CN100455576C - Cannabinoid crystalline derivatives and process of cannabinoid purification - Google Patents

Cannabinoid crystalline derivatives and process of cannabinoid purification Download PDF

Info

Publication number
CN100455576C
CN100455576C CNB200380101845XA CN200380101845A CN100455576C CN 100455576 C CN100455576 C CN 100455576C CN B200380101845X A CNB200380101845X A CN B200380101845XA CN 200380101845 A CN200380101845 A CN 200380101845A CN 100455576 C CN100455576 C CN 100455576C
Authority
CN
China
Prior art keywords
cannaboid
sulphonate
aromatic
alkyl
esters
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB200380101845XA
Other languages
Chinese (zh)
Other versions
CN1705655A (en
Inventor
约翰·R·达切克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Inc filed Critical Mallinckrodt Inc
Publication of CN1705655A publication Critical patent/CN1705655A/en
Application granted granted Critical
Publication of CN100455576C publication Critical patent/CN100455576C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Pyrane Compounds (AREA)

Abstract

Delta9 tetrahydrocannabinol (THC) esters comprising the reaction product of THC with at least one aryl sulfonyl chloride in the presence of at least one tertiary amine. The resulting aryl sulfonic THC esters are highly crystalline and stable at room temperature in air, allowing for indefinite storage. The aryl sulfonic THC esters can be recrystallized for purification, and then hydrolyzed to recover the purified THC.

