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    • 专利摘要:
    There are described novel 1-hydroxy-3- substituted- tetrahydro and hexahydro- dibenzo[b, d]- pyrans having an amino group or amino derivative at the 9-position, of the following formula: …<CHEM>… in which R<1>, R<2>, R<3> and Z are as defined herein. The compounds are useful as analgesics, anti-depressants anti-anxiety agents, hypotensive agents and as intermediates for the preparation of other compounds.
    公开号:SU812177A3
    申请号:SU792728600
    申请日:1979-02-16
    公开日:1981-03-07
    发明作者:Аллен Дей Вильям；Рольф Лавагнино Эдвард
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The method is based on the reaction of the reaction of a carbonyl compound with hydroxylamine ll known in organic chemistry.
    The aim of the invention is to obtain new derivatives of 1-hydroxy-3-substituted tetrahydro- or hexahydrodibenzo (b, d) pyrans, which have a biologically active effect.
    The goal is achieved in that the compound of formula
    .0
    where R is a hydrogen atom, R and R have the indicated meanings,
    interact with amins and the general formula
    HjNR (III) where R has the above meaning, | With the formation of a compound of formula 1, | Where Z is a group of the general formula
    AT
    i
    (ff)
    HCH
    and, if desired, a compound of Formula 1, where 2 is a group of formula IV, where R is an oxngroup, is reacted with a weak reducing agent, selected from group r including diborane, sodium borohydride, sodium cyanoborohydride and lithium hydride |
    a solvent such as an alcohol, especially methanol or ethanol, or a "physical carbon, such as benzene or toluene, to form a compound of formula 1, where Z is of formula
    "X x®"
    t
    (V)
    ."and
    and {upon desire, a compound of formula 1, rie Z is a group of formula V, acylated to form a compound of formula 1, where Z is a group of the general Formula
    t, south
    J
    .S where R is an eshcanoyloxy alkanoyl C. — C ,, or a compound of formula 1, where Z is a group of formula IV, where R is hydroxy, acylated
    and get the compound of formula 1, where Z is a group of the General formula
    or
    TO
    (W.)
     ) b
    ..
    where K, R and R8 are each al canon l, and if desired, the obtained compound of formula 1 is hydrolyzed to form a compound of formula 1, where Z-rpynna of formula V I I or V I 1 I, R
    and
    8 R - hydrogen atom, R °
    alkanoyl
    or a compound of formula 1, where Z is a group of formula IV, where R 5 is a hydroxy group, is hydrogenated to form a compound of formula 1, where Z is a group of formula VI, where R and R are hydrogen atoms, the resulting compound is acylated to form a compound of formula 1, where Z is a group of formula VI, where R5 is a hydrogen atom and R is alkanoyl C ;, -C or a group. ABOUT . . ,
    -C- {CHj) COOH, where n is an integer equal to 2, 3 or 4 and, if desired, the resulting compound, where R is a hydrogen atom and R is alkanoyl, is reduced to form a compound of formula 1, where R is a hydrogen atom and R is alkyl, and, if desired, the obtained compound is acylated to form a compound of formula 1, where Z is a group of formula VI., where R is alkanocles or fe, nyl- (C ;; - C5, -E1Lcanoyl) And R - alkyl 4, or a compound of formula II, is reacted with an aminating agent, such as a primary or secondary amine, including methylgyne, diethylamine, 2-propenylamine, pyrrolidine, pi yeridine, morpholine 3-butynylamine, N-methyl-3-butenylamine, 3-hydroxypropylamine, benzylamine, N-lutyl-2-phenylstilamine, N-isopropylisobutylamine, distilamine / under reducing conditions, using a reducing agent such as hydrogen, and a catalyst, such as sodium borohydride or sodium cyanoborohydride, in a solvent such as methanol or zanol, at a temperature of from 10 to form a compound of formula 1, where
    S
    Z is a group of formula VI, where R
    alkyl C-C4fCHjt (Cn-C alkyn), phenyl- (C-C2-akyl), or a group of the formula (CH2) and -OH, where n is 2, 3 or 4, R is a hydrogen atom, alkyl, CH2 ( C2-C4-alkynyl), R and R, taken together with the nitrogen atom to which they are bound, form a piperidi0 or mrfoline ring, and if desired, a compound of formula 1, where Z is a group of formula VI, where R is a group of formula ( CH), - OH and R is a hydrogen atom, are acylated to form5 a compound of formula 1, where Z is a group of formula VI, where (CHg), is 0- (C-Cgalkanoyl) and R is alkanoyl, and if desired, the compound obtained is subjected interaction with a strong base to form a compound of formula 1, where Z is a group of formula-VI, where R is a group (CHa) j, -OH, and R alkanoyl, and the desired product is isolated as optical isomers or a mixture thereof, in free form or salt.
    The process is best carried out in an environment of a mutually miscible solvent, such as methanol, ethanol, water, in a mixture of these solvents. Usually the reaction takes about 30 minutes to 4 hours at a temperature of 25-100 ° C. The resulting oxime or p-alkyloxime is easily separated by diluting the reaction mixture with water or an aqueous acid solution and then extracting the oxime with a solvent, such as diethyl ether benzene, chloroform, dichloromethane, ethyl acetate .. After evaporation of the solvent from the organic extracts, the oxime usually remains (as a evaporation residue) in the form of an oil or solid, which can be crystallized from solvents such as n-hexane and petroleum ether.
    The reduction of the iminoproducts obtained in this way to obtain 9-amino and 9-substituted amino derivatives can be carried out by any known method. For this purpose, diborane, sodium borohydride, sodium cyanoborohydride, and lithium aluminum hydride are commonly used as reconstituents. If desired, catalytic hydrogenation can also be carried out. Such reduction processes usually take place in an environment of an organic solvent, such as an alcohol, especially methyl or ethyl alcohol, or aromatic hydrocarbons, such as benzene and toluene. Recovery of the oxime, i.e. 9-hydroxy-derivative with the aim of obtaining the corresponding 9-hydroxy-amine compound usually proceeds within 6-20.4 at. Reduction of the 9-alkoxyimine derivative results in the corresponding 9-alkoxy-amino derivative.
    The target product is epimers. If desired, this epimeric mixture can be separated by fractional crystallization, adsorption chromatography, gas-liquid chromatography, high pressure liquid chromatography and other similar methods. Typically, such separation of the isomers is not carried out until the local product forms.
    The compounds of formula I have a useful pharmaceutical effect. Many of them, in addition, are valuable intermediates used in the synthesis of pharmaceutically active compounds. The pharmaceutical composition contains at least one biologically active compound of pho (n4 uly I mixed with one or more appropriate diluents, carriers, or excipients. In addition, other pharmaceutical active drugs can be added to the composition containing the active ingredient. The most preferred pharmaceutical composition is used to treat hypertension. Particularly preferred compositions are those that contain
    The active ingredient is 9-amide derivative.
    The compositions are made in such a form that can be easily introduced into the patient's body in a specific way, in each specific case. When administered through the mouth, the compound is mixed with carriers and diluents, such as (Extrose, Lactose, Mannitol, Cocoa Butter, Ethyl Lactate, Methyl Cellulose, Alzi Silicate, Potato Starch, Microcrystalline Cellulose, Polyvinyl Pyrrolidone, Potassium Benzoate, and Relative excipients for them. Such compositions MAY be
    molded into tablets or enclosed in gelatin capsules. In addition, these mixtures can be dissolved in liquids, such as 10% aqueous glucose solution, isotonic saline, sterilized water, etc., and introduced into the body by intravenous injection. At ° C, these solutions can be lyophilized and kept in a sterile ampoule, ready to take when adding sterilized water1. The most preferred treatment used to treat hypertension in humans includes a compound such as right-, left-handed-trans-1-hydroxy-3g (1,1-dimethylheptyl) -6, b-dimethyl-9-acetyl-1IDo-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo (b, d) pyran in an amount of about 0.01 to 1.0 mg in admixture with a carrier such as sucrose or starch, benzyl 4 in an amount of about 500 mg. Such a composition can be molded into tablets, which can be administered to a human body having an increased blood pressure, at a dose of about 1 to 4 tablets per day.
