CN106810426B - Method for synthesizing cannabidiol - Google Patents
Method for synthesizing cannabidiol Download PDFInfo
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- CN106810426B CN106810426B CN201611245047.XA CN201611245047A CN106810426B CN 106810426 B CN106810426 B CN 106810426B CN 201611245047 A CN201611245047 A CN 201611245047A CN 106810426 B CN106810426 B CN 106810426B
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- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 32
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 31
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 31
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 31
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 33
- 238000000605 extraction Methods 0.000 claims abstract description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- -1 alcohol amine Chemical class 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 150000002148 esters Chemical group 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 40
- 239000007787 solid Substances 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 14
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000011592 zinc chloride Substances 0.000 claims description 7
- 235000005074 zinc chloride Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- RQGAOBDPFOADCM-UHFFFAOYSA-N methyl 2,4-dihydroxy-6-pentylbenzoate Chemical compound CCCCCC1=CC(O)=CC(O)=C1C(=O)OC RQGAOBDPFOADCM-UHFFFAOYSA-N 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 abstract 2
- 239000002841 Lewis acid Substances 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 150000007517 lewis acids Chemical class 0.000 abstract 1
- 229940095102 methyl benzoate Drugs 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- MKPMHJQMNACGDI-VHSXEESVSA-N (1S,4R)-p-Mentha-2,8-dien-1-ol Chemical compound CC(=C)[C@@H]1CC[C@](C)(O)C=C1 MKPMHJQMNACGDI-VHSXEESVSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 238000005809 transesterification reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- SWKPGMVENNYLFK-UHFFFAOYSA-N 2-(dipropylamino)ethanol Chemical compound CCCN(CCC)CCO SWKPGMVENNYLFK-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000036572 Myoclonic epilepsy Diseases 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- VRSOZWPIVQJKAT-UHFFFAOYSA-N OC1=C(C(=O)OC)C(=CC(=C1)O)C=CCCC Chemical compound OC1=C(C(=O)OC)C(=CC(=C1)O)C=CCCC VRSOZWPIVQJKAT-UHFFFAOYSA-N 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing cannabidiol, which comprises the steps of taking 2, 4-dihydroxy-6-pentane methyl benzoate as a raw material, carrying out ester exchange with N, N-dialkyl alcohol amine under the catalysis of potassium hydroxide, carrying out coupling reaction with (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of Lewis acid, carrying out acid-base extraction and recrystallization to obtain a high-purity key intermediate product, carrying out hydrolysis and decarboxylation to obtain a crude cannabidiol product, and carrying out primary recrystallization on the crude cannabidiol product to obtain the cannabidiol meeting the quality requirements of raw material medicines. The raw materials and reagents in the method are low in price and easy to obtain commercially, the total yield of the finally prepared raw material medicine with qualified purity can reach 35-40% at most, the process is obviously improved, and the method has a good industrial application prospect.
Description
Technical Field
The invention relates to a method for synthesizing cannabidiol, belonging to the technical field of organic synthesis.
Background
Cannabidiol is also called levo-trans-Cannabidiol, and is called (-) -Cannabdiol, and is a very valuable raw material medicine, and the structural formula of the compound is as follows:
at present, cannabidiol is mainly applied to nerve protection, spasm resistance, inflammation resistance, anxiety resistance and the like. In 2015, uk GW biopharmaceutical company announced: the clinical trial data of the pure cannabidiol for the intractable child epilepsy is updated, the medicine has been approved by the US FDA rare disease medicine and the fast channel approval in 2014, and is used for treating the infant severe myoclonic epilepsy, so that the market prospect of the medicine becomes wider. Low cost, high efficiency and simple operation, is suitable for industrial production, and has great promotion effect on the application of cannabidiol.
US20090036523a1 uses olive alcohol as a starting material, and uses p-toluenesulfonic acid for catalysis, and obtains a target product by a one-step method, which specifically comprises the following steps:
however, the reaction system is complex, has more isomers and dimers, is troublesome in post-treatment, needs column chromatography for purification, has low yield of only 24 percent, and is not suitable for large-scale production.