Description

The crystalline derivatives of cannaboid and the purification process of cannaboid
Technical field
The present invention relates to the crystalline derivatives of cannaboid (cannabinoid), more specifically, the cannaboid aromatic yl sulphonate that the present invention relates to can be used for purifying and/or store cannabinoid compounds.
Background technology
Naturally occurring cannaboid is the biologically active components of hemp.Because FDA approval Δ 9Several treatments of-tetrahydrocannabinol (THC) are used, so the medicine interests of cannaboid have increased.This interests have caused the exploitation of synthetic cannabinoid compounds.
Usually, natural and synthetic cannaboid all is the molecule of intractable, because they usually are the hard glass shape, at room temperature is easy to oxidation.THC is the vitreum of amorphous at room temperature, is easy to reset and oxidation by air.Though THC is generally held in the refrigerating installation of the dark under the rare gas element, it is very difficult keeping purity between the shelf lives.These characteristics also make cannaboid complicated as the application of the reactant of other synthetic method or purposes.
The characteristic of listing above also makes the purifying complexization of cannaboid.And many impurity of finding in the cannabinoid mixtures of being everlasting also are problems.Conventional purification process generally includes and uses HPLC.These method inconveniences and expense height, it is unrealistic to make purge process amplify in proportion.
Therefore need provide a kind of method for preparing cannabinoid derivatives, this cannabinoid derivatives makes to be handled easily, stable storing, and purification process improves, and converts cannaboid again to easily.
Summary of the invention
On the one hand, the invention provides the cannaboid aromatic yl sulphonate shown in the following formula A:
Figure C20038010184500061
Formula A
In the formula
R 1, R 2, R 3And R 4Be H or alkyl;
A is the diene or the aromatic ring of saturated alkane, alkene, six Yuans condensed ring of formation; And
Y is an aryl.
On the other hand, the invention provides a kind of method for preparing cannabinoid esters, be included under the situation of at least a alkali existence, make the reaction of cannaboid and at least a aryl sulfonyl halide.
Again on the one hand, the invention provides a kind of method of purifying cannaboid, be included under the situation of at least a alkali existence,, form the cannaboid aromatic yl sulphonate with at least a aryl sulfonyl halide esterification cannaboid; Crystallization cannaboid aromatic yl sulphonate; And hydrolysis cannaboid aromatic yl sulphonate, to reclaim cannaboid.Cannaboid aryl sulfonic acid crystalline esters can recrystallization, with purifying cannaboid aromatic yl sulphonate.
These only are to illustrate all respects of the present invention, and should not think exhaustive to all aspects relevant with the present invention.Because following disclosure, these and other aspect of the present invention should be conspicuous for a person skilled in the art.
Embodiment
According to following reaction, provide a kind of method of esterification cannaboid:
Figure C20038010184500071
Reaction 1
In the formula
R 1, R 2, R 3And R 4Be H or alkyl;
A is saturated alkane, alkene, diene or aromatic ring;
Y is an aryl; And
X is a halogenide.
Impure cannaboid can be handled with at least a aryl sulfonyl halide under the situation that at least a alkali exists, and causes phenolic hydroxyl group to react, and then makes aromatic yl sulphonate.
The purpose that adds alkali is to absorb the haloid acid that esterification produced.Therefore, can use any suitable alkali that does not hinder esterification.For the present invention, low-grade alkylamine, particularly tertiary amine such as triethylamine are suitable cheap alkali.Also can use primary amine and secondary amine, but can cause unwanted and reaction sulfonic acid halide.Preferred formula R 5R 6R 7The amine of N, R in the formula 5, R 6And R 7Can typically be low-grade alkyl group with about 1～6 carbon atom.
The aryl of sulfonic acid halide can be any replacement or unsubstituted aroma system that does not hinder esterification.Suitable aroma system includes but not limited to benzene and replacement and the unsubstituted Haphthyl compounds that benzene, the benzene of halogen replacement, oil of mirbane, the alkoxyl group of benzene, alkyl replacement replace.Preferred alkoxy substituent comprises the alkoxide that is directly connected on the tertiary carbon, and wherein said alkoxy substituent can have about 1～6 carbon atom usually.
In preferred embodiments, cannaboid, aryl sulfonyl halide and tertiary amine are blended in the organic solvent, and at room temperature react, and up to complete reaction, generally need some hrs.Choice of Solvent is not strict, and The suitable solvent includes but not limited to: toluene, methylene dichloride, chloroform and heptane.In alternative embodiment, described reaction can be to carry out at elevated temperatures, and does not influence the effectiveness of reaction, though speed of reaction has small increase.Temperature range is generally room temperature to 80 ℃.
Then remove solvent, can then carry out crystalline oily matter so that the cannaboid aromatic yl sulphonate forms with suitable method.Crystallization can be by means of the interpolation of solvent and crystal seed, and this is well-known in this area.The suitable solvent includes but not limited to: heptane, hexane, t-butyl methyl ether, Pentyl alcohol, propyl carbinol, Virahol, isopropylcarbinol, ethanol, acetone, acetonitrile and isopropyl acetate.Preferably include the alcohols of methyl alcohol.Usually, the purity of this thick crystalline ester surpasses 90% easily.In first crystallization, can obtain the cannaboid of about 70～80% initial trial.By a recrystallization, can reach the purity more than 99% usually, preferably carry out recrystallization with alcohol, (all percentage ratios given here are weight percentage to the loss of yield minimum, unless otherwise noted).