    As mentioned above, the compounds of the formula I have different
    application. These compounds exhibit pharmaceutical activity in one or more standard tests, i.e. have shown themselves in these trials as both exository agents / anti-glaucoma agents, anti-depres-. sites and sedatives as well as hypotensive activity. Compounds of formula I that are strong with respect to pharmaceutical activity are 9-amide-producing JQ compounds (for example, compounds of the above formula, where R and R are alkanoyl even if other compounds of formula I show beneficial pharmaceutical action. So, for example, right-, left-handed-trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, 6-dimethyl-9-oxamino-6a, 7, 8, 9, 10, 10a Hexahydro-6H-dibenzo (b, d) Pyran, when tested for its analgesic effect when sub-; 20 skin injections into the body of pain from mice, showed the value of EO about 2 mg / kg. Similarly, the right-, left-handed. -trans-1-hydroxy-3- (I, 1-dimethylheptyl) -6,6-dimethyl-9-hydroxy-25 HO-fra, 7, 8, 9, 10, 10a-hexahydro-H-dibenzo (b, d) pyran causes a response in behavior with a minimum effective dose (NEO) of only 5.0 mg / kg. In addition, jn when tested in rats with a damaged heart partition right -, .left of trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, 6-dimethyl-9- (H-ethyl) -acetamido-ba, 7, 8, 9, "10, 10a-hexahydro -6H-dibeneo (b, d) -pyran shows a MED value of 10.0 mg / kg. When the drug was tested on dogs for the determination of the ability to lower the blood pressure of the pre-levorot.-trans-1-hydroxy-40 -3- (1,1-dimethylheptyl) -6, b-dimethyl-9-acetamcdo-6a, 7, 8 , 9, 10, 10atexgondro-bN-dibenzo (b, d) Pyran shows an MED value of 0.5 μg / kg for intravenous injection. 45
    Thus, myogie of compounds. I can use
    for the treatment of hypertension, for anesthesia, for the suppression of depression, as well as for the treatment of hypertensive agents, for the treatment of gp & vax and other related diseases in animals and animals.
    jk Compounds of pho (the "IJ of I that exhibit a hypotonic effect can be administered to the patient's body in any known manner, including oral, subcutaneous injection, intramuscular and intravenous injection. Typical doses of the drug used for the treatment of the skin are different 40 depending on depending on the particular condition, weight and age of the patient, but, typically, they are approximately 0.001-20 mg per patient per day. For treatment, for example, gui-6S
    Pertoniums The preferred daily doses of the drug are about 0.1-10 mg per patient. For example, a typical method for treating hypertension is to administer to the patient about 5 mg per day of the right, levorotum-1-hydroxy-3 (1,2-dimethylheptyl) -9- (2, b-dioxopiperidino) -b, 7, 8, 9, 10, 10a-hexahydro-bH-dibenzo (b, d) pnrana. The preferred method of treating this disease is to administer approximately 2 mg per day of the right, left-handed, trans-1-ca b-3- (1,1-dimethylheptyl) -6, b-dimethi-9-acetamido-ba , 7, 8, 9, 10, 10a-hexahydro-bH-dibenzo (b, d) pyran.
    Example 1. Right-, levovrasch-trans-1-hydroxy-3G (1,1-dimesh1heptyl) -b, b-dimethyl-9-oxyimine-ba, 7, 8, 9, 10, 10a-hexahydro-bN-dibenzo (B, d) pyran.
    A solution of 4.0 g of right-, levovra1a ..- trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-ba, 7 is mixed,
    8,9,10, 10a-hexahydro-bH-dibenzo (b, d) pyran-9-one and 1.155 g of hydroxylamine hydrochloride in 60 ml of ethanol and 10 MP of water while adding 4.4 ml of 5 n. sodium hydroxide in one portion. The reaction mixture is then heated to reflux temperature and stirred at this temperature for 30 minutes. After cooling the reaction mixture to room temperature, the atura is introduced into it. 100 g of ice and then acidified to pH 2.5 with concentrated hydrochloric acid. The aqueous acidic solution of this reaction mixture is extracted several times with diethyl ether. The ethereal extracts were combined, sp: 1 was watered with a 5% aqueous solution of sodium bicarbonate and water, and then dried. After removal of the solvent by evaporation under reduced pressure, 2.0 g of product are obtained in the form of an oil. This oil is crystallized and 50 ml of n-hexane, polutaiot 3.8 g right-, levorotum. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-hydroxy-imino-ba, 7, 8, 9, 10, 10a-hexahydro-bN-dibenzo (b, d) pyran in the form of a white powdered product, so pl. 143-145 C.
    Found,%: C 74.61, H 9.37, H 3.78, t / e 387.
    C44H57N03.
    } isleno,%: C 74.38, H 9.62, N3.61, t / e 387.
    The procedure described above is repeated using 7.5 g of optically active (-) -trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, 6-dimethyl-ba, 7, 8,
    9,10, 10a-hexahydro-bn-dibenzo (b, d) pyran-9-one as starting ketone. This product is extracted as described above, and 5 g of oil is obtained. Found: m / e. Reference: m / e 387. 4, oMdf; ; -b 34.6 Purification by chromatography of a sample of this product, carried out using high pressure liquid chromatography, results in the separation of the syn and anti-isomers of the optically active oxime Sin-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6 , 6-dimethyl-9-oxyimino-ba, 7, 8, 9, 10, 10a-hexahydro-bN-dibenzo (bd) pyran, oPS "" s + 34.8®, 137.3 °, anti-trans- 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxyimino-6a, 7, 8, 9, 10, 10a-hexahydro-bH-dibenzo (bd) pyran, 26.8, - 71.9 “Example 2. Pravo-, levovrshv-trans-1-hydroxy-3- (1, l-dimethylgreptl) -6, 6-dimethyl-9-oxy-amino-6a, 7,8, 9, 10, 10a-hexahydr -BH-dibenzo (b, d pyrai. To a mixed solution of 3.87 g of the right-, left-handed-trans-1-jsi-3- (1,1-dimethylheptyl) -6,6-da1Mvtil-9-oxyimino-6a , 7, 8, 9, 10, 10-hexahydro-bn-dibenzo (b, d) pyran (prepared as described at 8 with measure 1) in 50 ml of methanol containing traces of bromocresol green, 1.0 g of sodium cyanoborohydride are added in one portion. The reaction mixture is stirred at and at the same time, concentrated methanol solution of hydrogen chloride is added in separate portions until the solution becomes yellow. Then the reaction mixture was stirred for 2 hours and then the solvent was removed by evaporation under reduced pressure. The result is a product in the form of an oil. This oil is suspended in 50 ml of a 5% aqueous solution of sodium bicarbonate, and then extracted with diethyl ether. The ether extracts are combined, washed with water and dried. After the drying of the solvent, 3.72 of a white foam-like product is obtained, which is a right, levorghitz. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-hydroxyamino-6a, - 7, 8, 9 10,10a-hexahydro-6H-dibene (.b, L} pyran. Found,%: C 73.69, H 9.85, N 3.39, t / e 389 .. Cj4 H ,, N0,. Calculated,%: C 73.39, H 10.09, N 3.60, t / e 389. This white foamy product is reacted with 1.16 g of maleic acid in diethyl ether, as a result of which a crystalline maleic acid salt of right-, left-handed-trans-l-hydroxy-3- ( 1,1-dimethylheptyl) -b, 6-dimethyl-9-oxyg1MINO-6a, 7, 8, 9, 10, 10a-hexahydro-6H-dibenzo (b, d) pyran, t. Pl., 145-147 C Found,%; C 66.34, H 8.36, 3.04., Calculated,%: C 66.51, H 8.57, N 2.77. Prim p 3. Right, -leaf, -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9-amino-ba 7, 8, 9, 10, 10a-hexaghy Dro-bN- Dibenzo (b, d) Pyran. A solution of 1.93 g of a right, left-handed-sw-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxyimino-6a, 7, 8 , 9, 10, 10a-hexahydro-6H-dibenzo (b, d) pyran (as in example 2) in 100 ml of methanol and 25 ml of liquid anhydrous ammonia, contents 1, ..., Rene nickel, is stirred and heated at 100 ° C in for 6 hours in a hydrogen gas atmosphere at a pressure of 1000 psi (70 kg / cm). Then the reaction mixture is cooled to cm.snat temperature and filtered. The filtrate is concentrated by evaporation of the solvent under reduced pressure to obtain a solid mass. The latter is dissolved in 300 ml of diethyl ether and washed with 50 ml of 1N hydrochloric acid, 50 ml of 5% aqueous sodium bicarbonate solution and water. The ether solution is dried and evaporated to dryness under reduced pressure, yielding 500 mg of a white solid product. The resulting solid product is converted from a mixture of diethyl ether and hexane to a mixture, resulting in 1.85 grams of right-, levovorgian-trans-1-. hydroxy-3- (1, l-dimethylheptyl) -6,6-diethyl-9-allOlHO-6a, 7, 8, 9,10,10a-hexahydho-6H-dibenzo (b, d) pyran. Found,%: c 77.77, H 10.08, N 3.27, m / e 373. m e Calculated,%: C 77.16, H 10.52, N 3.75, ffl / e 373. Example 4. Acid maleic acid, right-, left-handed. Trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8,9,10,10 hexahydro-bN-dibenzo ( bd) piran. Solution 340 m right-, levorot.-trans-1-hydroxy-3, 3- (1,1-dimethylheptyl) -6, b-dimethyl-9-amino-6a, 7.8,9,10, 10a-hexahydro 6H-dibenzo (b, d) pyran in 50 ml of simple diethyl ether, containing 164 mg of maleic acid, stirred and heated with
    backcircuit for 10 min. The product precipitates from the solution and is recovered by filtration, thereby obtaining the acidic, right, levravrac-trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, 6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-bN-dibenzo (b, d) pyran as a white solid, so pl. 157-159 0.
