US3873576A - Tetrahydrodibenzopyrans - Google Patents

Tetrahydrodibenzopyrans Download PDF

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US3873576A
US3873576A US295262A US29526272A US3873576A US 3873576 A US3873576 A US 3873576A US 295262 A US295262 A US 295262A US 29526272 A US29526272 A US 29526272A US 3873576 A US3873576 A US 3873576A
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Theodor Petrzilka
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Formula 1 compounds where the alkyl group is a straight or branched chain alkyl of from 14 and 6-10 C- atoms are novel homologues of the 3-n-pentyl compound, a metabolite of tetrahydrocannabinol known per se.
  • Formula 1 compounds have bactericidic, sedative, analgetic and psychomimetic effect when applied to the human organism. Novel compounds'(Formulae 4a, 5b, 6 and 7) are disclosed as starting materials and/or intermediates, some of them having pharmacological utility similar to the Formula 1 compounds.
  • metabolites of THC i.e. tetrahydrocannabinol.
  • the ll-hydroxy metabolite also referred to herein as the 9-hydroxymethyl metabolite
  • a process of synthesizing such active metabolites in good yields was required. Previous attempts to achieve such synthesis failed, apparently due to the complex and stereo-specific structure of this type of compounds.
  • Another object is to provide for novel starting substances and intermediates for such synthesis.
  • thermal conversion of compound 2 into compound 3 is achieved by simply heating compound 2, e.g. at temperatures of above 200C, e.g. from about 250 to about 300C, a temperature of 290C i 10C being particularly preferred.
  • Inert diluents need not be present during the heating step and, preferably, air is excluded during the thermal conversion of compound 2.
  • Removal of the two acyl groups from compound 3, Le. from the conversion product can be achieved by methods known in the art, e.g. reduction techniques, preferably by heating compound 3 in an enert solvent and in the presence of LiAlI-I,.
  • the invention provides; as novel substances, the compounds of Formula I in which R is straight or branched alkyl of l-lO C-atoms excluding the compound where R, is n-pentyl, and the compounds of Formulae 4a, 5b, 6 and 7 in which R is the pentyl group or another C -C alkyl group.
  • Formula 1 shows the target compound and the numbering system used throughout the specification. Before proceeding tothe details of the compounds shown it is to be understood that the bonds or lines shown in 6-position of all Formulae do not represent free bonds but methyl groups 'CH each line representing one such group. By the same token, the free line in 9-position of Formulae 6, 7 and also designates a methyl group.
  • the two hydrogen atoms in 6a and 10a are sterically arranged such that the hydrogen at the end of the full line in 6a-position is above the plane of drawing while the hydrogen attheend of the broken line in IOa-position is below the plane of drawing.
  • Group R in Formulae 2 and 3 is hydrogen or a lower alkye group of from 1 to about 5 C-atoms, R methyl being a preferred embodiment so that the preferred acyl group in positions 1 and 8 of Formula 2, and l and ll of Formula 3 is the acetyl group.
  • R in Formulae l-l2 is straight or branched chain alkyl, e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, etc.
  • R in Formulae 4a, 4b and I2 is a protective group of the type known in the art, preferably the tetrahydropyranyl group.
  • R in Formulae 8a, 8b, 8c and l l is a protective group and can be the same as R,.
  • a preferred protective group R is the acetyl group.
  • the starting substance, i. e. a Formula 2 compound, for the process of the invention may be obtained in various ways, the following methods A and B being preferred, however. Each method comprises a sequence of steps identified below as A-l to A-S and B-l to B-S:
  • both preferred methods A and B start from a Formula 9 compound which in turn can be ob- Formula 2 tained in good yields according to the process disclosed in my US Pat. No. 3,560,528, issued Feb. 7, l97l, incorporated by reference into the present specification.
  • Step A-l The protective group R introduced in this step should be stable under alkaline conditions.
  • suitable R groups are the trimethylsilyl group and the O-tetrahydropyranyl group, the latter being particularly preferred.
  • Suitable procedures are well known per se in the art, as are other suitable groups. Product isolation is neither critical nor required.
  • Step A-2 Epoxydation of 10 can be effected according to methods known per se, e.g. by means of peracids such as m-chloro perbenzoic acid in inert solvents.
  • the epoxides 4a, 4b are diastereomers and can be used singly or in mixture for the next step. Product isolation is not required.
  • Step A-3 Here, the epoxide ring is opened to produce a Formula 12 compound in a manner known per se in the art, e. g. by treatment with a base in an inert solvent using such bases as alkali metal alcoholates, e. g. lithium, sodium or potassium salts of methyl, ethyl, propyl, t-butyl or t-amyl alcohol, butyl lithium being the preferred base.
  • bases as alkali metal alcoholates, e. g. lithium, sodium or potassium salts of methyl, ethyl, propyl, t-butyl or t-amyl alcohol, butyl lithium being the preferred base.