The gained cannabinoid esters is a highly crystalline, and at room temperature stable.They can at room temperature unrestrictedly store in air.
Then, can pass through macromolecule alkali for hydrolysis hydrolysis cannabinoid esters, reclaiming purified cannaboid, shown in following reaction formula:
Figure C20038010184500081
Reaction 2
In the formula
R 1, R 2, R 3And R 4Be H or alkyl;
A is saturated alkane, alkene, diene or aromatic ring;
Y is an aryl;
M is a metal; And
Z is an alkyl, and is generally the alkyl of 1～10 carbon.
Hydrolysis can be finished according to any method well known in the art.In preferred embodiments, described alkali is included in the metal-salt of at least a alkyl oxide at least a alkyl alcohol.Suitable alkali includes but not limited to: the methylate of potassium, ethylate, propylate, isopropoxide, tert butoxide and tertiary amyl alcohol salt, preferred tertiary alkoxide.Suitable alcohol includes but not limited to: methyl alcohol, ethanol, n-propyl alcohol, Virahol, the trimethyl carbinol and tertiary amyl alcohol, the preferred tertiary alcohol.Preferred alkoxide uses identical alkyl with alcohol, and to prevent the exchange of group, for example, potassium tert.-butoxide is several in the trimethyl carbinol of water gaging in being added with.Every use 1 normal cannaboid comprises at least 3 normal alkali and at least 4 normal water in the preferred reaction.Reaction is preferably carried out under at least 40 ℃ temperature.The purity of the cannaboid that is reclaimed surpasses 99% usually, and productive rate is 85～95%.For practical purpose, alkyl oxide (alkyl oxide) and alcohol comprise the alkyl with about 1～6 carbon atom usually, although can use bigger alkyl.
Suitable method for hydrolysis is included under the inert atmosphere tosylate is placed in the three-necked flask.Described flask is equipped with magnetic stirring and electronic temp control, condenser, inert gas bubbler and heating jacket usually.In flask, add earlier deionized water, and then add the alcoholic solution of alkyl oxide.By using inert gas blown, make all used solvent removal oxygen.In one embodiment, then the gained slurry is heated at least about 40 ℃,, and forces described reaction to be finished with the increase speed of reaction.Though the reaction meeting is carried out under lower temperature, still preferably reactant is heated to about 40～80 ℃, the best is about 50～70 ℃ temperature, and top temperature is by the boiling point decision of employed solvent.Reaction mixture is remained on required temperature, till reaction is finished basically, need about 2～12 hours usually, then cool to room temperature.
Add deionized water, and reaction stirred.Add organic solvent, stir the gained mixture, and be placed in the separating funnel and separate.The organic fraction that then comprises cannabinoid product with the deoxidation deionized water wash of at least one aliquots containig.Press usual method then with dry this organic fraction of salts solution, filter and vacuum-evaporation, form oily matter.Gained oily matter is distilled under high vacuum, obtain high-purity cannabinoid product.
Provide the following examples that many-side of the present invention is described, and these embodiment and do not mean that by any way restriction or limit the present invention.
Embodiment 1
Δ 9Synthesizing of-tetrahydrocannabinol tosylate
Under nitrogen atmosphere, with the Δ of 64.9g 9-tetrahydrocannabinol, the toluene of 292mL, the triethylamine of 21.7mL, and the Tosyl chloride of 41.3g is added in the three neck round-bottomed flasks of 1000mL.With reactant stir about 16 hours round the clock at room temperature.Check reactant with LC, find to react and finish.Add water (292mL), and reaction stirred 20 minutes.Divide water-yielding stratum, and with this toluene solution of water washing of 292mL aliquots containig more than twice.Saturated nacl aqueous solution with 292mL washs this toluene solution, anhydrates to help to remove, then with this toluene solution of anhydrous magnesium sulfate drying.This exsiccant toluene solution of evaporation on vaporizer is up to the oily matter that only is left 99.76g.This oily matter is poured in the Erlenmeyer flask of 500mL, and added the heptane of 150mL.This solution is with deriving from the crystal seeding of test early, store overnight in refrigerator on a small quantity.Filter the solid that is generated.When crystal is on strainer, with the chilled heptane washed twice of about 10mL aliquots containig.With crystal on the B under vacuum dry 15 minutes and weigh.Little wet crystal weighs 65.4 grams.When it " after the dried overnight, is weighed as 65.37g under the vacuum of Hg in room temperature and 23.By evaporating most of heptane, and, obtain second batch of crystal of 6.34g by freezing mother liquor overnight under refrigeration.