    Found,%; C 68.51; H 8.57; N 2.66.
    CiftH jno.
    Calculated,%: C 68.68, H 8.85, N 2.86.
    Example 5. Right-, levovrasch-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9-acetamido-6a, 7.8.9, 10.10a-hexahydro-6H- dibenzo (b, d) pyran.
    To mix 4y ° solution of 750 mg of right-, levrovsvts.-trans-1-oxy-3f (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-ba, 7,8,9,10,10- For agarganobi-dibenzo (b, d) pyran ib 10 ml of ethanol are added in one portion to 1.5 ml of triethylamine and 1.0 ml of acetic anhydride. The reaction mixture is stirred for 12 hours at and then it is added to 50 ml of water. The aqueous solution of the reaction mixture is extracted with simple diethyl ether. the extracts are combined, washed with water and 10% aqueous sodium bicarbonate solution and dried. After removal of the solvent by evaporation under reduced pressure, 840 mg is obtained. solid product in the form of foam. This foam product was injected into the column, filled with 30 g of Wpelm activated with a gel (activity 1) and eaten with this acetate. The fractions, hotm, khgis showed a thin-layer chromatography study, measuring the desired content, conjunction and evaporation to dryness. Get 735 mg right-, levovrshts. -trans-1-0 | {si-3- (1,1-dimethylI heptyl) -6,6-dimethylg 9-acetam11To-6a, 7,8,9,10,1 Oa-hexa-syngene-eH-dibenzo (b , (} pyran.
    Found,%: C 75.51, H 9.75, N 3.43, t / e 415.
    ,
    ; calculated,%: C 75.14, H 9.94, m / e 414.
    Example 6. The process of osuststv lu, as in example 5, with the right-, levovrats.-trans-l-QKcit-3 (1,1-Dimethylheptyl) -6, b-dimethyl-9-amnno-6a "7, 8,9,10,10a-heccaris-bH-dibenzo (b, d) pyran, taken in an amount of 5.98 g, is reacted with 8.0 MP of acetic anhydride and 12 ml of triethylamine in 100 ml of methanol. After treatment with the received VDO6CM, 3.97 g of product is obtained in
    in the form of a white solid. This product is subjected to chromatographic separation by passing it through a column filled with 240 g of activated silica gel Woelm (activity 1). The target fractions (obtained by this separation) are carefully collected and the solvent is removed from them, resulting in 1.06 g of right-, left-handed-trans-1-hydroxy-3- (1,1-dimethylheptyl), b-dimethyl -9 o1-acetamido-6a, 7,8,9,10,10a-hexahydro-bn-dibenzo (b, d) pyran7 A sample of this axial isomer crystallizes out. from 20 ml of n-hexane. Melting point of the product obtained is 195-197 s,
    Found,%: C 75.37, H 10.05, 3.12.
    Calculated,%: C 75.14, H 9.94,
    0 N 3.37.
    After further chromatographic separation of this product, collecting the desired fractions and then evaporating the solvent, 2.16 g are obtained.
    5 right-, levovrasch.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9a -acetamido-6a, 7,8,9,10,1 Oa-hexagndro-bH- dibenzo (b, d) pyran. Melting point of the product 200-202 s.
    Found,%: C 74.95, H 9.58,
    N 3.11.
    ,
    G20
    Yochiyo enb,%: C 75.14, H 9.94, "3.37 l
    Example 7: Pravo-, levovrasch.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b -dimethyl-9-propnonamide o-6a, 7,8,9,10, Yua- hexahydrobH-dibenzo (b, d.) nHpaH.
    A solution of 373 mg of the right-, levovrosht-trans-1toxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-gi-6a, 7,8,9,10, 10a-hexagndro-bN- dibenzo (b, d) pyramine in 20 MP of methanol, containing 1.3 g of prprionic acid anhydride and 2.5 MP of triethylamine, is boiled at room temperature for 48 hours, the reaction mixture is diluted with 25 ml of water and washed in for 2 h at room temperature. Next, the excess methanol is removed by &lt; RTI ID = 0.0 &gt; Sh1Ary1 </ RTI> under reduced conditions and the product is extracted with diethyl ether, the ether extracts are combined, washed with water, 2N hydrochloric acid, 10% strength sodium bicarbonate solution, and dried.
