzes: Theoretical value of C ₃₀ H ₃₀ O ₃ : C, 82.16; H, 6.89%

Found: C, 82.07; H, 6.84%

The method of GJ is followed except that 3,5-dibenzyloxy derivatives of benzylaldehyde, acetophenone or propiophenone and the appropriate alcohol, phenol, thiophenol, hydroxypyridine or hydroxypiperidine are used as reactants. The following compound is obtained repeatedly.

[Recipe K]

3- (3,5-dihydroxyphenyl) -1-phenoxybutane

Dissolve 3- (3,5-dibenzyloxyphenyl) -1-phenoxybutane (14.7 g., 133.5 mM) solution in a mixture of ethyl acetate (110 ml), ethanol (110 ml) and concentrated hydrochloric acid (0.7 ml). % Reduced for 2 hours under 60 p.si hydrogen in the presence of palladium on carbon (1.5 g). This is filtered to remove the catalyst and the filtrate is concentrated to give an oil. The oil is purified by chromatography on silica gel (100 g), eluting with benzene-ethyl acetate containing 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product. 7.8 g (80%), oil

R _f = 0.25 silica gel, benzene (4), methanol (1)

MS: (molecular ion) 258

Analyzes: Theoretical of C ₁₆ H ₁₈ O ₃ : C, 74.39; H, 7.02%

Found: C, 74.13; H, 7.00%

In a similar manner, the residual ether (X = 0) of Preparation J is debenzylated to give the corresponding 3,5-dihydroxy derivative.

The thioethers are debenzylated by treatment with trifluoroacetic acid.

This method consists of stirring the dibenzyl ether (X = S) solution dissolved in trifluoroacetic acid at room temperature for 2 hours. The reaction mixture is evaporated to dryness and the residue is taken up in ether.

The ether solution is washed with water, dried (MgSO ₄ ) and evaporated to give the debenzylated compound.

[Manufacturing L]

1-bromo-3- (3,5-dimethoxyphenyl) butane

3- (3,5-dimethoxyphenyl) -1-butanol dissolved in ether (20 ml) in a solution of phosphorus tribromide (5.7 ml., 0.06 mol) dissolved in ether (30 ml) 30.Og., 0.143 mol)) and the reaction mixture is stirred at -5 [deg.]-10 [deg.] C. for 2.5 hours. It is allowed to warm to room temperature and then stirred for 30 minutes of addition. The mixture is poured onto ice (200 g) and the resulting mixture is extracted with ether (3 x 50 ml). The combined extracts are washed with 5% sodium hydroxide solution (3 × 50 ml), saturated sodium chloride solution (1 × 50 ml) and dried (Na ₂ SO ₄ ).

The ether was removed and the residue was vacuum distilled to afford the title product: 25 g (55% yield: 0.4 mm boiling point 125 ° -132 ° C.).

The following compounds were prepared from 3,5-dimethoxybenzaldehyde, 3,5-dimethoxyacetophenone and 3,5-dimethoxypropiophenone and suitable carbuethoxyalkylidene triphenylphosphorane G, H and L It is prepared by the method.

[Manufacturing M]

4- (3,5-dihydroxyphenyl) -1- (4-pyridyl) pentane

4-pyridinecar, a mixture of 3- (3,5-dimethoxyphenyl) butyl triphenylphosphonium bromide (19.Og., 35.4 mmol) dissolved in dimethyl sulfoxide (50 ml) in tetrahydrofuran (40 ml) To voxaldehyde (3.79 g., 35.4 mmol). The resulting mixture was added dropwise to the slurry with 50% sodium hydride (1.87 g, 39 mmol) dissolved in tetrahydrofuran (20 ml) at 0-5 ° C. under nitrogen atmosphere. After addition is complete the mixture is stirred at 0 ° -5 ° C. for 1 h and concentrated under reduced pressure.

The concentrate is diluted with water (200 ml) and acidified with 6N-HCl. The acidic aqueous solution is extracted with benzene (4 x 50 ml). This is made basic and extracted with ethyl acetate (3 x 50 ml). The combined extracts are evaporated and dried (MgSO ₄ ) to give oily 4- (3,5-dimethoxyphenyl) -1- (4-pyridyl) -1-pentene (7.1 g., 70%).

