CN109970516A - A kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield - Google Patents
A kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield Download PDFInfo
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Abstract
The present invention provides a kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield, it is related to field of medicine preparing technology, it is using formula (III) or formula (V) compound as starting material, is reset through Fries, Diels-Alder reacts the techniques such as cyclization, elimination reaction and is prepared.Using preparation method of the present invention, can effectively solve previous synthetic route yield is low, side reaction is more, purification difficult, it is at high cost, industrialization is difficult the problems such as.Present invention process process is simple, require relatively low, agents useful for same safety and environmental protection, product yield and purity is high to reaction condition and is able to achieve industrial scale production.
Description
Technical field
The present invention relates to field of medicine preparing technology, and in particular to a kind of cannabinol of preparation of industrialization high-purity high-yield
The synthetic method of substance.
Background technique
Though hemp is acknowledged as one of big drugs in the world three, due to the valuable pharmacological and physiology of its active constituent cannboid
Activity and increasingly paid attention to by common people, separated more than 100 kinds plant-derived cannboids so far.And content is more in cannboid
And there is what is shown clinical value day to have tetrahydrocannabinol and cannabidiol.In nearest research find the cannabinol property of can choose with by
Body, which combines, generates unique pharmacological action.Especially in FDA approval its cannabidiol class drug of GW company in 2015 for treating baby
After youngster's severe myoclonic epilepsy, market is even more to have started one research cannabinoids substance especially cannabidiol in medicine
The research boom in the fields such as object, food, cosmetics.
It is naturally just increasingly bright to the wilderness demand of cannabinoids raw material of substance due to the extensive market prospects of substance of this kind
It is aobvious.It is your victory gold by taking cannabidiol as an example.The raw material supply of cannabidiol relies primarily on plant extract at present, and plants
Object extracts separation and is that step is tediously long, and inefficiency.Therefore the mode for seeking organic synthesis replaces the natural nature that extracts to become
A kind of trend.
The synthesis mode for the cannabidiol reported at present is main are as follows:
The chemical synthesis of 1:CBD was broken through by Mechoulam seminar in 1967 earliest:
Meanwhile Mechoulam seminar also reports that method is similar to the chemical synthesis of THC.The method synthetic route
It is short, but because reacting while generating the side reactions such as dimer, this reaction system purification difficult is caused, yield is low.Hereafter similar report
Also have, mainly use different catalyst, such as: US20090036523A1.
The report of 2:US20100298579A1 is as follows:
It is also reported in US20170008868 by Dialer et al., this patent category PCT Patent, patentee is
NORAMCO company, the U.S..
Using this two patents as representative, it is that protecting group is added on the basis of the research of Mechoulam seminar, reduces portion
The generation of point side reaction, improves yield, but cause being significantly increased for cost, and purification difficult, and due to CBD fusing point compared with
Low, what is obtained is all the CBD oil of yellow, hardly results in clean CBD crystal.Also not substantive figure breaks through Mechoulam project
The research achievement of group.
3:2018 delivers a report fully synthetic about CBD by Zachary P.Shultz et al. on Org.Lett.
Road, specific synthetic route is as shown in Figure 1, this report at last breaks through the research of Mechoulam seminar, with a kind of completely new
Synthetic method obtained CBD.But the method yield is low, and purifying needs column to chromatograph, and is not easy to realize industrialization.
Therefore, low yield, High Purity in order to overcome the shortage of prior art, effectively during solution synthesis chemical compounds I
The problems such as difficulty, Gao Chengben, industrialization, develop it is a kind of synthesis high-purity high-yield can industrialized production cannabinoids substance it is outstanding
It is that the preparation method of CBD and THC is very important.
Summary of the invention
(1) the technical issues of solving
In view of the deficiencies of the prior art, the present invention provides a kind of cannabinoids objects of preparation of industrialization high-purity high-yield
The synthetic method of matter.