    By evaporation of the solution under reduced pressure, a foamy product is obtained, which is further separated by chromatographic separation, passing it through a chromatographic column filled with silica gel (20 g) and eluted with diethyl ether, collecting 10 ml fractions. 5-30 ml fractions are mixed and the solvent is removed from them (by evaporation), resulting in 434 mg of right-, left-folding, trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl -9-propionamido-6a, 7,8,9, 10 g 10a-hexahydro-bH-dibenzo (b, d) pyran. Found,%: C 75.23, H 9.84, N 3.26, t / e 429. C. scsleno,%: c 75.48, H 10.09, Shc (N 3.26, t / e 429. Example 6. Right-, left-handed rotation -trans-1-acetoxy-3- (1,1-dimethylheptyl) - 6,6-dimethyl-9-acetamido-6a, 7.8 9, .10,10a-hexahydro-6H-dibenzo (b, A) pyran, A solution containing 373 mg of right-handed rotation.-Trans-1-hydroxy-3- (1,1-dimeti heptyl) -6,6-dimethyl-9-amino-6a, 7 8, 9,10,10a-hexahydro-6H-di6enzo (b, d) pyran, 10 ml of acetic anhydride and 10 ml of pyridine, stirred at room temperature for 48 hours. The reaction mixture is cooled and the methanol is removed by evaporation. The product left after evaporation is dissolved in diethyl ether and washed Hyotocic acid with water, 1N hydrochloric acid, and saline solution. The ether solution is dried and the solvent is removed by evaporation, and the resulting product is obtained .S as a white foamy substance. The resulting foamy product is purified by chromatography / passage through a chromatographic column. filled with 20 g of activated silica gel and eluted with diethyl ether. After evaporation of the solution from the target fractions, collected by chromatographic separation, 420 mg of pravo-, levovrchts.- trans-1-acetox-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-acetamido- 6a, 7.8, 9, 10, 10a-hexahydro-6H-dibenac (b, d) pyran. Found,%: C 73.26, H 9.36, k 3.28, t / e 457. C lN N0. Calculated,%: C 73.49, H 9.47, N 3.06, m / e 457.. PRI me R 9. Right-, left-handed-trans-1-hydroxy-3- (1,1-dimethylgevigyl) -6 6-dimethyl-9-formamido-6a, 7g8,9, 10,10a-hexahydro bn-dibeiso (b, d) liray. A solution of 15 ml of acetic anhydride and 7.5. Ml of 98% formic acid is mixed and heated with reflux w. 15. Mine. The mixture is cooled to room temperature and 2.5 g of sodium acetate and 373 mg right-levogurgi are added to it. -trans-1-hydroxy-3 - {1,1-dimethyl heptyl) -6,6-dimethyl-9-amino-6a, 7.8, 9,10,10a-hexahydro-bH-dibenzo (b. dl pyran The reaction mixture is stirred for 4 hours at room temperature and then injected into a solution of methanol containing sodium bicarbonate and water, the mixture is stirred for 1 hour, after which the solvent is removed by evaporation under reduced pressure. The aqueous layer is extracted with diethyl ether and the ether extracts are combined with each other, washed with water and dried. After the solvent is successful, 410 mg is obtained by evaporation as a white solid. The resulting solid is purified by chromatography by passing it through a column filled with 20 g of silica gel. 276 mg of right-, left-handed-trans-1-hydroxy-3- (1,1-dimethylheptyl) are obtained. -6,6-limetip-9-formamide-6a, 7,8,9,10,10a-hexahydro-bH-dibenzo (b, d) pyran. Found: C 74.61, H 9.53, N 3.64, m / e 401. SzzNz NOZ. Vyisleno,%: C 74.77, H 9.79, N 3.49, ha / e 401. Example 10. Right-, left-handed. -trans-1-acetoxy-3- (1, 1-dimethylheptyl) -6,6-dimethyl-9- (W, N-diacetylamino) -6a, 7, 10, 1ba-tetrahydro-bi-dibenzo (b, d ) piran. A solution of 2.59 g of the right-, levovdel.-trans-1 - hydroxy- 3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxyimino-6a, 7, 8,9,10,10a-hexahydro -6H-dibenzo (b, d) nHpaHa in 25 m of acetic anhydride and 75 MP of pyridine was mixed under an atmosphere of nitrogen gas and heated under reflux for 24 hours. After cooling the reaction mixture to x.1L, the solvent was removed. by evaporation under reduced motion, semi-oily product. The latter is dissolved in 50 ml of diethyl ether and 30 ml of water and stirred for 1 hour. The mixture is filtered and the organic layer is separated. The ether solution is washed with 1N. hydrochloric acid, water, saturated sodium chloride solution and dried. After removal of the solvent, 3.57 g of a dark oily product are obtained, and C is further subjected to chromatographic separation, passage through 100 g of activated silica gel and eluting with hexane (50%) - diethyl ether (50%). The fractions containing the main product were combined and evaporated to dryness, yielding 3.12 g of mostly right, levorazr.-1-acetoxy-3- (1,1-dimethylheptyl1) -6,6-dimethyl-9- (N, N-diacetylamine) -6a, 7,10,10a-tetrahydro-6H-,
    -dibenzo (b, d) pyran containing a small amount of A compound.
    Found t / e 497,
    Calculated: m / e 497.
    Example 11. Right-, levorus.-Trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, b-dimethyl-9- (acetamido) -b, 7,10,10a-tetrahydro-bN-dibenzo {B, d) piran.
    Prepare a solution of 5.4 g of right-, lv.c.-trans-1-acetoxy-3- (1,1-dimethylheptyl) -6, b-dimethyl-9- (M, M-diacetylamino) -b, 7,10 , 10a-tetrahydro-bH-dibenzo (b, d) pyran in 150 MP of methanol containing 50 MP of a 20% aqueous solution of potassium carbonate. The reaction mixture was stirred for 2 hours and then dryed under reduced pressure. The resulting oily substance is suspended in 100 ml of water and the aqueous mixture is extracted with diethyl ether. The ether extracts are combined, diluted with 20 ml of ethyl acetate and then washed with 2N. hydrochloric acid, 10% aqueous solution of sodium bicarbonate and dried. After removal of the solvent, 1.54 g of solid are obtained, which is then crystallized from hexane to form 133 g of right-, levorot.-trans-1-hydroxy-3T (1I1-dimethylheptyl) -6, b-dimethyl-9- (acetamido) -bad, 7.1 O, 10a-tetrahydro-bH-dibenzo (b, d) pyran, t. pl. 186-188 ° C.
    Found,%; C 73.74, H 8.79, N 3.16, O 13.90, t / e 413.
    -2..Calculated,%: C 73.81, H 9.07,
    M 3.07, O 14.05, m / e 413.
    Example 12. Right-, levorus.-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9- (acetamido) -6a, 7.8,910, 10a-hexahydro-bN-dibenzo (b d) piran.
    A solution of 1.177 g of the right-, levovrgits-1-ox-3- (1,1-dimethylpentyl) -6, b-dimethyl-9- (acetamido) ba, 7,10,10 a1-tetrahydro-bN-di6enzo (b, d a) pyran in 100 ml of a 10% aqueous solution of ethnol containing 0.5 g of 5% suspended palladium on carbon carrier is stirred for 12 hours in an atmosphere of hydrogen at 50 psi pressure (3.5 kg / cm). Then the reaction mixture is cooled to room temperature and the filter is cleaned. The filtrate is concentrated to dryness by evaporation under reduced pressure to give 1.06 g of right-, left-handed-trans-1-hydroxy-3- (1,1.-dimethylheptyl) -b , b-dimethyl-9- (ace amido) -ba, 7/8, 9, 10, Yua-hexahydro-BN-dybenzo b, b) pyran. In the study of the NMR spectrum, it was established that the product formed is identical to the product obtained according to Example 3 ,.
    Example 13. Right-, levovrazh. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-ethylamino-ba, 7, 8, 9, 10,10a-hexahydro-bH-dibenzo (b, d) pyran . To a mixed solution of 650 mg of right-, left-handed. -Trans-1-hydroxy-3, - (1,1-dimethylheptyl) -b, b-dimethyl-9-acetamido-ba, 7,8,9,10,10a- hexahydro-bH-dibenzo (b, d) pyran in 5 ml of anhydrous tetrahydrofuran is added dropwise over 5 minutes to 5 ml of 1 M diborane in tetrahydrofuran. The reaction mixture is heated to reflux and stirred at reflux for 5 hours. Then the reaction mixture is cooled to and stirred while injecting 5 ml of 2N. hydrochloric acid to decompose excess diborane. The aqueous solution of the acidic reaction mixture is heated for about 30 minutes and then cooled again to 0 ° C. The solution is basified with a 10% aqueous solution of sodium bicarbonate and the product is extracted from this solution with diethyl ether 4, the ether extracts are combined and concentrated to dryness by evaporation under reduced pressure, to give 600 mg of right-, left-syrup-trans-1-hydroxy-3 - (1,1-dimethylheptyl) -b, b-dimethyl-9-ethylamino-ba, 7,8,9, 10,1 Oa-hexahydro-6H-dibenzo (b, d) pyran.
    Example 14. Right-, levovrshd.-Trans-1-hydroxy-Z- (1,1-dimethylheptyl) -b, b-dimethyl-9- (N-ethyl) -acetamido-ba, 7,8,9,10 , 1Oa-hexahydro-bH-dibenzo (b, d) pyran.
    A solution of 600 mg of right-, levorot.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-ethylamino-ba, 7,8,9, 10,10a-hexahydro-bN -dibenzo (b, d) pyran in 25 ml of methanol. and stirred at room temperature while adding 1.5 ml of triethylamine and 1.5 ml of acetic anhydride in one portion. The reaction mixture was stirred at 25 ° C for 36 hours The solvent is then removed from the reaction mixture by evaporation under reduced pressure, the residue is dissolved in diethyl ether, washed with water and an aqueous solution of sodium bicarbonate and high sutured. The solvent is removed by evaporation under reduced pressure, after which 550 mg of a white foamy product remain. The product obtained is subjected to chromatographic separation, passing it through 50 g of activated silicate (activity 1) and eluting with ethyl acetate. Fractions which, as shown The analysis by thin layer chromatography, contains the main product, is combined and evaporated to dryness, to obtain 410 mg right, left-handed, -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, b-dimethyl-9- (M- ethyl) -acetamido-ba, 7,8,9,10,10a-gwxacidro-6H-dibvnzo {b , d) pirana. The ratio t / e 443.
    Found,%; C 75.56; H 9.93; 2.98; O, 10.82.