WO2006053766A1 utilizes zinc chloride catalysis to synthesize the target product. This document reports a process for obtaining the product without column purification, but the product purity is only 97.1% and the yield is only 22%. Repeated experiments are carried out on the document to find that the maximum single impurity in the reaction process is a dimer and reaches more than 20%, and the impurity can be reduced to be within 0.1% by more than 3 times of crystallization (meeting the requirement of the index of the raw material medicine). Finally, the total yield of the qualified raw material medicine is only 13%, and the process cost is high.
US20100298579a1 starts from methyl 2, 4-dihydroxy-6-pentanenylbenzoate and catalyzes the preparation of the coupled methyl ester intermediate (I) with boron trifluoride in diethyl etherate in slightly higher purity than the one-step process, and with significantly less isomers and dimers than the one-step process. However, after the coupling, the methyl ester intermediate is still only about 75% pure after acid-base treatment, and the melting point of the compound is possibly low, so that the compound cannot be crystallized (the intermediate I is not reported to have a melting point, and cannot be precipitated into a solid finally even if the intermediate I with the purity of 98% obtained by column chromatography is crystallized). The methyl ester intermediate I cannot be recrystallized and purified by a conventional method, so that the requirements of chemical purity and single impurity index of a key intermediate serving as a raw material medicament cannot be met.
In addition to the above two chemical synthesis methods, some documents report that cannabidiol is obtained by biological extraction, but the steps of the methods are complicated, and the industrial production is limited too much.
Disclosure of Invention
The present invention aims to solve the above technical problems and provide a method for synthesizing cannabidiol.
The purpose of the invention is realized by the following technical scheme:
a method for synthesizing cannabidiol, the reaction formula of which is shown as follows,
the method comprises the following steps:
s1, taking methyl 2, 4-dihydroxy-6-pentylbenzoate as a raw material, and carrying out ester exchange reaction with N, N-dialkyl hydramine under the action of potassium hydroxide to obtain an intermediate I; in the intermediate I, n is 1-8, and R is any one of methyl, ethyl, propyl and butyl;
s2, carrying out coupling reaction on the intermediate I prepared in the S1 and (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol to prepare an intermediate II; in the intermediate II, n is 1-8, and R is any one of methyl, ethyl, propyl and butyl;
s3, hydrolyzing the intermediate II at high temperature under the action of sodium hydroxide for decarboxylation, and finally obtaining the cannabidiol.
Preferably, the S1 includes the following steps:
s11, taking methyl 2, 4-dihydroxy-6-pentylbenzoate as a raw material to react with N, N-dialkyl hydramine under the action of potassium hydroxide through nitrogen protection;
s12, adding an acid solution, adjusting the pH value of the solution to acidity, and extracting for the first time;
s13, adding alkali to adjust the pH value of the solution to be alkaline, and extracting again;
s14, washing with water, drying, and concentrating under reduced pressure to obtain an intermediate I.
Preferably, the pH of the solution in S12 is adjusted to 2-3.
Preferably, the pH of the solution is adjusted to 10 in S12.
Preferably, the pH is adjusted in S13 by adding a basic solid.
Preferably, the alkaline solid added in S13 is an aqueous phase sodium carbonate solid. Of course, the solid or solution of the alkali can be adjusted, and the solid can be added to avoid the too large water consumption for adjusting the alkali, and the common alkali such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide can be used.
Preferably, the S2 includes the following steps:
s21, carrying out a condensation reaction on the intermediate I and (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of anhydrous zinc chloride;
s22, adding acid after the reaction is finished, and purifying by an acid-base extraction method to obtain a crude product of the intermediate II which has the purity of at least 90% and can be recrystallized;
s23, recrystallizing the crude product of the intermediate II by using a solvent to synthesize the key intermediate II of the bulk drug with high purity.