(2) technical solution
In order to achieve the above object, the present invention is achieved by the following technical programs:
A kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield, the cannabinoids substance
Shown in molecular formula such as following formula (I) and formula (II):
Wherein, R1、R2、R3And R4Be independently selected from group consisting of: H, OH, halogen, alkyl, alkenyl, alkynyl,
Acyl group, aryl, heterocycle, heteroaryl, condensed ring and naphthenic base;
Wherein the alkyl, alkenyl, alkynyl or acyl group optionally pass through one or more independently selected from group consisting of
A substituent group replaces: halogen ,-OH, alkyl ,-O- alkyl, NRARB,-S- alkyl ,-SO- alkyl ,-SO2Alkyl, alkenyl, alkynyl,
Aryl, heteroaryl, naphthenic base or heterocycle;Wherein RAAnd RBIt is each independently selected from hydrogen and C1-5 alkyl;
Wherein the aryl or the heteroaryl a part of substituent group (no matter individually or as) optionally through independently selected from
One or more substituent groups of group consisting of replace: halogen ,-OH, alkyl ,-O- alkyl ,-COOH ,-C (O)-C1-4 alkane
Base ,-C (O) O-C1-4 alkyl, NRCRD,-S- alkyl ,-SO- alkyl and-SO2Alkyl;Wherein RCAnd RDIt is each independently selected from hydrogen
With C1-5 alkyl;
Specifically, the chemical synthesis process of the cannabinoids substance is as follows:
(1) Fries rearrangement generation formula (IV) compound occurs under certain catalytic condition for formula (III) compound:
Or Fries occurs under certain catalytic condition and resets generation formula (VI) compound for formula (V) compound:
Above-mentioned catalytic condition is that addition Lewis acid makees catalyst, addition Brown acid does catalyst, illumination, heating
Any one in mode;
(2) Diels-Alder reaction is occurred into a heated condition for formula (IV) compound and formula (VII) compound to be formed
Formula (VIII) compound:
Or Diels-Alder reaction occurs in a heated condition for formula (VI) and formula (IX) compound to form formula (VIII)
Compound:
(3) formula (VIII) compound reacts under alkaline condition generates formula (I) compound:
(4) formula (I) compound reacts in acid condition generates formula (II) compound:
Wherein R5 is optionally from one of following group: H, OH, halogen, alkyl, alkenyl, alkynyl, acyl group, aryl, heterocycle,
Heteroaryl, condensed ring and naphthenic base;
X is optionally from one of following halogen element: F, Cl, Br, I.
Further, Lewis acid used is aluminium chloride, zinc chloride, Antimony pentachloride, tin tetrachloride, boron trifluoride, bromine
Changing iron, any one in iron chloride, the Brown acid is trifluoracetic acid copper, any one in copper trifluoromethanesulfcomposite,
It is preferred that aluminium chloride.
Further, when Fries rearrangement generation formula (IV) compound occurs in a heated condition for formula (III) compound, institute
It is 35 DEG C -150 DEG C with heating temperature.
Further, Fries occurs in formula (III) compound solvent under certain catalytic condition and resets generation formula (IV)
Close object, solvent for use are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol,
One or more of ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or acetonitrile, solution additional amount are and raw material solid-liquid
Product is than 1:10~1:30, preferably methanol.
Further, it is used when Fries rearrangement generation formula (VI) compound occurs in a heated condition for formula (V) compound
Heating temperature is 35 DEG C -150 DEG C.
Further, Fries occurs in formula (V) compound solvent under certain catalytic condition and resets generation formula (VI) chemical combination
Object, solvent for use are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, second
One or more of alcohol, petroleum ether, dimethyl sulfoxide, dioxane or acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:
10~1:30, preferably methanol.
Further, formula (IV) and the reaction of formula (VII) compound generate formula (VIII) compound, and heating temperature used is 50
℃-300℃。
Further, formula (IV) and the reaction of formula (VII) compound generate formula (VIII) compound, solvent for use are as follows: toluene,
Tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl are sub-
One or more of sulfone, dioxane or acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30, preferably dimethyl
Sulfoxide.
Further, formula (VI) and the reaction of formula (IX) compound generate formula (VIII) compound, and heating temperature used is 50
℃-300℃。
Further, formula (VI) and the reaction of formula (IX) compound generate formula (VIII) compound, solvent for use are as follows: toluene,
Tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl are sub-
One or more of sulfone, dioxane or acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30, preferably dimethyl
Sulfoxide.
Further, alkali used when formula (VIII) reaction generates formula (I) compound are as follows: sodium carbonate, potassium carbonate, sodium methoxide,
One of potassium ethoxide, sodium hydroxide, potassium hydroxide, sodium acetate, cesium fluoride, potassium phosphate, additional amount be feed molar amount 3~
10 times, preferably sodium methoxide.
Further, solvent for use when formula (VIII) reaction generates formula (I) compound are as follows: toluene, tetrahydrofuran, acetic acid second
Ester, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or second
One or more of nitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30, preferably methanol.
Further, formula (I) reaction generates acid used when formula (II) compound are as follows: sulfuric acid, hydrochloric acid, p-methyl benzenesulfonic acid, vinegar
One of acid, phosphoric acid, formic acid, preferably p-methyl benzenesulfonic acid.
Further, solvent for use when formula (I) reaction generates formula (II) compound are as follows: toluene, tetrahydrofuran, acetic acid second
Ester, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or second
One or more of nitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30, preferably dimethyl sulfoxide.