  • Step A-4 Now, the protective group will be removed in a manner known per se in the art, e. g. by treatment with a mineral acid, generally a diluted aqueous or alcoholic acid such as hydrochloric, hydrobromic or hydroiodic acid.
  • a mineral acid generally a diluted aqueous or alcoholic acid such as hydrochloric, hydrobromic or hydroiodic acid.
  • the preferred acid is hydrochloric acid.
  • Suitable inert solvents in this and other steps are normally liquid hydrocarbons such as pentane, hexane, benzene, toluene, xylene or ethers, e. g. diethyl ether, benzylmethyl ether, tetrahydrofurane or dimethoxy ethane.
  • the preferred solvent is diethyl ether.
  • the reaction temperature is not critical; in a preferred embodiment of the reaction, the base is added at C, whereupon the temperature is allowed to rise to 35-80C.
  • steps A-3 and A-4 can be combined into a single treatment, i. e. if group R will be removed by the reaction conditions selected to open the epoxide ring. In either case, isolation of product 511, 5b is not required, nor is separation of the diastereomers necessary or advantageous.
  • Step A-5 This is the acylation of both hydroxyls in 8- and l-position.
  • treatment with the corresponding acid, acid anhydride, acid chloride, etc. under conditions of esterification is quite suitable.
  • Acetylation e. g. with acetic anhydride in pyridine, is a preferred embodiment.
  • the product of Formula 2 thus obtained is recovered and purified, but a raw product is suitable for subsequent thermal conversion explained more in detail below.
  • Step 8-1 The protective group R introduced in this step into compound 9 is not particularly critical and both suitable groups and suitable methods are known per se.
  • acyl groups are preferred for R and his even more preferred to use such acyl groups, e. g. the acetylgroup, which carry the group R adjacent to the carbonyl group.
  • R in Formulae 2 and 3 is to stand for methyl, R preferably is acetyl because this will avoid the necessity of exchanging R for R in the later stages of this method.
  • Acylation or acetylation can be effected as in step A-5. Purification of product (Formula I l) is not required.
  • Step B-2 Photooxydation of the Formula II compound can be effected by treatment with actinic radiation, preferably UV light, in the presence of oxygen, e. g. gaseous oxygen.
  • actinic radiation preferably UV light
  • oxygen e. g. gaseous oxygen.
  • sensitizers can be used in this step, fluorescein and rose bengal being typical examples, and operation in liquid media, e. g. a solvent inert tothe irradiation, is preferred.
  • solvents include normally liquid hydrocarbons such as pentane, hexane, benzene, toluene, xylene and/or alcohols'such as methanol, ethanol, propanol, n and t butanol and n and t amyl alcohol.
  • a preferred solvent is a 1:1 mixture of benzene/methanol.
  • the product of this step is a mixture of 8a, 8b 'compound with the peroxy-precursor of the compound of Formula (i.e. where the hydroxyl in 9-position is a peroxy group).
  • this mixture is used directly as the starting material for the subsequent step B-3, and in practice the entire reaction mixture can be used for conducting step B-3.
  • Step 8-3 This involves reduction of the perhydroxy group formed in step 8-2 which is another technique well known per se.
  • the result of this step is a mixture of diastereometric compound 5a, 5b (with either free hydroxyl in l-position or still carrying group R on the oxygen in l-position) together with compound of Formula 6 which is a side product of this method but also an interesting new chemical species as explained below.
  • a preferred reduction technique for step 8-3 is treatment with sodium borohydride, e.g. in methanol. Reductions of this type yield the free l-phenols of Formulae 5a, 5b and 6 directly.
  • Step B-4 This involves separation of the combined diastereomers 5a, 51) from compound 6, both for the purposes of improving the yields in the subsequent use of 5a, 5b toward production of compound I as well as for recovering the valuable side-product of Formula 6.
  • Simple distillation and/or chromatography techniques are suitable for this purpose.
  • Step B-51 The diastereomers recovered in step B-4 (i.e. Formulae 5a, 5b compounds) are acylated to produce the desired Formula 2 compound. This step is the same as A-5.
  • compounds of Formula 6 are a novel species. They are obtained according to step l-3 of the above method B and isolated as a product from step 8-4. In general, they exhibit valuable pharmacological properties of the type disclosed herein for Formula 1 compounds. In addition, they can be converted into another novel species, i.e. compounds of Formula 7, by conventional catalytic hydrogenation methods. The novel Formula 7 compounds exhibit pharmacological utility of the type disclosed for Formula 1 compounds.
  • Presence of a liquid inert phase is not necessary for the thermal conversion and is not even preferred. If a liquid inert phase or diluent is to be used, common inert solvents such as benzene, toluene, xylene, biphenyl ether, etc. are suitable. When such liquids are used for the thermal conversion of compound 2, apparatus means suitable for withstanding the autogenic pressure of the mixture at conversion temperatures of above 200C will have to be used.