The resulting pentene derivative was subjected to catalytic reduction according to the method of Preparation D to obtain 4- (3,5-dimethoxy-phenyl) -1- (4-pyridyl) pentane in quantitative yield: Melting point 131 ° -133 ° C

The mixture of the compound (7.15 g, 25 mmol) and pyridine hydrochloride (35 g) was heated at 210 ° C. under nitrogen atmosphere for 8 hours to demethylate the pentane derivative. The hot mixture is poured into water (40 ml) and the resulting solution is basified with 6N-sodium hydroxide. Moles and pyridine are removed by distillation in vacuo. Ethanol (50 ml) is added to the residue and the precipitated inorganic salts are filtered off. The filtrate was concentrated in vacuo and the residue was purified by silica gel using 5% ethanol / benzene (4 L), 10% ethanol / benzene (1 L), 13% ethanol / benzene (1 L) and 16% ethanol / benzene (5 L) as eluent. Chromatography on (150 g). The appropriate fraction of the eluate is concentrated to separate the product as a glassy solid. Yield = 5.Og (78%)

A mixture of 1-bromo-3- (3,5-dimethoxyphenyl) butane (21.5 g., 78.5 mM) and triphenylphosphine (20.5 g, 78.5 mmol) dissolved in xylene (60 ml) was refluxed for 18 hours. To prepare 3- (3,5-dimethoxyphenyl) butyltriphenylphosphonium bromide.

The reaction mixture is cooled to room temperature and filtered. The filter cake is washed with ether and dried in a vacuum desiccator to yield 36.4 g (86%) of product. Melting point 190 ° -200 ° C.

The method is repeated except that the appropriate bromo- (3,5-dimethoxyphenyl) alkane and the appropriate aldehyde or ketone are used to afford the following compounds.