(3) beneficial effect
The present invention provides a kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield, have with
It is lower the utility model has the advantages that
The present invention be using formula (III) or formula (V) compound as starting material, through Fries reset, Diels-Alder it is anti-
The techniques such as cyclization, elimination reaction are answered to be prepared.Using preparation method of the present invention, previous synthetic route yield can effectively solve
It is low, side reaction is more, purification difficult, it is at high cost, industrialization is difficult the problems such as.Technical process is simple, it is opposite to require reaction condition
Lower, agents useful for same safety and environmental protection, product yield and purity is high and be able to achieve industrial scale production.
Detailed description of the invention
Fig. 1 be 2018 by Zachary P.Shultz et al. delivered on Org.Lett. one it is fully synthetic about CBD
The specific synthetic route of report.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention,
Technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is the present invention one
Divide embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not making
Every other embodiment obtained, shall fall within the protection scope of the present invention under the premise of creative work.
(1) preparation of formula (IV) class compound B:
Method is as follows: raw material A 5.00g weighed, is added in 100mL methanol, aluminium chloride 0.50g is continuously added under stirring,
50 DEG C of heating are reacted 3 hours, after TLC shows raw material fully reacting, stop reaction.Filtering, filter residue are washed with 50mL methanol, are closed
And organic layer, it is concentrated into 50mL, is crystallized 5 hours at 10 DEG C.Obtain B white solid 4.88g, yield 97.60%.
(2) preparation of formula (VI) class compound D
Method is as follows: it weighs raw material C 5.00g and is added in 60mL DMSO, ferric bromide 0.20g is continuously added under stirring,
60 DEG C of heating are reacted 2 hours, after TLC shows raw material fully reacting, stop reaction.Filtering, the washing of filter residue 20mL ethyl acetate,
Merge organic layer, concentration is added 50mL and purifies water crystallization, obtains D white solid 4.91g, yield 98.20%.
(3) preparation of formula (VIII) class compound F
Method is as follows: weighing raw material B 3.00g and E 0.50g and is added in 100mL ethyl alcohol, reaction is heated at reflux under stirring
10 hours, after TLC shows raw material fully reacting, stop reaction.It is concentrated into 50mL, is crystallized at 10 DEG C, F solid 2.93g is obtained,
Yield 97.60%.
(4) preparation of formula (VIII) class compound H
It weighs raw material D 3.00g and G 0.55g to be added in 70mLDMF, 130 DEG C is heated under stirring and is reacted 6 hours,
TLC shows raw material fully reacting, stops reaction.70mL water is slowly added dropwise, crystallization 2 hours, filters, it is dry, obtain H solid
2.89g, yield 96.33%.
(5) preparation of formula (I) class compound CBD
It weighs raw material H 2.00g to be added in 50mL methanol, sodium methoxide 0.2g, heating reflux reaction is continuously added under stirring
6 hours, 0.2g active carbon is added and continues reflux 30 minutes, stops reaction.Filtering, is concentrated into 20mL, crystallization at 10 DEG C obtains
CBD solid 1.72g, yield 86.00%.
(6) preparation of formula (II) class compound THC
It weighs CBD 1.0g to be added in 20mL acetonitrile, is added with stirring p-methyl benzenesulfonic acid 0.10g, reaction 2 is small under room temperature
When, stop reaction.Sodium bicarbonate is added and adjusts PH to neutrality, filters, concentration, crystallization obtains THC 0.82g, yield
82.00%.
It should be noted that, in this document, relational terms such as first and second and the like are used merely to a reality
Body or operation are distinguished with another entity or operation, are deposited without necessarily requiring or implying between these entities or operation
In any actual relationship or order or sequence.Moreover, the terms "include", "comprise" or its any other variant are intended to
Non-exclusive inclusion, so that the process, method, article or equipment including a series of elements is not only wanted including those
Element, but also including other elements that are not explicitly listed, or further include for this process, method, article or equipment
Intrinsic element.In the absence of more restrictions, the element limited by sentence "including a ...", it is not excluded that
There is also other identical elements in process, method, article or equipment including the element.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations;Although with reference to the foregoing embodiments
Invention is explained in detail, those skilled in the art should understand that: it still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features;And these modification or
Replacement, the spirit and scope for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution.