  • the Formula 2 compound is heated without additives to a temperature of from about 200 to about 300C, preferably 250-300C, and most preferred to about 290C (i C).
  • Heating under vacuum e.g. 0.001 torr, is preferred, for example by introducing Formula 2 compound into a suitable recipient, evacuation of air therefrom, and sealing the recipient, e. g. a heavy glass tube.
  • the reaction time can be varied between about 1-60 minutes with higher temperatures requiring shorter re action times, and vice-versa. At about 290C a reaction time of about minutes is preferred and renders yields of Formula 3 compound in the order of about 60 7c by weight.
  • Removal of the acyl groups in 1- and ll-position of Formula 3 yields the target compound of Formula 1.
  • Suitable techniques for removing acyl groups such as to leave the hydroxyl group instead of the acyl are well known per se, e.g. reduction or hydrolysis.
  • the reduction technique in an inert liquid medium is preferred here for practical reasons (product purity), e.g. using lithium aluminium hydride (LiAlH,) as reduction agent and an inert solvent, e.g. tetrahydrofuran, dimethoxyethane. diethyl ether, etc. the last named solvent being preferred for ease of subsequent removal and product recovery.
  • LiAlH lithium aluminium hydride
  • an inert solvent e.g. tetrahydrofuran, dimethoxyethane. diethyl ether, etc. the last named solvent being preferred for ease of subsequent removal and product recovery.
  • the product thus obtained can be purified in a manner known per se, e.g. chromatography.
  • compounds of formula 1 are useful as psychomimetic agents, sedatives and analgesics. They can be formulated as novel pharmaceutical preparations together with conventional pharmaceutical organic or inorganic carrier materials suitable for internal administration. Pharmaceutical Formula compositions containing the compounds of Formula 1 can be administered parenterally or orally, the dosages to be adjusted according to individual requirements. For example, these compounds can be adminstered in dosages of from about 0.1 mg/kg to about 5 mg/kg per day, either in a single or in a repeated divided dosage.
  • the novel pharamceutical compositions can contain such conventional organic or inorganic inert carrier materials as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols,
  • the pharmaceutical preparations can be in the conventional solid forms such as tablets, dragees, suppositories, capsules or in conventional liquid form such as solutions, suspensions of emulsions.
  • the pharmaceutical compositions can be submitted to conventional pharmaceutical expedients such as sterilization and/or can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers or the like. They also can contain other therapeutically useful materials.
  • Example 2 2.86 g of the compound obtained in Example 1 are dissolved in 20 ml of methylene chloride. Then 1.6 g of m-chloro-perbenzoic acid (commercial grade) dissolved in 30 ml of methylene chloride are added dropwise to the solution at room temperature. The resulting mixture is kept at room temperature for 15 hours. Thereafter, the excess of m-chloro-perbenzoic acid is destroyed by addition of aqueous 10 sodium sulfite solution. The organic layer obtained is washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. The crude residue is chromatographed on 60 g ofFlorisil, a commercial magnesium silicate absorbent.
  • the Rf value in chloroform is 0.19.
  • the boiling point is 170C/0.01 mml-lg.
  • the Rf value in chloroform is 0.10.
  • the boiling point is 210220C/0.001 mmHg.
  • the Rfvalue in chloroform/methanol 9:1 is 0.50.
  • the boiling point is 215C/0.00l mmHg.
  • the Rf value in chloroform is 0.40.
  • the Rf value in chloroform/methanol 97:3 is 0.30.
  • the boiling point is 220C/0.001 mm torr. (a),, 231C (0.21 in chloroform).
  • the Rf value in chloroform/methanol 97:3 is 0.70.
  • the boiling point is 145C/0.00l torr.
  • the Rf value is 0.16 in chloroform/methanol 97:3. ((1) -76.5 (0.5 in chloroform).
  • R is selected from the group consisting of straight and branched chain alkyl radicals containing from about 10 C-atoms. comprising the steps of (a) heating a compound of the formula 10 where R is selected from the group consisting of hydrogen and alkyl radicals of from 1 to about 5 C-atoms to form a compound of the formula (b) reacting said formula (3) with a deacylationagent, and (c) recovering the formula 1) compound thus obtained.
  • R is selected from the group consisting of straight and branched chain alkyl radicals having from 1 to about C-atoms, comprising the steps of oxidizing a compound of the formula where R;; is a protective group, by treatment with actinic radiation in the presence of oxygen to obtain compounds of the formulae k/ [H (iLRa I HOO reacting compounds (81)) with a reducing agent to obtain compounds of the formulae reacting compounds (5a), (5b) with an acylating agent to yield compound (2).
  • R is selected from the group consisting of from 1 to about lOC-atoms. straight and branched chain alkyl radicals containing 11.
  • R is selected from the group consisting of from 1 to about 10 C-atoms, with the proviso that R is not the n-pentyl group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Pyrane Compounds (AREA)
US295262A 1971-10-14 1972-10-05 Tetrahydrodibenzopyrans Expired - Lifetime US3873576A (en)