Z W

(CH ₂ ) ₃ 2-pyridyl

(CH ₂ ) ₃ 3-pyridyl

(CH ₂ ) ₃ 4-pyridyl

(CH ₂ ) ₃ 2-piperidyl

(CH ₂ ) ₃ 4-piperidyl

(CH ₂ ) ₄ 2-pyridyl

(CH ₂ ) ₄ 4-pyridyl

(CH ₂ ) ₄ 3-piperidyl

(CH ₂ ) ₄ 4-piperidyl

CH ₂ CH (CH ₃ ) CH ₂ 2-pyridyl

CH ₂ CH (CH ₃ ) CH ₂ 4-piperidyl

CH (CH ₃ ) CH (CH ₃ ) CH ₂ 3-pyridyl

CH (CH ₃ ) CH (CH ₃ ) CH ₂ 4-pyridyl

CH (CH ₃ ) CH (CH ₃ ) CH ₂ 3-piperidyl

CH (CH ₃ ) (CH ₂ ) ₂ 2-pyridyl

CH (CH ₃ ) (CH ₂ ) ₂ 3-pyridyl

CH (CH ₃ ) (CH ₂ ) ₂ 4-piperidyl

CH (CH ₃ ) (CH ₂ ) ₃ 3-pyridyl

CH (CH ₃ ) (CH ₂ ) ₃ 4-piperidyl

CH (CH ₃ ) CH (C ₂ H ₅ ) CH ₂ 4-pyridyl

CH (C ₂ H ₅ ) (CH ₂ ) ₂ 4-pyridyl

CH (C ₂ H ₅ ) (CH ₂ ) ₂ 2-piperidyl

CH (C ₂ H ₅ ) (CH ₂ ) ₂ 4-piperidyl

CH ₂ CH (C ₂ H ₅ ) CH ₂ 3-pyridyl

CH (C ₂ H ₅ ) (CH ₂ ) ₃ 3-pyridyl

CH (C ₂ H ₅ ) (CH ₂ ) ₃ 4-piperidyl

CH (C ₂ H ₅ ) CH (CH ₃ ) CH ₂ 2-pyridyl

CH (C ₂ H ₅ ) CH (C ₂ H ₅ ) CH ₂ 4-pyridyl

CH (C ₂ H ₅ ) CH (C ₂ H ₅ ) CH ₂ 2-piperidyl

(CH ₂ ) ₃ C ₆ H ₁₁

CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₁₁

(CH ₂ ) ₄ C ₃ H ₅

(CH ₂ ) ₂ C ₄ H ₇

CH ₂ CH (CH ₃ ) CH ₂ C ₅ H ₉

CH (CH ₃ ) (CH ₂ ) ₂ C ₇ H ₁₃

CH (CH ₃ ) CH (CH ₃ ) CH ₂ C ₆ H ₁₁

(CH ₂ ) ₆ C ₆ H ₅

(CH ₂ ) ₇ C ₆ H ₅

(CH ₂ ) ₈ C ₆ H ₅

CH (CH ₃ ) (CH ₂ ) ₆ C ₆ H ₅

CH (CH ₃ ) (CH ₂ ) ₇ C ₆ H ₅

CH (CH ₃ ) (CH ₂ ) ₃ 4-FC ₆ H ₄

C (CH ₃ ) ₂ (CH ₂ ) ₃ C ₆ H ₅

CH (CH ₃ ) (CH ₂ ) ₃ 4-ClC ₆ H ₄

CH (CH ₃ ) (CH ₂ ) ₄ 4-ClC ₆ H ₄

CH (CH ₃ ) (CH ₂ ) 4-ClC ₆ H ₄

CH (CH ₃ ) (CH ₂ ) 4-FC ₆ H ₄

CH (CH ₃ ) (CH ₂ ) ₂ 4-FC ₆ H ₄

CH (CH ₃ ) (CH ₂ ) ₂ 4-ClC ₆ H ₄

(CH ₂ ) ₃ CH (CH ₃ ) C ₆ H ₁₁

CH (CH ₃ ) (CH ₂ ) ₂ CH (CH ₃ ) C ₆ H ₅

CH (CH ₃ ) (CH ₂ ) ₂ CH (CH ₃ ) C ₆ H ₁₁

CH (CH ₃ ) (CH ₂ ) ₂ CH (CH ₃ ) 4-piperidyl

CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₁₁

CH (CH ₃ ) (CH ₂ ) ₂ CH (CH ₃ ) C ₆ H ₁₁

(CH ₂ ) ₃ C ₆ H ₁₁

(CH ₂ ) ₄ C ₆ H ₁₁

(CH ₂ ) ₈ C ₆ H ₁₁

Recipe N

3,5-dimethoxy-α-methylstyrene oxide

To a solution of dimethyl sulfonium methylide (69.4 mM) dissolved in dimethyl sulfoxide (65 ml) at room temperature was added solid 3,5-dimethoxyacetophenone (10 g., 55.5 mM).

The reaction mixture is stirred at 25 ° C. for 1 hour and at 50 ° C. for 30 minutes and then cooled.

에테르(250ml)

비점이 낮은 석유 에테르(25ml)의 혼합물에 가한다. 유기 추출물을 물(250ml)로 2번 세척한 후 건조시키고(MgSO₄) 증발시켜 기름을 얻는다.The mixture was diluted with water (50 ml) and this was iced water (200 ml) ×

Ether (250 ml)

It is added to a mixture of low boiling petroleum ether (25 ml). The organic extract is washed twice with water (250 ml), dried (MgSO ₄ ) and evaporated to give an oil.

Fractional distillation of the oil yields 8.0 g (75%) of 3,5-dimethoxy-α-methylstyrene oxide. Boiling point 93 ° -97 ° C. at 0.2 mm.

IR (CCl ₄ ): 2,780, 1,595, 1,196, 1,151, 1,058cm ^-1

UV (95% ethanol): λmas = 279 nm (ε = 2,068)

MS (Molecular Ion): 194

), 2.95(d, J 6Hz,

), 3.81(S,CH₃O-), 6.41(t,J=2Hz, ArH) 및 6.58(d, J=2Hz, ArH).PMR (CDCl ₃ ) (60MHz): δ 1.70 (S, CH ₃ ⁻ ), 2.76 (d, J = 6Hz,

), 2.95 (d, J 6 Hz,

), 3.81 (S, CH ₃ O−), 6.41 (t, J = 2 Hz, ArH) and 6.58 (d, J = 2 Hz, ArH).

Analysis: C ₁₁ H ₁₄ 0 ₃ Theoretic: C, 68.02: H, 7.27%

Found: C, 67.96; H, 7.28%

[O recipe]

2- (3,5-dimethoxyphenyl) -2-hydroxypropyl-2-phenylethyl ether

A mixture of anhydrous 2-phenylethanol (30 ml., 251 mM) and metallic sodium (690 mg., 30 mM) is heated at 110 ° C. for 30 minutes. The resulting 1 mole of sodium 2-phenylethoxide was cooled to 60 ° C, and then 3,5-dimethoxy-methylstyrene oxide (2 g., 10.3 mM) was added thereto, and the reaction solution was heated at 60 ° C for 15 hours. The reaction mixture is cooled and added to a mixture of ether and water. The ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenyl-ethanol is removed by vacuum distillation (b. P. 65 ° C., 0.1 mm) and 3.5 g of residue is liberated.

The residue is purified by column chromatography on merxsilica gel 60 (300 g) and eluted in 15 ml fractions containing 60% ether-pentane. Yield 2.9 g (89%) of 2- (3,5-dimethoxyphenyl) -2-hydroxy-propyl-2-phenylethyl ether in fractions 52-88.