By refluxing, with described dissolution of crystals in the hot methanol of 440mL.This crystal is easily 66 ℃ of dissolvings down.Make flask lentamente to the room temperature cooling, and crystallization takes place in the time of 51 ℃.Then flask is cooled in ice bath near 0 ℃, simultaneously that fresh methyl alcohol is freezing, as washings.Flask was kept 1.5 hours at 0 ℃, filter slurry then.With the cold methanol of 110mL altogether, divide two parts of described solids of washing.The crystalline weight in wet base is 64.09g.Crystal is in room temperature and 23 " dry weekend under the vacuum of Hg.Institute's exsiccant crystals weighed is 62.64g.With the free Δ 9-tetrahydrocannabinol difference, this toluenesulphonic acids ester derivative are in room temperature and to have under the situation that the illumination of air and laboratory exists be stable.Δ 9THC-4-tosylate (tosylate) crystalline feature IR, proton N MR, C 13NMR and MS method characterize.The infrared spectra of tosylate and Δ 9The infrared spectra unanimity of THC just has the bands of a spectrum of organic sulfonic acid ester functional group extraly.NMR analyzes the strong Δ of supporting 9The structure of THC-4-tosylate (tosylate).Mass spectral result shows that principal constituent has the molecular weight of 468Da, this and Δ 9The molecular weight unanimity of THC-4-tosylate (tosylate).And the MS/MS fragmentation pattern is a Δ with the confirmation main component also 9THC-4-tosylate (tosylate) unanimity.
Embodiment 2
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-benzene sulfonate crystal utilizes benzene sulfonyl chloride to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 3
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-4-methoxy benzenesulfonic acid crystalline esters utilizes 4-anisole SULPHURYL CHLORIDE to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 4
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-4-bromo-benzene sulfonic acid crystalline esters utilizes the 4-bromobenzene sulfonyl chloride to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 5
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-4-chlorobenzenesulfonic acid crystalline esters utilizes the 4-chlorobenzene sulfonyl chloride to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 6
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-2-nitrobenzene-sulfonic acid crystalline esters utilizes the 2-nitrobenzene sulfonyl chloride to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 7
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-3-nitrobenzene-sulfonic acid crystalline esters utilizes the 3-nitrobenzene sulfonyl chloride to replace Tosyl chloride.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 8
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-4-nitrobenzene-sulfonic acid ester utilizes the 4-nitrobenzene sulfonyl chloride to replace Tosyl chloride, oily non-crystallizable except gained.
Embodiment 9
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-1-naphthyl sulphonate utilizes 1-naphthyl SULPHURYL CHLORIDE to replace Tosyl chloride, oily non-crystallizable except gained.
Embodiment 10
As among the embodiment 1, forming Δ 9-tetrahydrocannabinol-2-naphthyl sulphonate utilizes 2-naphthyl SULPHURYL CHLORIDE to replace Tosyl chloride, oily non-crystallizable except gained.
Embodiment 11
As among the embodiment 1, forming Δ 8-tetrahydrocannabinol-4-toluenesulphonic acids crystalline esters is utilized Δ 8-tetrahydrocannabinol replaces Δ 9-tetrahydrocannabinol.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 12
As among the embodiment 1, forming cannabinol-4-toluenesulphonic acids crystalline esters, utilize cannabinol to replace Δ 9-tetrahydrocannabinol.In room temperature with have under the situation that the illumination of air and laboratory exists, the gained crystal is stable.
Embodiment 13
Δ 9-tetrahydrocannabinol tosylate is to free Δ 9The hydrolysis of-tetrahydrocannabinol
Under nitrogen atmosphere, be the pure Δ of 99+% with 25 gram purity 9-tetrahydrocannabinol-4-tosylate (tosylate) places the three neck round-bottomed flasks of 500mL.This flask is equipped with magnetic stirring and electronic temp control, condenser, nitrogen foam maker, and heating jacket.
Before the use, utilize N 2Foaming was removed the oxygen in all used solvents by 15 minutes.The deionized water that adds 3.9mL in flask adds butanols potassium-butanol solution of 1 mole (explaining 1) of 162.5mL then.The gained slurry is heated to 65 ℃.Reaction is a slight exotherm, raises the temperature to 70.1 ℃, but falls back to 65 ℃ very soon.Reactant was kept 5 hours at 65 ℃, be cooled to room temperature then.
Add water (250mL) and reaction stirred 1.0 hours.Can expect that this process is destroyed a spot of t-butyl tosylate that forms in reaction.Add heptane (250mL) then.Stir after the several minutes, transfer in the separating funnel (1000mL) mixture and separation (, then can add a spot of water) if find a spot of trimethyl carbinol phase.Deoxidation deionized water wash with the 250mL aliquots containig contains the n-heptane solution of cannabinoid product more than twice.The pH of first washings is that the pH of 14, the second washingss is that the pH of 9, the three washingss is 8.
By washing this n-heptane solution, finish preliminarily dried with the saturated sodium chloride solution of 250mL.
Use anhydrous MgSO then 4Dry this n-heptane solution.Filter this solution, and vaporising under vacuum becomes oily matter (16.68g).
This oily matter distills under about 200～220 ℃ and high vacuum less than 2mm Hg.Obtain being close to colourless glassy mass, be weighed as 15.41g, productive rate is 88%.
The LC analysis revealed of described product, the area greater than 99.9% are Δ 9-tetrahydrocannabinol.Compare with the reference material of buying, its purity is 104%.Make this product lucifuge, keep away oxygen, and be stored in the freezing plant, to keep this purity.
Described the present invention in detail, person of skill in the art will appreciate that and to make modification and not break away from its essence and scope the present invention.And do not mean that scope of the present invention is defined in the described specific embodiment therefore.On the contrary, mean that appending claims and Equivalent thereof determine scope of the present invention.