    N
    SavNDUMOZ ..
    Calculated,%: C 75.80, H 10.22, N 3.16, O 10.82.
    The component present in an insignificant amount is right or levorot.-trans-1-acetoxy-3- (1,1-dimethylheptyl) -6, b-dimethyl-9- (M-ethyl) -acetamido-ba, 7.8, 9,10,1 Oa-hexahydro-6H-dibenzo (b, d) pyran. m / e 485.
    Example 15. Right-, levovrazh. -trans-1-hydroxy-3- (1, 1-dimethylheptyl) -6,6-dimethyl-9-dimethylamino-6a, 7.8,9,10,10a-hexahydro-6H-dibenzo (b, d) pyran .
    The solution of 1.48 g of the right-, levorot.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-6a, 7,8,9,10,10a-hexahydro-6H-dibenzo {b, d) pyran-9-one in 50 ml of methanol, containing 3.24 g of dimethylamine hydrochloride, 3.03 g of triethylamine and 378 mg of sodium cyanoborohydride, is stirred at room temperature for 60 hours. The reaction mixture is concentrated by evaporation of the solvent and the residue is dissolved in 50 ml of diethyl ether. The ether solution is taken with 0.5N hydrochloric acid, water, 10% aqueous sodium bicarbonate solution and again with water. This solution is dried and then the solvent is removed by evaporation under reduced pressure, to give the product as an oil. The latter is dissolved in 50 ml of hexane and diluted with 1.0 mg of 6.5N. Methanol solution of hydrochloric acid. The precipitated solid formed, as the analysis showed, is right-, left-handed-trans-1-hydroxy-3- {1, 1-dimethylheptyl) -6,6-dimethyl-9-dimevtilamino-6a hydrochloride, 7.8 , 9,10,10a-hexahydro-6H-dibenzo (b, d) pyrana, the amount of which is 1.67 g.
    Found,%: C, 70.60; H, 9.78; N, 2.98; ce, 7.62; t / e 401.
    C ,, H44N02CI.
    isleno,%: C 71.28, H 10.12, N 3.20, ce 8.09, t / e 401.
    Examples 16-19. In carrying out the process as in example 15 ,. The chemical interaction of the right-, left-handed-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10, Yua-hexahydro-bN-dibenzoC, d ) pyrana with the corresponding amine, resulting in the following compounds:
    Hydrochloride right-, levovrasch.-trans-1-hydroxy-3- (1,1-dimethylheptyl) 1
    -6,6-dimethyl-9-isopropylamino-6a, 7, 8,9,10,10a-hexahydro-6H-dibenzo (b, d) nHpaHa.
    Found,%: C 71.44, H 10.00, 3.28, cross 7.54, m / e 415.
    N
    Cj H fcNOjfCI.
    Calculated,%: C 71.73, H 10.26, 3.10, cross 7.84, t / e 415.
    N
    Right-, left-handed. -Trans-1-hydroxy--. -3- {1,1-dimethylheptyl) -6,6-dimethyl-9 - (2-propynyl) -amino 6a, 7,8,9,10, Y-hexahydro-bH-dibenzo (b, d) pyran.
    Found,%: C 78.55, H 9.83, 3.39, t / e 411. N
    C, j, H4, N02,
    five
    Calculated,%; C 78.78, H 10.04, N 3.40, t / e 411.
    The hydrochloride-right-, levorot.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9-M-methyl-N- {2-propylo) -amino, 7 , 8,9,10, Yua-hexahydro-bN-dibenzo (b, d) pyran.
    Found,% t C 71.01, H 9.54, N 2.52, C 7.13, w / e 425.
    C28 "44 02С
    W 1Number,%: C 72,78, H 9.60,
    five
    3.03, - ce 7.67, m / e 425.
    N
    Right-, levovrasch.-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-benzylamino-6a, 7,8,9,10, Yua-hexahydro-bN-dibeiso ( b, d) piran.
    D
    Found,%: C 80.31, H 9.86, 3.01, t / e 463.
    N
    Calculated,%: C 80.30, H 9.78, N 3.02, t / e 463.
    five
    Example 20. Right-, levovrazh. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (2-hydroxyethyl) amino-ba, 7,8,9,10,1 Oa-hexahydro-bN-dibenzo (b, d) pyran.
    6
    To a solution of 1.48 g right-, levorotum. -trans-1-hydroxy-3- (1, 1-dimethylheptyl) -6, b-dimethyl-6a, 7.8.9.10 10a - hexahydro-bN-dibeno (b, d) pyra-9-one in 50 ml of methanol was added 2.44 g of ethanolamine ideally one
    5 servings. The reaction mixture is stirred at room temperature for 30 minutes and then diluted with a solution of 1.5 ml of 6.5N hydrochloric acid in 10 ml of methanol. The acidic mixture
    0 is entrapped for 15 P1H, 378 mg of sodium cyanoborohydride is added to it and stirred for 72 hours at room temperature. The reaction mixture is filtered and the solvent is evaporated, resulting in a product in the form of a resin. This crude product is dissolved in 100 ml of simple distil zfir and washed with 0.5N. hydrochloric acid
    0 saturated sodium chloride solution, 10% sodium bicarbonate solution.  The ether layer is dried and the solvent is evaporated, after which a white foam-like product is obtained.  The latter is dissolved in 50 ml of hexa5a, to which 1.0 ml of 6.5N is added.  methanol solution of hydrochloric acid).  The resulting crystalline solid was recovered by filtration.  As the study showed, this product (g) before. is a right-, left-handed, hydrochloride, trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9- (2-hydroxyethyl) -amino-ba, 7,8,9, 10,10a-hexahyd u-bn-dibenzb (b, d) pyran.  Found,%: C 68.48, H 9.58, M 3.25, ce 7.51, t / e 417.   C2fcH44MO, CI.  Calculated,%: C 68.77, H 9.77, N 3.08, its 7.81, t / e 417.  Example 21  Right-, levovrashgg.  -1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-piperidino-6a, 7,8,9, 10,10a-hexahydro-bH-dibenzo (b, d) pi wounds.  Analogously to the example 20 744 mg right, levrash. -1-hydroxy-3- (1,1 dimethyl heptyl) -6,6-dimethyl-6a, 7,8,9,10,10d-hexahydro-6H-dibenzo (b, d) nHpaH-9-it chemically interacts 1.7 g of piperidine to form a mixture of imine, which is then reduced by chemical interaction with 190 mg of sodium cyanoborohydride and 0.75 ml of 6.5 n.  hydrochloric acid.  As a result of the accepted treatment of this reaction mixture, each product is in the form of an oil. which is then treated with methanolic solution of hydrochloric acid.  Get 689 mg of crystalline hydrochloride right-, levovoraed. -1-hydroxy-3- (1,1-dimethylheptil). -6,6-dimethyl-9-piperidone-ba, 7,8,9,10,1 Oa-hexahydro-6H-dibenzo (b, d) pyran.  found,%: C 72.70, H 10.12, M 3.14, CK 7.16, t / e 441.  C-ANDNAUS, Isleno,%: C 72.85, H 10.12, N 2.93, ce 7.41, ffl / e 441.  Example 22  Analogously to example 20, using morpholine as a gishna, get the product in the form of oil.  The latter is reacted with a solution of hydrochloric acid in methanol, as a result of which 615 mg of hydrochloride is obtained, levrash, is obtained. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-morph-lino-6a, 7,8,9,10,10a-hexag1C1C about-4n dibaze (b, d pyran, %: C 69.79. , H 9.40, N 3.04, ce 7.15, m / e 443.  C, "H4bNOjCI.  Blended,%: C 70.04, AND 9.66, N 2.92, Ct 7.38, m / e 443.  Example 23  Right-, left-handed. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (3-hydroxycarbon l) -propionamido-ba, 7,8,9,10,10a-hexyagidro-6H- dibenzo (b, d) pyran.  A solution of 372 mg of right-, levovrai-trans-hydroxy-3- (1,1-di-methylheptyl.  -6,6-dimethyl-9-amino-6a, 7,8,9,10,10a-hexahydro-bH-dibenzo (b, d) pyran in 20 ml of methanol, containing 1.0 g of succinic anhydride and 2, 5 ml of triethylamine, stirring at room temperature for 72 hours.  The reaction mixture is then diluted with 50 ml of water and the organic solvent is removed by evaporation.  