IR (CCl ₄ ): 3,534, 1,595, 1,202, 1,153cm ^-1

UV (595% ethanol): λ max = 278 (ε = 1,830), 273 (ε = 1,860)

MS (Molecular Ion) 316

PMR (CDCl ₃ , 60 MHz): δ 1.46 (S, CH ₃ ⁻ ), 2.86 (S, OH), 2.86 (t, J = 7 Hz, -CH ₂ -Ph), 3.53 (S, -CH ₂ O) , 3.71 (t, J = 7 Hz, -CH ₂ O), 3.80 (S, OCH ₃ ), 6.38 (t, J = 2 Hz, ArH), 6.61 (d, J = 2 Hz, ArH) and 7.23 (S, PhH ).

Analyzes: Theoretic of C ₁₉ H ₂₄ 0 ₄ : C, 72.12; H, 7.65%

Found: C, 71.92; H, 7.63%

[Production P]

2- (3,5-dimethoxyphenyl) propyl 2-phenylethyl ether

Phosphorus oxychloride (477 ml., 5.22) in a 0 ° C. solution of 2- (3,5-dimethoxyphenyl) -2-hydroxypropyl 2-phenyl ethyl ether (550 mg., 1.74 mM) in pyridine (2 ml). mM) is added dropwise. The reaction is warmed to 20 ° C. for 1.5 hours. Stir at 20 ° C. for 1.5 h and add to ether (150 ml) and 15% sodium carbonate (100 ml). The organic phase is separated, washed with 15% sodium carbonate (3 x 50 ml), dried over magnesium sulfate and evaporated to give an oil. The oil is dissolved in anhydrous ethanol (15 ml), 10% decalcified palladium (100 mg) is added and the mixture is stirred under 1 atmosphere of hydrogen gas.

At the end of hydrogen absorption (26.5 ml., 20 minutes), the reaction solution is filtered through diatomaceous earth and the filtrate is evaporated to give an oil. The oil was purified via preparative chromatography on silica gel plate and eluted twice with 6: 1 pentane: ether to yield 211 mg (40%) of 2- (3,5-dimethoxyphenyl) propyl 2-phenylethyl ether. do.

IR (CCl ₄ ): 1,600, 1,205, 1,155, 1109cm ^-1

MS: (molecular ion) 300

PMR (CDCl ₃ , 60MHz), δ1.22 (d, J = 7Hz, CH ₃ ⁻ ), 2.82 (t, J = 7Hz, CH ₂ Ph), 2.8 (HC-Me), 3.6 (-CH ₂ -0 -CH _2- ), 3.75 (S, OCH ₃ ), 6.35 (m, ArH) and 7.18 (S-, PhH).

[Production Q]

2- (3,5-dihydroxyphenyl) propyl 2-phenylethyl ether

A mixture of 2- (3,5-dimethoxyphenyl) propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine (0.4 ml., 4.96 mM) and anhydrous pyridine hydrochloride (4 g., 34.6 mM) was subjected to 190 ° C. Heat for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml) and ether (150 ml). The ether extract is first washed with water (50 ml), followed by the ether extract in an aqueous phase, dried over magnesium sulfate and evaporated to give an oil.

The oil was purified by preparative chromatography on silica gel plate and eluted six times with 39% ether-pentane to give 65.8 mg (37%) of 2- (3,5-dihydroxylophenyl) propyl 2-phenylethyl ether. Calculate

IR (CHCl ₃ ): 3,559, 3,279, 1,605, 1,147, 1,105 cm ^-1

MS: (molecular ion) 272

_{PMR (CDCl 3, 60MHz):} δ1.18 (d, J = 7Hz, CH 3 - -), 2.80 (t, J = 7Hz, -CH 2 Ph), 2.80 (HC-Me), 3.4-3.8 (- CH ₂ OCH ₂₋ ), 6.08 (t, J = 2 Hz, ArH), 6.2 l (d, J = 2 Hz, ArH) and 7.16 (S, PhH).

The following compounds are prepared from suitable alkanols according to the methods of Preparation 0 and P.