Claims (22)

1. the cannabinoid esters shown in the following formula:
Figure C2003801018450002C1
Formula A
In the formula
R 1, R 2And R 3Be methyl, R 4It is n-pentyl;
A is alkene or phenyl; And
Y is an aryl, and is selected from benzene, the benzene of halogen replacement and the benzene that alkoxyl group replaces that alkyl replaces.
2. the described cannabinoid esters of claim 1, wherein Y is the 4-tolyl.
3. the described cannabinoid esters of claim 1, wherein Y is the 4-p-methoxy-phenyl.
4. the described cannabinoid esters of claim 1, wherein Y is the 4-bromophenyl.
5. the described cannabinoid esters of claim 1, wherein Y is the 4-chloro-phenyl-.
6. the method for a purifying cannaboid comprises:
Under the situation that at least a alkali exists, with at least a aryl sulfonyl halide esterification cannaboid, to form the cannaboid aromatic yl sulphonate shown in the following formula A:
Figure C2003801018450002C2
Formula A
In the formula
R 1, R 2And R 3Be methyl, R 4It is n-pentyl;
A is alkene or phenyl; Reaching Y is aryl, and is selected from benzene, the benzene of halogen replacement and the benzene that alkoxyl group replaces that alkyl replaces, and
Make this cannaboid aromatic yl sulphonate crystallization, and
This method also comprises this cannaboid aromatic yl sulphonate of hydrolysis, to reclaim cannaboid.
7. the described cannabinoid esters of claim 6, wherein Y is the 4-tolyl.
8. the described cannabinoid esters of claim 6, wherein Y is the 4-p-methoxy-phenyl.
9. the described cannabinoid esters of claim 6, wherein Y is the 4-bromophenyl.
10. the described cannabinoid esters of claim 6, wherein Y is the 4-chloro-phenyl-.
11. according to the method for claim 6, the wherein said cannaboid aromatic yl sulphonate crystalline step that makes further comprises at least a solvent of interpolation and at least a crystal seed.
12. according to the method for claim 11, wherein said at least a solvent is selected from methyl alcohol, heptane, hexane, t-butyl methyl ether, Pentyl alcohol, propyl carbinol, Virahol, isopropylcarbinol, ethanol, acetone, acetonitrile and isopropyl acetate.
13., further comprise the described cannaboid aromatic yl sulphonate of recrystallization, with the step of purifying cannaboid aromatic yl sulphonate according to the method for claim 6.
14. according to the method for claim 6, wherein said cannaboid is naturally occurring hemp component.
15. according to the method for claim 6, wherein said at least a alkali is at least a tertiary amine.
16. according to the method for claim 15, wherein said at least a tertiary amine is by formula R 5R 6R 7N represents, R in the formula 5, R 6And R 7It is alkyl.
17. according to the method for claim 6, wherein said hydrolysis cannaboid aromatic yl sulphonate comprises basic hydrolysis.
18. according to the method for claim 6, wherein said hydrolysis cannaboid aromatic yl sulphonate comprises:
Make the cannaboid aromatic yl sulphonate at least a alkyl alcohol with at least a alkyl oxide reacting metal salt.
19. according to the method for claim 18, wherein said at least a alkyl oxide metal-salt and described at least a alkyl alcohol comprise 1～6 carbon atom.
20. according to the method for claim 18, wherein said at least a alkyl oxide metal-salt comprises identical alkyl with described at least a alkyl alcohol.
21. according to the method for claim 6 or 18, wherein said hydrolysis cannaboid aromatic yl sulphonate is to finish under 40～80 ℃ temperature.
22. according to the method for claim 6 or 18, wherein said hydrolysis cannaboid aromatic yl sulphonate is to finish under 50～70 ℃ temperature.
CNB200380101845XA 2002-11-12 2003-11-06 Cannabinoid crystalline derivatives and process of cannabinoid purification Expired - Fee Related CN100455576C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US42554302P 2002-11-12 2002-11-12
US60/425,543 2002-11-12
US60/435,027 2002-12-20

Publications (2)

Publication Number Publication Date
CN1705655A CN1705655A (en) 2005-12-07
CN100455576C true CN100455576C (en) 2009-01-28

Family

ID=35578186

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB200380101845XA Expired - Fee Related CN100455576C (en) 2002-11-12 2003-11-06 Cannabinoid crystalline derivatives and process of cannabinoid purification

Country Status (2)