The aqueous layer was extracted with diethyl ether and the ether extracts were combined, washed with water, 2N.  hydrochloric acid, again. water and then 10% sodium bicarbonate.  After drying the solution, the solvent is removed by evaporation under reduced pressure, resulting in a product in the form of a foamy substance.  The latter is passed through a column filled with 20 g of Woelm activated silica gel (activity 11} and eluted with ethyl acetate.  The fractions, which, as shown by a study using thin-layer chromatography, contain the main component, are collected and evaporated in a solvent, resulting in 507 mg of the right, levrashara1-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9- (3-hydroxycarbonyl) -propionamido-6a, 7,8,9,1O, 1Oa-hexahydro-bH-dibenzo (b, d) pyran.  Found,%: C 70.98, H 9.35, M 2.97, t / e 473.  Sloe.  Isleno,%: C 71.00, H 9.15, N 2.98, t / e 473.  Example 24  Right, levvrsha. -1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9-benzamido-6a, 7,8,9,10, 10a-hexahydro-6H-dibenzo (b, d) pyran.   To a solution of 373 mg right-, left-spin. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-amino-6a, 7,8, 9,10,10a-hexahydro-bN-dibenzo (b, d) pyran in 20 ml of methanol, a solution of g of aji benzoic acid hydride in 2.5 ml of triethylamine is added in one portion.  The reaction mixture is stirred for 60 hours at room temperature and then it is diluted with 20 ml of water and stirred for another 2 hours.  The organic solvent is removed by evaporation and the aqueous phase is extracted with diethyl ether.  The ether extracts are combined, washed with water, 2N.  hydrochloric acid, again with water and finally with 10% aqueous sodium bicarbonate solution.  The organic layer is dried. and the solvent is removed by evaporation, at,. the result is getting the product as a foam in quality.  The latter is subjected to chromatographic separation, passing it through 20 g of activated silica gel Woelm (activity I) and eluting with 50% solution.  rum diethyl ether in hexane.  The desired fractions are collected and the solvent is removed from them by evaporation, resulting in half a 525 mg of the right-hand, left-handed. -trans-l-hydroxy-3- (1,1-dimethylheptyl) -6. , 6-di methyl-9-benzamidr-ba, 7,8,9,10,10a-hexaghi Dro-b-dibenzo (b, d) pyran.  Found,%: C 77.75, H 9.30, M, m / e 477.  -30 4b. ШSh number,%: C 77.95, H 9.07, N 2.93, t / e 477.  Example 25  Right-, left-handed.  -trans-1-hydroxy- (1,2-dimethylheptyl) -6,6-dimesh1-9-hydroxy-6a, 7,8,9,10,10a-hexahydro-6H-dib aoCb df-DHpaH.  .  To a mixed solution of 2.0 g right- ,. left-handed -trans-1-hydroxy-3- (1,2-dimethylheptyl) -b, b-dimethyl-ba, 7,8,9,10 lba-hexaidro-bN-dibenzo (b, d) pyran-9-one in 40 ml of ethanol, containing 10 ml of water, are added in one portion of 560 ml of hydroxylamine hydrochloride, followed by 2 ml of 5 and.  sodium hydrate.  The reaction mixture is heated to reflux temperature and stirred under reflux for 90 minutes.  This reaction mixture is cooled and ethanol is recovered by evaporation.  The aqueous layer was extracted with diethyl ether and the ether extracts were combined, washed with water and dried.  After removal of the solvent by evaporation under reduced pressure, 2.3 g of product are obtained in the form of an oil.  The latter is subjected to purification by the method of hrsilatography, passing it through 100 g of strength of the cagel and eluting with simple diethyl ether.  The corresponding fractions {co-collect and evaporate the solvent from them, resulting in 1.46 g of the right-, levravd. -trans-1-oxy-3- (1,2-dimethylheptyl) -b, 6-di methyl-9-oxyimino-ba, 7,8,9,10,10a-hexahydro-bn-dibene (b, d) pirana.  Found,%: C 74.13, H 9.50, N 3.39, t / e 387.  C44H5, NOE.  Calculated,%: C 74.38, H 9.62, H 3.61, t / e 387.  Example 26  The process is resolved as described in Example 25, with the right-, left-handed. -cis-1-hydroxy-3- (1,1-dimet g1hept l) -6,6-dimethyl-ba, 7,8,9,10,10a-hexagnium-6H -dibeiso (b, d) pyran-9 - It interacts with 2.1 g of hydroxychlorine hydrochloride and 8 ml of 5 n.  sodium hydroxide in 100 ml of ethanol containing 25 MP of water.  As a result of the above treatment, a foamy PRODUCT is obtained, which crystallizes out of 75 ml of hexane with an image (5.46 g of right-, left-handed. -cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxyimino-ba, 7,8,9,10,1Oa-hexahydro-bN-dibenzo (b, d) pyran .  The melting point of the product is 162164 C.  Found,%: C 74.56, H 9.41, 3.78.  C24H 7 ° 3 Calculated,%: C 74.38, H 9.62, N 3.61.  Example 27  Right-, left-handed.  -trans-1-hydroxy-3- (1, 2-dimethylheptyl) -6, b-dimethyl-9-amino-6a, 7, 8.9, 10, 10a-he1ssagidro-bN-dibenzo-.  (b, d) pyran.  A solution of 1.12 g of the right-, left-handed, -trans-1-hydroxy-3- (1,2-di-methylheptyl) gb, 6-dimethyl-9-oxyimino-6a, 7.8.9, 10.10- Hexahydro-bH-dibenzo {b, d) pyran in 100 ml of methanol containing 25 ml of liquid a &amp; shaka and 1.0 g of Rene nickel is stirred at 100 s for 8 hours in an atmosphere of hydrogen at a pressure of 1000 psi (70 kg / cm).  Then the reactionary.  the mixture is filtered, concentrated to a residual volume of about 50 ml and diluted with 25 ml of 10% sodium bicarbonate.  This aqueous mixture is extracted with diethyl ether.  The ether extracts are combined, water is dried, and the solvent is evaporated from them, resulting in 861 mg of the right-, left-handed rotation. -trans-1goxy-3- (1,2-dimethylheptyl) 6,6-dimethyl-. 9-amino-6a, 7,8,9,10,10a-hexahydro-bN-dibenzo (b, d) pyran.  Found,%: C 77.54, H 10.52, N 3.94.  ffi / e 373.   Calculated,%: C 77.16, H 10.52, N 3.75.  m / e 373.  .  Example 28  The process is carried out as described in Example 27, with 9TOM 3.87 g, right, levvorgits. -.  -CIS-1-OXY-3- (1,1-dimethylheptyl) -6, 6-dimvtil-9-oxyimino-6a, 7.8.9, 10.1 Oa-hexahydro-6H-dibenzo (b, d) Pyran is hydrogenated at 1000 psi pressure (70 kg / cm) in the presence of 2.0 g of Rene nickel in 100 ml of metamole containing 25 ml of liquid ammonia, resulting in a yield of 3.38 g of right- and levovorgi. -Cis-1-hydroxy-3- (1, lj№ "MeTimrenTiin) -6,6-dimvtil-9-amino-6a, 7,8,9,10,1 Oa-hexahydro-bN-dibenzo (b, d ) pyran.  Found,%: C 76.87, H 10.44, M 3.70, t / e 373.  .   C44H39 “H  Calcined,%: C 77.16, H 10.52, N 3.75, t / e 373.  PRI me R 29.  Right-, left-handed. -Trans-1-hydroxy-3- (1, 2-dimethylheptyl) -6,6-day (Tyl-9-acetamido-6a 7, 8,9,10,10a-hexahydro-6H-dibenzo (b, d ) nHpaH.  A solution of 960 mg right-, left-handed.  -trans-1-hydroxy-3- (1,2-dimethylheptyl) -6, b-dimethyl-9-amino-6a, 7,8,9,10,10-hexahydro-bN-dibenzo (b, d) pyran in 40 ml of methanol containing 5 ml of triethylamine and 5 ml of vinegar anhydride.  Acidic acid, stirred at room temperature for 24 hours.  The methanol is then removed by evaporation and the solution is diluted with 50 ml of 10% sodium bicarbonate and stirred for 2 hours.  