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CH1496671A CH558792A (de) 1971-10-14 1971-10-14 Verfahren zur herstellung von tetrahydrodibenzopyranen.

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3968125A (en) * 1973-11-05 1976-07-06 Eli Lilly And Company Dihydroxyhexahydrodibenzo[b,d]pyrans
US4024275A (en) * 1973-11-05 1977-05-17 Eli Lilly And Company Method of reducing elevated blood pressure with dihydroxy-hexahydrodibenzo(b,d)pyrans
US4133819A (en) * 1977-06-17 1979-01-09 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4209520A (en) * 1977-06-17 1980-06-24 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4647578A (en) * 1983-12-02 1987-03-03 Sterling Drug Inc. Phototoxic insecticidal compositions and method of use thereof
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US5498419A (en) * 1994-06-03 1996-03-12 Pars; Harry G. Fumarate salt of 4-(diethyl-3-(1-methyloctyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol, 4-(diethyl-amino) butyric
US20030232101A1 (en) * 2002-03-18 2003-12-18 Immugen Pharmaceuticals, Inc. Topical formulations of resorcinols and cannibinoids and methods of use
US20040138315A1 (en) * 2000-09-28 2004-07-15 Immugen Pharmaceuticals, Inc. Methods and compounds for inhibiting eicosanoid metabolism and platelet aggregation
US20040242870A1 (en) * 2000-09-28 2004-12-02 Immugen Pharmaceuticals, Inc. Antiviral methods and compounds
US7105685B2 (en) 1999-03-22 2006-09-12 Travis Craig R Cannabinol derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3388136A (en) * 1966-01-11 1968-06-11 Edward C. Taylor Dibenzo [b, d] pyrans and process
US3668224A (en) * 1970-07-02 1972-06-06 Theodor Petrzilka PROCESS OF PRODUCING 6a, 10a-TRANS-6a,7,8,10a-TETRAHYDRODIBENZO (b,d)-PYRANS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3388136A (en) * 1966-01-11 1968-06-11 Edward C. Taylor Dibenzo [b, d] pyrans and process
US3668224A (en) * 1970-07-02 1972-06-06 Theodor Petrzilka PROCESS OF PRODUCING 6a, 10a-TRANS-6a,7,8,10a-TETRAHYDRODIBENZO (b,d)-PYRANS

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3968125A (en) * 1973-11-05 1976-07-06 Eli Lilly And Company Dihydroxyhexahydrodibenzo[b,d]pyrans
US4024275A (en) * 1973-11-05 1977-05-17 Eli Lilly And Company Method of reducing elevated blood pressure with dihydroxy-hexahydrodibenzo(b,d)pyrans
US4133819A (en) * 1977-06-17 1979-01-09 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4209520A (en) * 1977-06-17 1980-06-24 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4232018A (en) * 1977-06-17 1980-11-04 Pfizer Inc. Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents
US4647578A (en) * 1983-12-02 1987-03-03 Sterling Drug Inc. Phototoxic insecticidal compositions and method of use thereof
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US5498419A (en) * 1994-06-03 1996-03-12 Pars; Harry G. Fumarate salt of 4-(diethyl-3-(1-methyloctyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol, 4-(diethyl-amino) butyric
US7105685B2 (en) 1999-03-22 2006-09-12 Travis Craig R Cannabinol derivatives
US20040138315A1 (en) * 2000-09-28 2004-07-15 Immugen Pharmaceuticals, Inc. Methods and compounds for inhibiting eicosanoid metabolism and platelet aggregation
US20040242870A1 (en) * 2000-09-28 2004-12-02 Immugen Pharmaceuticals, Inc. Antiviral methods and compounds
US20030232101A1 (en) * 2002-03-18 2003-12-18 Immugen Pharmaceuticals, Inc. Topical formulations of resorcinols and cannibinoids and methods of use

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FR2157859B1 (de) 1976-04-23
CH558792A (de) 1975-02-14
GB1367819A (en) 1974-09-25
FR2157859A1 (de) 1973-06-08
DE2249720A1 (de) 1973-04-19
JPS4848471A (de) 1973-07-09

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