Claims (14)
1. a kind of synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield, which is characterized in that the hemp
Shown in the molecular formula of phenolic substances such as following formula (I) and formula (II):
Wherein, R1、R2、R3And R4Be independently selected from group consisting of: H, OH, halogen, alkyl, alkenyl, alkynyl, acyl group,
Aryl, heterocycle, heteroaryl, condensed ring and naphthenic base;
Wherein the alkyl, alkenyl, alkynyl or acyl group optionally take through the one or more independently selected from group consisting of
Replace for base: halogen ,-OH, alkyl ,-O- alkyl, NRARB,-S- alkyl ,-SO- alkyl ,-SO2Alkyl, alkenyl, alkynyl, virtue
Base, heteroaryl, naphthenic base or heterocycle;Wherein RAAnd RBIt is each independently selected from hydrogen and C1-5 alkyl;
Wherein the aryl or the heteroaryl a part of substituent group (no matter individually or as) are optionally through independently selected from following
One or more substituent groups of the group of composition replace: halogen ,-OH, alkyl ,-O- alkyl ,-COOH ,-C (O)-C1-4 alkyl ,-C
(O) O-C1-4 alkyl, NRCRD,-S- alkyl ,-SO- alkyl and-SO2Alkyl;Wherein RCAnd RDIt is each independently selected from hydrogen and C1-
5 alkyl;
Specifically, the chemical synthesis process of the cannabinoids substance is as follows:
(1) Fries rearrangement generation formula (IV) compound occurs under certain catalytic condition for formula (III) compound:
Or Fries occurs under certain catalytic condition and resets generation formula (VI) compound for formula (V) compound:
Above-mentioned catalytic condition is that addition Lewis acid makees catalyst, addition Brown acid does catalyst, illumination, heating method
In any one;
(2) Diels-Alder reaction is occurred into a heated condition for formula (IV) compound and formula (VII) compound to form formula
(VIII) compound:
Or Diels-Alder reaction occurs in a heated condition for formula (VI) and formula (IX) compound to form formula (VIII) chemical combination
Object:
(3) formula (VIII) compound reacts under alkaline condition generates formula (I) compound:
(4) formula (I) compound reacts in acid condition generates formula (II) compound:
Wherein R5 is optionally from one of following group: H, OH, halogen, alkyl, alkenyl, alkynyl, acyl group, aryl, heterocycle, heteroaryl
Base, condensed ring and naphthenic base;
X is optionally from one of following halogen element: F, Cl, Br, I.
2. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, Lewis acid used is aluminium chloride, in zinc chloride, Antimony pentachloride, tin tetrachloride, boron trifluoride, ferric bromide, iron chloride
Any one, the Brown acid is trifluoracetic acid copper, any one in copper trifluoromethanesulfcomposite.
3. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, when Fries rearrangement generation formula (IV) compound occurs in a heated condition for formula (III) compound, heating temperature used is
35℃-150℃。
4. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, Fries occurs in formula (III) compound solvent under certain catalytic condition and resets generation formula (IV) compound, it is used molten
Agent are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum
One or more of ether, dimethyl sulfoxide, dioxane or acetonitrile, solution additional amount be with raw material solid-liquid volume ratio 1:10~
1:30。
5. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, when Fries rearrangement generation formula (VI) compound occurs in a heated condition for formula (V) compound, heating temperature used is 35
℃-150℃。
6. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, Fries occurs in formula (V) compound solvent under certain catalytic condition and resets generation formula (VI) compound, solvent for use
Are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether,
One or more of dimethyl sulfoxide, dioxane or acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30.
7. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (IV) and the reaction of formula (VII) compound generate formula (VIII) compound, and heating temperature used is 50 DEG C -300 DEG C.
8. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (IV) and the reaction of formula (VII) compound generate formula (VIII) compound, solvent for use are as follows: toluene, tetrahydrofuran, second
Acetoacetic ester, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane
Or one or more of acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30.
9. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (VI) and the reaction of formula (IX) compound generate formula (VIII) compound, and heating temperature used is 50 DEG C -300 DEG C.
10. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (VI) and the reaction of formula (IX) compound generate formula (VIII) compound, solvent for use are as follows: toluene, tetrahydrofuran, acetic acid
Ethyl ester, methylene chloride, chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or
One or more of acetonitrile, additional amount are and raw material solid-liquid volume ratio 1:10~1:30.
11. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (VIII) reaction generates alkali used when formula (I) compound are as follows: sodium carbonate, potassium carbonate, sodium methoxide, potassium ethoxide, hydroxide
One of sodium, potassium hydroxide, sodium acetate, cesium fluoride, potassium phosphate, additional amount are 3~10 times of feed molar amount.
12. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
Be, formula (VIII) reaction generate formula (I) compound when solvent for use are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride,
One of chloroform, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or acetonitrile or
Several, additional amount is and raw material solid-liquid volume ratio 1:10~1:30.
13. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, formula (I) reaction generates acid used when formula (II) compound are as follows: sulfuric acid, hydrochloric acid, p-methyl benzenesulfonic acid, acetic acid, phosphoric acid, formic acid
One of.
14. the synthetic method of the cannabinoids substance of preparation of industrialization high-purity high-yield as described in claim 1, feature
It is, solvent for use when formula (I) reaction generates formula (II) compound are as follows: toluene, tetrahydrofuran, ethyl acetate, methylene chloride, chlorine
One of imitative, acetone, normal heptane, hexamethylene, methanol, ethyl alcohol, petroleum ether, dimethyl sulfoxide, dioxane or acetonitrile are several
Kind, additional amount is and raw material solid-liquid volume ratio 1:10~1:30.
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