The aqueous mixture is extracted with diethyl ether and the ether extracts are combined, dried and the solvent is removed, resulting in a product in the form of a foam-like substance.  The latter is subjected to chromatographic separation, passing through 50 g of silica gel and eluting first with 600 ml of chloroform, 1000 ml of 0.5% solution of methanol in chloroform, and then 2000 ml of 1% solution of methanol in chloroform, and finally 500 ml of 2% -No methanol solution in chloroform.  Fractions of 20 ml volumes each are collected.  Fractions 61-95 are combined and evaporated to dryness, resulting in 354 mg of right-, left-handed. -trans-1-hydroxy-3- (1,2-dimethyl heptyl) -6,6-dimethyl-9-acetylMido-6a, 7,8,9. 1O, 1Oa-hexahydro-6H-dibenzo (b, d} pyran.  The melting point of the product is 140-145 ° C.  Found: C, 74.91; H, 9.93; N, 3.53.  Set NlJ MO, Calculated,%: C 75.14, H-9.94, N 3.37.  Fractions 101-150 are combined and the solvent is evaporated from them, resulting in 591 mg of right- and left-handed rotation.  -trance-. (1,2-dimethylheptyl) -6,6-dimethyl-9 "t-acetamido-ba, 7,8, 9,10,10a-hexahydro-6H-dibenzo (b, d) pyran.  Found,%: C 74.89, H 9.65, N 3.61, 1 / e 415.  .  Calculated,%: C 75.14, H 9.94, N 3.37, m / e 415.  Example 30  The process is carried out as in example 29, with 1D8 g right-, levovrschts. -cis-1-hydroxy-3Jr (1, D-dimethylheptyl) -hexahydro-6H-dibeiso (b, d) pyran is gnified by acetic acid anhydride and triethylamine in methanol, resulting in 545 mg of right- and left-handed rotation after chromatographic separation.  -cis- 1-hydroxy-3- (1, 1 -dn-methylheptyl) -6,6-dimethyl-9j-acetamidr-6a, 7, 8.9, 10.1 Oa-hexahydro-6H-dibe zo (b, d ) pirana, t.  square  107-120 C, and 494 mg right-, levovrasch. -cis 1-hydroxy-3- (. 1,1-dimethylheptyl-6, b-dimethyl-9 c1-acetamido-6a, 7,8,9,10,10a-hexahydro-bN-dibenzo I b, d) pyran, t.  square  164-168C.  Example 31  Trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-N- (2-acetoxyethyl) -acetamido-6a, 7,8,9,10,10a-hexahydro-6H- dibenzo (b, d) pyran.  A solution of 500 mg of trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9- (2-hydroxyethyl) amino-6a hydrochloride, 7, 8,9,10,1 Oa-hexahydro 6H-dibenzo (b, d) pyran, prepared as described in Example 20, in 25 ml of methanol containing 1.5 ml of triethylamine and 1.5 ml of acetic anhydride, is stirred at 25 ° C. for 48 h.  Then this reaction mixture is diluted with 50 ml of chloroform and the diluted solution is heated with reflux for 24 hours.  the reaction mixture is cooled to room temperature and the solvent is evaporated from it, as a result of what trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimet is obtained. yl-9-M- (2-acetoxyethyl) -acetamido-ba, 7,8,9,10, Yu-hexahydro-bH-dibenzo (b, d) pyran.  Found,%: C 69.46, H 8.72, N 2.56, t / e 501.  .  Calculated,%: C 71.82, H 9.44 N 2.79, t / e 501.  Example 32  Trans-1-hydroxy-3- {1, 1-dimethylheptyl) -6 j 6-dimethyl-9-N- (2-hydroxyethyl) -acetamido-6a, 7.8, 9,10,10a-hexahydro-6H- dibene (b, d) pyran. .  .  A solution of 500 mg of trans-1-hydroxy-Z- (1,1-dimethylhepton) -6,6-dimethyl-9-N- (2-acetoxyethyl) -acetamido-ba, 7,8,9,10,1Oa-hexahydro -6 H-dibenzo (b, d) pyran, prepared as described in example 31, was dissolved in a solution of 40 ml of methanol and 10 ml of water containing 138 mg of potassium carbonate.  The reaction mixture was stirred for 90 minutes and then diluted with 150 ml of a saturated aqueous solution of sodium chloride.  The aqueous mixture is extracted several times with diethyl ether.  The ether extracts are combined, taken up with water, dried and the solvent is removed by evaporation under reduced pressure, resulting in half of 5QO mg.  product as a white solid.  The resulting solid crystallizes out from a mixture of cyclohexane-hexane ethyl acetate, resulting in 395 mg of trans-1-hydroxy-3- (1,1-dimethylhept1-1) -b, 6-dimethyl-9-M- (2-oxydyl) acetamide-2 6a, 7,8,9,10,10a-hexahydro-bN-dibenzo (b, d) pyran.  The melting point of this product is 148-158 C.  t / e 459.  Found,%: C 73.05, H 9.84, N 3.15.  .  CzgH + jNO.  Calculated,%: C 73.16, H 9.87, N 3.05.  PRI m and p 33.  Pravo-, levovra -trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, b-dimethyl-9-M- (acetoxy) -atsvtg sh to-ba, 7.8,9,10,10a -hexahydro-bH-dibeeio (b, d) pyran.  A solution of 2.5 ml of acetic anhydride in 25 ml of methanol containing 500 mg of right-, levovrats. t-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, b-dimethyl-9-hydroxyamino-6a, 7,8,9, 10,10a-hexahydro-bN-dibenzo (b, d) pyran (prepared according to example 2), stirred at 24 h.  The solvent is then removed by evaporation, the oil remaining after evaporation is dissolved in diethyl ether and washed with dilute aqueous sodium bicarbonate solution.  The ether layer is dried and the solvent is evaporated from it, resulting in 550 mg of product in the form of a foamy substance.  The latter crystallization is made from 20 ml of hexane, as a result of which 230 mg is obtained in the right and left-handed direction. -trans-1-hydroxy-3- {1,1-dimethylheptyl) -6, b-dimethyl-9-M- (acetoxy) -acetamido-ba, 7,8,9,10, 10a-hexahydro-6H-dibenzo (b, d) pyrana.  The melting point of this product is 153-155 ° C.  After the second crystallization, 167 mg of product is obtained. Its melting point is 133-135 °. Both crystalline products are combined and subjected to analysis.  Found,%: C 71.21, H 8.95, N 3.06, t / e 473.  Cjtt Hj NOy, Calcined,%: C 71.00, H 9.15, N 2.96, ha / e 473.  Example 34  Right-, left-handed. -trans-1-hydroxy-3- (1,1-dintetilheptyl) -6,6-dimethyl-9-H- {2-propyne-1-yl) -acetse1mid6-6a, 7,8,9,10,10a -yr sahydro-6H-dibenzo (b, d) pyran.  To mix the solution 500 mg right-, levovrats. -trans-1-hydroxy-3- (1,1-dimethylhepty41) -6,6-dimethyl-9- (2-PROPIN-1-yl) -amino-ba, 7,8,9,10, 10a-gekcaridpo -6H-dibenzo (b, d} pyran in 25 ml of methanol containing 1.5 ml of triethylamine is added dropwise within 5 min. 1.5 ml of acetic anhydride.  After the addition was completed, the reaction mixture was stirred at 25 ° C for two days. Then the solvent was removed by evaporation, the resulting BOR5POT oil was dissolved in DIETHYL4 ether and added with an aqueous solution of sodium bicarbonate.  The ether solution is dried and the solvent is removed, whereby 500 mg of product is obtained as an oil.  The latter is purified by chromatographic separation, passing it through 25 g of activated silica gel Woelm (activity I) and eluting with simple ether diethyl ether.  The corresponding target fractions are sobgihiot and evaporated to dryness, resulting in 430 mg of the right and left vrgits. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-H- (2-propyn-1-yl) -acetateuedoba, 7,8,9,10, sagidro -BH-dibenzo (b, d) pyran.  Found,%: C 75.60, H 9.18, N 3.28, t / e 453.  Sdd Nd4 BUT.  Calculated,%; c 76.50, H 9.40, N 3.19, t / e 453.  Example 35  Bromide right-, levovr ssch. -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6 6-dimethyl-9- (N, N-dimethyl-M-propargyl) -ammonium, 7,8,9, 10,10- hexahydro-6H-dibenzo (b, d) pyran.  