Preferably, the acid in S22 is any one of hydrochloric acid, sulfuric acid, acetic acid, oxalic acid and citric acid.
Preferably, the solvent in the S23 is any one of petroleum ether, n-pentane, n-hexane and n-heptane.
Preferably, the cannabidiol prepared by the above method has a purity of 99.88% to 99.98%.
The invention has the beneficial effects that: the raw materials and reagents in the method are low in price and commercially available, and the high-quality cannabidiol can be obtained through three steps of ester exchange, coupling and decarboxylation. Although the steps are increased to 3 steps, the intermediate of each step can be purified through recrystallization, the single impurity can reach the index of the intermediate of the raw material medicine, the total yield of the finally prepared raw material medicine with qualified purity can reach 35-40 percent, the process is obviously improved, and the process has good industrial application prospect.
Detailed Description
The method of the present invention is described below with reference to specific examples to make it easier to understand and understand the technical solution of the present invention, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
In the case of adjusting the pH in the examples used in the present invention, sodium carbonate is used in the present application, but not limited thereto, and conventional bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide are acceptable. Other regulatory auxiliary agents may be substituted as is conventional.
Example one
Preparation of intermediate one:
first, 119g of methyl 2, 4-dihydroxy-6-pentanedibenzoate and 89g of N, N-dimethylethanolamine were put in a 250mL three-necked flask, 30.8g of potassium hydroxide was added thereto with stirring, and the mixture was heated to 130 ℃ under nitrogen protection and stirred for reaction for 4 hours. Cooling the reaction solution to below 30 ℃, adjusting the pH to 2-3 by using 1N hydrochloric acid aqueous solution, adding N-heptane (250mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (250mL multiplied by 2) for extraction, washing (150mL) once, drying by using anhydrous sodium sulfate, concentrating under reduced pressure until the water is dried, adding 4v/m N-heptane for recrystallization, and obtaining 103g after drying, wherein the yield is 70%, and the HPLC purity is 99.84%.
Preparation of intermediate II:
100g of the above-mentioned purified product obtained by transesterification and 800mL of methylene chloride were put into a 2000mL three-necked flask, and 50.8g of zinc chloride and 8g of water were added with stirring, and stirred at 25 ℃ for 0.5 hour, and 46.4g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was added dropwise thereto, and the system was kept warm and stirred for 24 hours after completion of the dropwise addition. Cooling the reaction solution to below 10 ℃, adjusting the pH to 2-3 by using 1N hydrochloric acid aqueous solution, adding N-heptane (500mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (500mL multiplied by 2) for extraction, washing (300mL) once, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Adding 4v/m n-heptane into the crude product, heating at 40 ℃ for dissolving, cooling to-5 ℃, preserving heat for crystallization for 16 hours, performing suction filtration, and drying to obtain 60.2g of white solid, wherein the yield is 46%, and the HPLC purity is 99.98%.
Synthesis of cannabidiol:
adding 50g of the coupling product and 250mL of methanol into a 1000mL three-neck flask, adding 5v/m 3N sodium hydroxide aqueous solution under the protection of nitrogen, heating to 95 ℃, keeping the temperature for reaction for 8 hours, cooling to within 25 ℃, adding N-heptane (200mL x 2) for extraction, combining organic phases, washing with 100mL saturated sodium chloride once, concentrating under reduced pressure to dryness, adding 4v/m N-heptane for recrystallization, keeping the temperature for crystallization for 16 hours at-5 ℃, performing suction filtration and drying to obtain 33.7g of white solid, wherein the yield is 92%, and the HPLC purity is 99.93%.