Country Link
CN (1) CN100455576C (en)
CA (1) CA2770448C (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI369203B (en) 2004-11-22 2012-08-01 Euro Celtique Sa Methods for purifying trans-(-)-△9-tetrahydrocannabinol and trans-(+)-△9-tetrahydrocannabinol

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Cannabis indica Resin. Part III. The Constitution ofCannabinol". ROBERT SIDNEY CAHN.J.Chem.Soc.. 1932
"Cannabis indica Resin. Part III. The Constitution ofCannabinol". ROBERT SIDNEY CAHN.J.Chem.Soc. 1932 *
"Chromophoric Labeling of Cannabinoidswith 4-Dimethylaminoazobenzene-4'-Sulfonyl Chloride". Maseda, C. et al.J.Forensic Sciences,Vol.28 No.4. 1983
"Chromophoric Labeling of Cannabinoidswith 4-Dimethylaminoazobenzene-4'-Sulfonyl Chloride". Maseda, C. et al.J.Forensic Sciences,Vol.28 No.4. 1983 *
"Dansyl Derivatives of △9-and △8-Tetrahydrocannabinols". MELIKIAN,ARMEN P. et al.J.Pharm.Sicences,Vol.62 No.6. 1973
"Dansyl Derivatives of △9-and △8-Tetrahydrocannabinols". MELIKIAN,ARMEN P. et al.J.Pharm.Sicences,Vol.62 No.6. 1973 *
"Structure of Cannabinol. I. Preparation of anIsomer,3-Hydroxyl-1-n-amyl-6,6,9-trimethyl-6-dibenzopyran". ROGER ADAMS, et al.J.Am.Chem.Soc.,Vol.62 . 1940
"Structure of Cannabinol. I. Preparation of anIsomer,3-Hydroxyl-1-n-amyl-6,6,9-trimethyl-6-dibenzopyran". ROGER ADAMS, et al.J.Am.Chem.Soc.,Vol.62. 1940 *
"The Total Synthesis of dl-△9-Tetrahydrocannabinol andFourof Its Isomers". K.E.Fahrenholtz, et al.J.Am.Chem.Soc.,Vol.89 No.23. 1967
"The Total Synthesis of dl-△9-Tetrahydrocannabinol andFourof Its Isomers". K.E.Fahrenholtz, et al.J.Am.Chem.Soc.,Vol.89 No.23. 1967 *

Also Published As

Publication number Publication date
CA2770448A1 (en) 2004-05-27
CA2770448C (en) 2014-03-25
CN1705655A (en) 2005-12-07

Similar Documents

Publication Publication Date Title
CA2504743C (en) Cannabinoid crystalline derivatives and process of cannabinoid purification
CA2751741C (en) Process for the preparation of (-) -delta 9-tetrahydrocannabinol
CA2426158A1 (en) Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
EP1474379A2 (en) Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
CN100455576C (en) Cannabinoid crystalline derivatives and process of cannabinoid purification
IL182439A (en) Intermediates useful for the preparation of aripiprazole and methods for the preparation of the intermediates and aripiprazole
MXPA03001470A (en) Processes for preparing cilostazol.
CN109574860B (en) Method for preparing vilanterol
CN112166108B (en) Method for producing polymerizable compound
JPH0742269B2 (en) 4-Alkoxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl ester and process for producing the same
WO2005044808A1 (en) A process for the manufacture of zonisamide
WO1998029386A1 (en) Sulphonyl compounds for use as linkers in solid phase and combinatorial synthesis
JP2004525971A (en) A new method for producing oxabispidin
JP2000500443A (en) Process for producing 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivative
CN117886725A (en) Preparation process of apremilast intermediate
WO2022079194A1 (en) Process for the production of glycopyrronium tosylate
WO2011132140A2 (en) Process for the conversion of (2r)-6-fluoro-2-[(2s)-oxiran-2-yl]-3,4-dihydro-2h-chromene to (2r)-6-fluoro-2-[(2r)-oxiran-2-yl]-3,4-dihydro-2h-chromene
CN118406039A (en) Three hydroxyl-containing 8-dihydropyrazolyl coumarin compounds and preparation method thereof
CN117186150A (en) Preparation method of LFA-1 inhibitor
HU204771B (en) Process for producing anilinofumarates from chloromaleates or chlorofumarates or from their mixture

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20090128

Termination date: 20101106