(alk ₂ ) W

-(CH ₂ ) ₆ -CH ₃

-(CH ₂ ) ₆ C ₆ H ₅

-(CH ₂ ) ₄ CH ₃

-CH (CH ₃ ) CH ₂ CH ₃

-CH (CH ₃ ) (CH ₂ ) ₄ CH ₃

-(CH ₂ )-4-FC ₆ H ₄

-(CH ₂ ) _2-4 -pyridyl

- (CH _{2) 2} - 2- piperidyl

-CH (CH ₃ ) CH ₂ -4-piperidyl

-(CH ₂ ) ₂ CH (CH ₃ ) (CH ₂ ) ₂ -CH ₃

-CH (CH ₃ ) -CH ₃

-C (CH ₃ ) ₂ -CH ₃

[Recipe R]

4- (3,5-dihydroxyphenyl) -1-pentoxy pentane

Under nitrogen atmosphere, 3-phenoxypropyltriphenyl-phosphonium bromide (7.18 g., 0.15 M) dissolved in 3,5-dibenzyloxyacetophenone and dimethyl sulfoxide (450 ml) dissolved in tetrahydrofuran (175 ml). The mixture is added dropwise to a 50% sodium hydride (7.89 g., 0.165 M) (washed with pentane in advance) dispersion, maintaining the temperature at 0 ° -5 ° C. over 1.7 hours. After stirring for 4 hours at 0 ° -5 ° C, the reaction solution was warmed to room temperature and carefully stirred into ice water (2,000 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (5 x 400 ml).

The combined organic phases are washed with saturated sodium chloride solution (3 x 300 ml), dried over sodium sulphate and concentrated in vacuo to give an oil which is triturated with ether and precipitated with triphenylphosphine oxide.

Filtration is followed by concentration of the filtrate to give an oily residue which is chromatographed on silica gel, eluting with benzene-hexane composed of 30% to 100% benzene.

From the middle fraction, 51 g (75%) of 4- (3,5-dibenzyloxyphenyl) -1-phenoxy-pent-3-ene are separated in oily form:

R _f = 0.8 (silica gel, 2-benzene: 1-hexane);

MS (Molecular Ion): 450

Analyzes: Theoretic of C ₃₁ H ₃₀ H ₃ : C, 82.63; H, 6.71%

Found: C, 82.90; H, 6.69%

4- (3,5-dibenzyloxyphenyl) -1-phenoxypent-3-ene (51 g., 0.113 M) dissolved in a mixture of anhydrous ethanol (160 ml), ethyl acetate (160 ml) and concentrated hydrochloric acid (0.2 ml) ) Solution is hydrogenated under 551bs, hydrogen in the presence of 10% pd / c for 12 hours. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to yield 30.8 g (100%) of product in viscous oil.

Anal: calcd for C ₁₇ H ₂₀ 0 ₃ : C, 74.97; H, 7.40%

Found: C, 74.54; H, 7.45%

[Production S]

3,5-dimethoxy-β-methylstyrene oxide

3,5-dimethoxybenzaldehyde (1.0 mole) was slowly added to a diphenylsulfonium ethylide (1.0 mole) solution at -70 ° C dissolved in tetrahydrofuran (1 L). The reaction mixture is stirred at −78 ° C. for 3 hours to warm to room temperature. This is added to ether-water and the ether phase is separated. The ether phase is washed with water, dried (MgSO ₄ ) and evaporated.

Fractional distillation of the residue gives the title product.

[Production T]

3- (3,5-dihydroxyphenyl) -2-propylbutyl ether

3,5-Dimethoxy-β-methylstyrene oxide (6.33 M) is added to a sodium butoxide solution dissolved in butanol (1 M 0.5 L). The mixture is heated at 70 ° C. for 18 hours, cooled and added to the ether-water mixture.

The ether solution is separated, dried (MgSO ₄ ) and evaporated to afford 3- (3,5-dimethoxyphenyl) -3-hydroxy-2-propylbutyl ether.

It is purified by column chromatography on silica gel with ether-pentane eluent.

The title product is prepared according to the method of Preparation P.

In a similar manner, the following materials are prepared from suitable alcohols.

(alk ₂ ) W (alk ₂ ) W

CH ₂ CH ₃ CH (CH ₃ ) CH ₂ CH ₃

(CH ₂ ) ₆ CH ₃ CH (C ₂ H ₅ ) (CH ₂ ) ₂ CH ₃

(CH ₂ ) ₃ C ₆ H ₅ CH (CH ₃ ) (CH ₂ ) C ₆ H ₅

(CH ₂ ) ₂ 4-FC ₆ H ₄

(CH ₂ ) ₂ 4-pyridyl

[Production U]

2-R ₄ R ₅ -5,7-dihydroxy-4-chromanones

The compounds in the table below are prepared using the British patent method. Reaction of appropriate R ₄ R ₅ C═CH-COOH with excess (50%) of 1,3,5-trihydroxybenzene and excess polyphosphoric acid (10-20 g per g of trihydroxybenzene) for 3 hours in a steam bath Let's do it.