Example two
Preparation of intermediate one:
119g of methyl 2, 4-dihydroxy-6-pentanedibenzoate and 234g of N, N-dimethylbutanolamine were added to a 500mL three-necked flask, and 33.6g of potassium hydroxide was added with stirring, and the mixture was heated to 130 ℃ under nitrogen protection and stirred for reaction for 4 hours. Cooling the reaction solution to below 30 ℃, adjusting the pH to 2-3 by using 1N hydrochloric acid aqueous solution, adding N-heptane (250mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (250mL multiplied by 2) for extraction, washing (150mL) once, drying by using anhydrous sodium sulfate, concentrating under reduced pressure until the water phase is dried, adding 4v/m N-heptane for recrystallization, and drying to obtain 134.1g, wherein the yield is 83% and the HPLC purity is 99.97%.
Preparation of intermediate II:
100g of the above-mentioned purified product obtained by transesterification and 800mL of methylene chloride were put into a 2000mL three-necked flask, and 46.4g of zinc chloride and 7.3g of water were added with stirring, and stirred at 25 ℃ for 0.5 hour, and 42.4g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was added dropwise thereto, and the system was kept warm and stirred for 24 hours after completion of the dropwise addition. Cooling the reaction solution to below 10 ℃, adjusting the pH to 2-3 by using 1N sulfuric acid aqueous solution, adding N-heptane (500mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (500mL multiplied by 2) for extraction, washing (300mL) once, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Adding 4v/m petroleum ether into the crude product, heating at 40 ℃ for dissolving, cooling to-5 ℃, preserving heat for crystallization for 16 hours, performing suction filtration, and drying to obtain 53.5g of white solid, wherein the yield is 42%, and the HPLC purity is 99.98%.
Synthesis of cannabidiol:
adding 50g of the coupling product and 250mL of methanol into a 1000mL three-neck flask, adding 5v/m 3N sodium hydroxide aqueous solution under the protection of nitrogen, heating to 95 ℃, keeping the temperature for reaction for 8 hours, cooling to within 25 ℃, adding N-heptane (200mL x 2) for extraction, combining organic phases, washing with 100mL saturated sodium chloride once, concentrating under reduced pressure to dryness, adding 4v/m N-heptane for recrystallization, keeping the temperature for crystallization for 16 hours at-5 ℃, performing suction filtration and drying to obtain 31.3g of white solid, wherein the yield is 91%, and the HPLC purity is 99.95%.
Example three:
preparation of intermediate one:
119g of methyl 2, 4-dihydroxy-6-pentaneacetate and 145g of N, N-dimethylhexanolamine were added into a 250mL three-neck flask, 30.8g of potassium hydroxide was added under stirring, and the mixture was heated to 130 ℃ under nitrogen protection and stirred for reaction for 4 hours. Cooling the reaction solution to below 30 ℃, adjusting the pH to 2-3 by using 1N hydrochloric acid aqueous solution, adding N-heptane (250mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (250mL multiplied by 2) for extraction, washing (150mL) once, drying by using anhydrous sodium sulfate, concentrating under reduced pressure until the water is dried, adding 4v/m N-heptane for recrystallization, and drying to obtain 142.2g, wherein the yield is 81% and the HPLC purity is 99.75%.
Preparation of intermediate II:
100g of the above-mentioned purified product obtained by transesterification and 800mL of methylene chloride were put into a 2000mL three-necked flask, 43.8g of zinc chloride and 6.9g of water were added with stirring, and stirred at 25 ℃ for 0.5 hour, and 40g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was added dropwise thereto, whereby heat was not substantially released, and stirring was carried out while maintaining the temperature for 24 hours after completion of the addition. Cooling the reaction solution to below 10 ℃, adjusting the pH to 2-3 by using 1N sulfuric acid aqueous solution, adding N-heptane (500mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (500mL multiplied by 2) for extraction, washing (300mL) once, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. And adding 4v/m of n-hexane into the crude product, heating at 40 ℃ for dissolving, cooling to-5 ℃, preserving heat, crystallizing for 16 hours, performing suction filtration, and drying to obtain 58.5g of white solid, wherein the yield is 47%, and the HPLC purity is 99.91%.