A solution of 600 mg right-, levorotum.   1-ox-3- (1,1-dimethylheptyl) -6, 6-dimeth: yl-9-dimethylamino-6a, 7,8, 9,10,10a-hexagIdfo-6H-dibenzo (b, d) pyran 25 mp of ethanol, containing 1.5 MP of propargyl bromide, is heated to reflux temperature and -mixed with reflux of phlegon within 48 hours.  After that, the reaction mixture is cooled to room temperature and evaporated to a volume of about 5 ml.  The residue is diluted with diethyl ether and hexaioma, resulting in the product falling out.  The latter is recovered by filtration.  Get 625 mg right-, levorotum. -tran -1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-9- (N, M-dimethyl-N-propargyl) -acon-ba, 7,8,9,10,10a -hexagidpo-6H-dibene (b, d) pyran.  Melt temperature. this product 104-107 with.  Found,%; C 65.45, H 8.42, N 2.66, Br 14.94.  CjftH. BrWOjr.  You isleno,%: C 66.39, H 8.76, N 2.77, Br 15.77.  Example 36  6aR, lOaR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -b, 6-dimethyl-9K- (and 9S) -metamido-6a, 7, 8.9,10,10a-gwxagidro-6H -dibenzo (b, d) pyran.  The process is carried out as in Example 1, with 7.5 g of 6aR, lOa R-trais-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-ba, 7 g 8.9, 10,10a-hexahydro-bH-dibenzo (b, d) nHpaH-9-OHa is reacted with 2.1 g of gndroxylamine to form the corresponding optically active oxime.  The latter is reduced by hydrogen in the presence of Rene nickel, resulting in 1.49 g of a mixture of 6aR, 10aK-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9 R (and 95) -amino -6a, 7,8,9,10,10a-hexahydro-bN-dibenzo (b, d) pyran, The solution of the latter compound in 35 ml of methanol containing 10 ml of triethylgr min is stirred at 25 ° C while adding to it drops for 10 min. 5 acetic anhydride.  The reaction mixture is then stirred at room temperature for 72 hours, after which the solvent is evaporated off under reduced pressure.  The remaining oil is dissolved in 50i ml of diethyl ether containing 10 ml of water.  The aqueous ethereal solution was stirred for 2 hours at room temperature, the organic layer was separated, washed with an aqueous solution of sodium bicarbonate and dried.  After evaporation of the solvent, 1.52 g of a white foamy product are obtained.  The obtained product is subjected to chromatic chromatography separation twice, passing it through columns filled with 100 g of Woelm activated silica gel (activity I) and eluting with 600 ml of chloroform, 1000 ml of a 0.5% (by volume) solution of methanol in chloroform and, finally, 1 % methanol in chloroform.  Fractions with a volume of 20 ml are collected.  The fractions, as the thin layer chromatography study showed, consist of one component, are combined and the solvent is removed from them by evaporation under reduced pressure.  Receive 297 mg of 6a R, 10a K-trans-1-hydroxy-3- (1 D-dimethylheptyl) -6, b-dimethyl-9 R-acetamido-6a, 7,8,9,10, 10a-hexahydro-bN -dibenzo (b, d) pyrana.
    Found,%: C 75.32, H 9.77, N 3.12, t / e 415.
    CogH, N0. . ,
    Calculated,%: C 75.14, H 9.94, N 3.37, m / e 415.
      , - 29.9
    As a result of further chromatographic separation, fractions containing 591 mg of 6aR, lOaR-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6, 6-dimethyl-95-acetamido-6a, 7.8, 9, 10 are obtained. , 10a-hexahydro-6H-dibenzo (b, d) pyran.
    Found,%: C 74.91, H 9.99, N 3.18, t / e 415.
    CjfeH. NOj.
    Calculated,%: C 75.14, H 9.94, N, t / e 415.
    -. sns. „O .., snsse„ ,, tso ul-jj -b4,9, toClg: - 236,5.
    EXAMPLE 37. A composition suitable for administration into the body by parenteral injection was prepared by BuoT by dissolving 25 mg of the right and left. Rotation-trans71-hydroxy-3- (1,2-dimethylhethyl) -b, 6-dimethyl-9- (N-ethyl) -acetamido-6a, 7.8,9,10,10a-hexahydro-bN. -dibenzo (b, d) pyran in 250 ml of a 0.9% aqueous solution of sodium chloride, and bringing the pH of this solution to 6-7.
    5 Example 38 .. Aqueous suspension suitable for oral administration is prepared by mixing 10 mg of finely ground right-, left-handed-trans-1-hydroxy-3-- (1-ethyl-2-hexanyl) -9-oxyimino-6a, 7,8,9,10,10a-hexahydro-bN-dibenzo (b, d) pyrana with 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, 5 mg of sodium saccharide, and 0.025 ml of vanillin tincture.
    15
    权利要求:
    Claims (1)
    [1]
    1. A method of producing 1-hydroxy-3-substituted tetrahydro- or 20 hexahydrodibenzo (b / d) pyran derivatives. General formulas
    OR
     (I)
    25
    where R is a hydrogen atom or alkanbyl
    U
    KG is alkyl,
    D R is a hydrogen atom or methyl, Z is selected from the following groups,
    Wb and f "
    R
    . "
    .
    Xx
    Jf
    one
     .
    Have
    five
    l
    jC L
    where R is hydroxy group, hydrogen atom, hydroxy group, alkyl, -CH2 (Cd, -C4-alkynyl), alkanoyl,
    0 alkanoyloxy group, phenyl C.-C /. - alkyl, phenyl-C-Cr-alkanoyl, group (CHi) v, -OH, - (CHa) and -0- (-alkanoyl), group
    ABOUT , -
    five
    -C- (CHi) nCOOH where n is an integer equal to 2.3 or 4,
    R6 is a hydrogen atom, alkyl, -CH 51 (Ca-C4 alkynyl), alkanoyl, R and R, taken with a nitrogen atom,
    0 to which they are bound, form a piperidine or morpholine ring, -
    R is a hydrogen atom or alkanoyl with-g L -7
    five
     - alkanoyl. or their optical isomers, or their salts, characterized in that the compound of the general formula O
    OR
    , (".
    S
    Ri - 4Q X; S Vjj2
    where R is a hydrogen atom.
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    同族专利:
    公开号 | 公开日
    DK68179A|1979-09-17|
    FI790503A|1979-08-18|
    EP0003883A1|1979-09-05|
    AR224359A1|1981-11-30|
    ES8502105A1|1980-07-16|
    JPS54122278A|1979-09-21|
    PH14622A|1981-10-12|
    FR2417510A1|1979-09-14|
    PL120661B1|1982-03-31|
    CS207769B2|1981-08-31|
    FR2417510B1|1980-08-14|
    RO82375A|1983-08-03|
    RO82369A|1983-08-03|
    AT366039B|1982-03-10|
    NZ189591A|1980-10-08|
    RO82370A|1983-08-03|
    AR225939A1|1982-05-14|
    IE790304L|1979-08-17|
    RO76886A|1982-02-01|
    PL121009B1|1982-04-30|
    PL213479A1|1980-03-10|
    DD142190A5|1980-06-11|
    RO82376A|1983-08-03|
    CH638800A5|1983-10-14|
    CA1111425A|1981-10-27|
    HU180729B|1983-04-29|
    ATA123979A|1981-07-15|
    ES8502106A1|1980-07-16|
    ES485621A1|1980-07-01|
    RO82369B|1983-07-30|
    BE873981A|1979-08-07|
    GB2014571B|1982-11-17|
    PL120645B1|1982-03-31|
    PL118576B1|1981-10-31|
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    ES477832A1|1980-04-01|
    ES485620A0|1980-07-16|
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    IE47999B1|1984-08-22|
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    法律状态:
    优先权:
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    US05/878,844|US4152450A|1978-02-17|1978-02-17|9-Amino-dibenzopyrans|
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