Cool the mixture and pour in water. Extract with ether precipitated, ether extract is washed with sodium hydroxide solution, dried and evaporated to afford product.

The residue is purified by distillation. This produces the following material:

R ₄ R ₅

CH ₃ H

H H

C ₂ H ₅ C ₂ H ₅

C ₂ H ₅ H

CH ₃ C ₂ H ₅

Recipe V

(4-halophenyl) cyclohexanols

A. 3- and 4- (4-Fluorophenyl) cyclohexanols

A benzene solution containing 4-fluorourostyrene and 2-methoxybutadiene and hydroquinone (1% by weight based on diene) is heated to 150 ° C. for 10 hours in a sealed tube. The reaction tube is cooled and the contents are removed and concentrated to give 1-methoxy-4 (and 5) -4- (furuophenyl) cycloheptene, which is separated by distillation in vacuo.

The ether is hydrolyzed with 3% hydrochloric acid to give 3- and 4- (4-fluorophenyl) cyclohexanone.

Ketones are reduced by sodium borohydride according to the method of Example 5 to obtain a keto compound.

In a similar manner, the corresponding 3- and 4- (4-chlorophenyl) cyclohexanol are prepared from 4-chlorostyrene.

B. 2- (4-Fluorophenyl) cyclohexanol

The compound is prepared from cyclohexane hexane oxide and P-fluorofluoro lithium according to the method of Hutric et al. Used to prepare 2- (4-chlorophenyl) cyclohexanol.

[Manufacturing W]

(2-halophenyl) cycloalkanol

The following compounds were prepared by applying the Hught method, except using the appropriate cycloalkenoxide and P-halo (Cl or F) phenyllithium reactant.

a X a X

2 Cl 2 F

3 Cl 3 F

5 Cl 5 F

Recipe X

5-hydroxy-7-mercapto-2,2-dimethyl-4-chromenone

A mixture of 3,5-dihydroxyphenyl methylsulfite (5.85 g) and 3-methylcrotonic acid (4.5 g) is heated to 125 ° C. in the presence of nitrogen and preserved trifluoride etherate (8.7 ml) is added. .

The mixture is refluxed for 1 hour and cooled. Water (10 ml) is added followed by 6N sodium hydroxide (40 ml). The mixture is heated in a steam bath for 5 minutes, cooled and acidified with 6N hydrochloric acid.

It is extracted with ether (3 x 100 ml) and the combined ethers are washed with 10% sodium bicarbonate (1 x 25 ml) and water (1 x 25 ml) and dried (Na ₂ SO ₄ ).

The extract is concentrated in vacuo to afford dl-5-hydroxy-2,2-dimethyl-7-methylmercapto-4-chromanon.

This is purified by silica gel chromatography.

The resulting methyl mercapto compound is hydrolyzed by refluxing with excess 48% embrittlement hydrochloric acid overnight.

The reaction mixture is concentrated to give the title compound.

This is purified by silica gel chromatography.

The following compounds are prepared in a similar manner using suitable acids with the formula R ₄ R ₅ C═CH-COOH instead of 3-methylcrotonic acid.

R ₄ R ₅

H CH ₃

H H

C ₂ H ₅ C ₂ H ₅

HC ₂ H ₅

CH ₃ C ₂ H ₅

[Manufacturing Y]

Alkylation of 3,5-dihydroxyphenylmulcaptan

A solution of 3,5-dihydroxy phenyl mercaptan (3.5 g., 0.01 mole) dissolved in anhydrous ethanol (50 ml) is made alkaline with sodium ethoxide.

Appropriate bromide (0.01 mole) of the formula Br- (alk ₂ ) _n -W is added and the mixture is refluxed for 3 hours. It is concentrated under reduced pressure and the residue is extracted with ether. Evaporate the ether to give the product. As a result, the following compounds are prepared.

n (alk ₂ ) W

1 -CH (CH ₃ ) (CH ₂ ) ₅ -CH ₃

1 -CH (CH ₃ ) CH (CH ₃ ) (CH ₂ ) ₄ -CH ₃

1 -C (CH ₃ ) ₂ (CH ₂ ) ₅ -CH ₃

1-(CH ₂ ) ₈ -CH ₃

1-(CH ₂ ) ₄ -CH ₃

1 -CH ₂ -C ₆ H ₅

1-(CH ₂ ) -C ₆ H ₅

1 -CH (CH ₃ ) (CH ₂ ) ₃ -C ₆ H ₅

1 -CH ₂ -C ₃ H ₅

1 -CH ₂ -C ₅ H ₉

1 -CH ₂ -C ₆ H ₁₁

1-(CH ₂ ) ₂ -C ₅ H ₉

1-(CH ₂ ) ₃ -C ₅ H ₉

1-(CH ₂ ) ₆ -C ₆ H ₁₁

1-(CH ₂ ) ₄ -C ₅ H ₉

1-(CH ₂ ) ₃ CH (C ₂ H ₅ )-C ₆ H ₁₁

1-(CH ₂ ) ₇ -C ₅ H ₉

1-(CH ₂ ) ₄ -C ₇ H ₁₃

1-(CH ₂ ) ₂ -C ₇ H ₁₃

1-(CH ₂ ) ₅ -C ₄ H ₇

1-(CH ₂ ) ₅ -C ₃ H ₅

1-(CH ₂ )-2-piperidyl

1-(CH ₂ ) _3-4 -piperidyl

1-(CH ₂ )-2-pyridyl

_{1 - (CH 2) 3 -} 3- pyridyl

_{1 - (CH 2) 4 -} 2- pyridyl

1 -CH (CH ₃ ) (CH ₂ ) ₂ -pyridyl

1-CH (CH ₃ ) (CH ₂ ) _3-4 -pyridyl

1 -CH (C ₂ H ₅ ) (CH ₂ ) ₂ -piperidyl

_{1 - (CH 2) 4 -} 4-FC 6 H 4

1 -CH (CH ₃ ) (CH ₂ ) ₂ -ClCl ₆ H ₄

1 -CH (CH ₃ ) (CH ₂ ) ₃ -4-FC ₆ H ₄

0-C ₆ H ₅

0-4-FC ₆ H ₄

0-4-ClC ₆ H ₄

0-C ₃ H ₅

0-C ₅ H ₉

0-C ₆ H ₁₁

0-C ₇ H ₁₃

0-4-pyridyl

0-2-piperidyl

0-2-pyridyl

0-2- (C ₆ H ₅ ) C ₃ H ₄

0-4- (C ₆ H ₅ ) C ₆ H ₁₀

0-3- (C ₆ H ₅ ) C ₇ H ₁₂

0-CH ₃

Recipe Z

dl-2- (3,5-dibenzyloxyphenyl) -2-hydroxy-1- (2-phenylethoxy) -propane

3,5-dibenzyloxyacetophenone (51.Og., 0.153 mol) is added to a 20 degreeC dimethyl sulfoxium methylide (0.184 mol) solution dissolved in dimethyl sulfoxide (185 ml).

After 1.5 h stirring at 20 ° C., the reaction is diluted with 200 ml of ice water and added to 500 ml of ether and 200 ml of ice water. The organic phase is washed with cold water (2 x 200 ml), dried over magnesium sulphate and evaporated to an oil.

The resulting solution obtained by dissolving impure 1- (3,5-dibenzyloxyphenyl) -2-methyloxirane (0.153 mol) in dimethyl sulfoxide (100 ml) was dissolved in dimethyl sulfoxide (150 ml) and 36.5 ml (0.30 mol) of penethanol. Was added to 7.34 g of sodium hydride slurry dissolved in 150 ml dimethyl sulfoxide) and rapidly added to a 20 ° C. solution of sodium penethoxide (100 ml).

The reaction solution is slowly heated to 70 ° C. over 30 minutes, stirred for 30 minutes and cooled to 20 ° C. The reaction solution is diluted with 200 ml ice water and added to ether (2 L) and ice water (1 L). The organic phase is washed with cold water (2 × 1 L), dried over magnesium sulfate and evaporated to give an oil. This impure oil was purified by column chromatography on 1.5 kg silica gel and eluted with 60% ether-pentane to give dl-2- (3,5-dibenzyloxyphenyl) -2-hydroxy-1- ( Calculate 30.Og (42%) of 2-phenylethoxy) propane.

IR: (CHCl ₃ ) OH 3,534cm ^-1

1.46(S, 메틸), 2.85(t, J=7Hz), -CH₂Ph), 2.81(d, 하이드록시), 3.55(S, -CH₂O-), 3.68(t, J=7Hs, -OCH₂-), 5.06(S, PhCH₂0-), 6.56(t, J=2Hz, C_-4ArH), 6.76(d, J=2Hz, C-2,6 ArH), 7.25(S, ArH) 및 7.43(S, ArH).NMR:

1.46 (S, methyl), 2.85 (t, J = 7 Hz), -CH ₂ Ph), 2.81 (d, hydroxy), 3.55 (S, -CH ₂ O-), 3.68 (t, J = 7Hs,- OCH _2- ), 5.06 (S, PhCH ₂ 0-), 6.56 (t, J = 2Hz, C _-4 ArH), 6.76 (d, J = 2Hz, C-2,6 ArH), 7.25 (S, ArH ) And 7.43 (S, ArH).

), 453, 377 및 335(100%)MS: m / e 468 (M

), 453, 377, and 335 (100%)

[Production AA]

dl-2- (3,5-dihydroxyphenyl) -1- (2-phenylethoxy) propane

0. dl-2- (3,5-dibenzyloxyphenyl) -2-hydroxy-1- (2-phenylethoxy) propane (29.Og) 61.9 m dissolved in pyridine (50 ml., 0.619 mol) Molar) to the solution is added intimately phosphoroxychloride (5.65 ml., 61.9 mmol). The reaction is warmed to 20 ° C. and stirred at 20 ° C. for 20 hours.

The reaction is added to 3.3 N NaOH (300 ml) at 0 ° C. and the mixture is extracted with ether (3 × 500 ml). Each extract is washed with saturated potassium carbonate (1 × 500 ml) and water (3 × 500 ml).

The combined organic extracts are dried over magnesium sulfate, silica gel, bleached (carbon) and evaporated to give an oil.

This oil is purified by column chromatography on silica gel (200 g) and eluted with 60% ether-pentane to yield 17 g (61%) of oil.

To this mixture solution of olefin (3.62 g) is added solid sodium bicarbonate (300 mg) and 10% pd / c (1.2 g).

The mixture is stirred under 1 atmosphere of hydrogen for 6 hours.

The reaction solution is diluted with ethyl acetate and filtered through diatomaceous earth. The evaporated filtrate was purified by column chromatography on silica gel (200 g) and eluted with 80% ether-pentane to give dl-2- (3,5-dihydroxyphenyl) -1- (2-phenylethoxy in oily state. ) 2.Og (92% ol) of propane is obtained.

IR (CHCl ₃ ) OH 3,571, 3,279 cm ^-1

1.10(d,J=7Hz, 메틸), 2.80(t,J=7Hz, -CH₂Ph), 2.90(M, 메틴), 3.5(m, -CH₂0-CH₂-), 6.10(t, J=2Hz, C-4 ArH), 6.20(d, J=2Hz, C-2,6 ArH), 6.5(넓은 m, 하이드록실) 및 7.19(S, ArH).NMR:

1.10 (d, J = 7 Hz, methyl), 2.80 (t, J = 7 Hz, -CH ₂ Ph), 2.90 (M, methine), 3.5 (m, -CH ₂ 0-CH _2- ), 6.10 (t, J = 2 Hz, C-4 ArH), 6.20 (d, J = 2 Hz, C-2,6 ArH), 6.5 (wide m, hydroxyl) and 7.19 (S, ArH).

), 181, 168, 151, 138, 137, 123, 105(100%) 및 91.MS: m / e 272 (M

), 181, 168, 151, 138, 137, 123, 105 (100%) and 91.

Claims (1)

Reducing the compound of formula (B) or formula (C); If Q is R is alkanoyl

Ramen, Q is R is hydrogen

A process for preparing dibenzo [b, d] -pyran of formula (A) by reacting a compound of formula A with a suitable acid, acid chloride or acid anhydride.

Where Q is

or

Is, R is hydrogen or alkanoyl of C ₁ -C ₅ ; R ₁ is hydrogen, alkanoyl of C ₁ -C ₅ or -CO- (CH ₂ ) _p -NR | ₂ R ₃ , where p is an integer of 0 or 1-4; when R ₂ and R ₃ are each independently hydrogen or alkyl of C ₁ -C ₄ ; When R ₂ and R ₃ are attached together with nitrogen, a 5- or 6-membered compound selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino with an alkyl group of C ₁ -C ₄ Form a summon; R ₄ and R ₅ are hydrogen, methyl or ethyl; Z is (a) alkylene of C ₁ -C ₉ ; (b)-(alk ₁ ) _m -X- (alk ₂ ) _n- , where (alk ₁ ) and (alk ₂ ) are each C ₁ -C ₉ , provided that (alk ₁ ) and (alk ₂ ) are the sum It should not be greater than nine. m and n are each 0 or 1; X is 0, S, S0 or S0 ₂ ; ego W is methyl, phenyl, P-chlorophenyl, P-fluorophenyl, pyridyl, piperidyl, cycloalkyl or mono-substituted cycloalkyl of C ₃ -C ₇ wherein the substituent is phenyl, P-chlorophenyl or P-Fluorophenyl); Provided that when W is methyl Z is-(alk ₁ ) _m -X (alk ₂ ) _n .