Synthesis of cannabidiol:
adding 50g of the coupling product and 250mL of methanol into a 1000mL three-neck flask, adding 5v/m 3N sodium hydroxide aqueous solution under the protection of nitrogen, heating to 90 ℃, keeping the temperature for reaction for 4 hours, cooling to within 25 ℃, adding N-heptane (200mL x 2) for extraction, combining organic phases, washing with 100mL saturated sodium chloride once, concentrating under reduced pressure to dryness, adding 4v/m N-heptane for recrystallization, keeping the temperature for crystallization for 16 hours at-5 ℃, performing suction filtration and drying to obtain 30.4g of white solid, wherein the yield is 94%, and the HPLC purity is 99.88%.
Example four:
preparation of intermediate one:
119g of methyl 2, 4-dihydroxy-6-pentanylbenzoate and 145.3g of N, N-dipropylethanolamine were placed in a 250mL three-necked flask, 30.8g of potassium hydroxide were added with stirring, and the mixture was heated to 130 ℃ under nitrogen protection and stirred for reaction for 4 hours. Cooling the reaction solution to below 30 ℃, adjusting the pH to 2-3 by using 1N hydrochloric acid aqueous solution, adding N-heptane (250mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (250mL multiplied by 2) for extraction, washing (150mL) once, drying by using anhydrous sodium sulfate, concentrating under reduced pressure until the water phase is dried, adding 4v/m N-heptane for recrystallization, and drying to obtain 127.8g, wherein the yield is 81% and the HPLC purity is 99.63%.
Preparation of intermediate II:
100g of the above-mentioned purified product obtained by transesterification and 800mL of methylene chloride were put into a 2000mL three-necked flask, 43.8g of zinc chloride and 6.9g of water were added with stirring, and stirred at 25 ℃ for 0.5 hour, and 40g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was added dropwise thereto, whereby heat was not substantially released, and stirring was carried out while maintaining the temperature for 24 hours after completion of the addition. Cooling the reaction solution to below 10 ℃, adjusting the pH to 2-3 by using 1N sulfuric acid aqueous solution, adding N-heptane (500mL multiplied by 2) for extraction, adjusting the pH to 10 by using aqueous phase sodium carbonate solid, adding N-heptane (500mL multiplied by 2) for extraction, washing (300mL) once, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Adding 4v/m n-heptane into the crude product, heating at 40 ℃ for dissolving, cooling to-5 ℃, preserving heat for crystallization for 16 hours, performing suction filtration, and drying to obtain 51g of white solid, wherein the yield is 41%, and the HPLC purity is 99.86%.
Synthesis of cannabidiol:
adding 50g of the coupling product and 250mL of methanol into a 1000mL three-neck flask, adding 5v/m 3N sodium hydroxide aqueous solution under the protection of nitrogen, heating to 95 ℃, keeping the temperature for reaction for 8 hours, cooling to within 25 ℃, adding N-heptane (200mL x 2) for extraction, combining organic phases, washing with 100mL saturated sodium chloride once, concentrating under reduced pressure to dryness, adding 4v/m N-heptane for recrystallization, keeping the temperature for crystallization for 16 hours at-5 ℃, performing suction filtration and drying to obtain 28.5g of white solid, wherein the yield is 88%, and the HPLC purity is 99.97%.
There are numerous specific embodiments of the invention. All technical solutions formed by using equivalent substitutions or equivalent transformations fall within the scope of the claimed invention.
Claims (9)
1. A method for synthesizing cannabidiol is characterized in that: the reaction formula is shown as follows,
the method comprises the following steps:
s1, taking methyl 2, 4-dihydroxy-6-pentylbenzoate as a raw material, and carrying out ester exchange reaction with N, N-dialkyl hydramine under the action of potassium hydroxide to obtain an intermediate I; n = 1-8 in the intermediate I, and R is any one of methyl, ethyl, propyl and butyl;
s2, carrying out coupling reaction on the intermediate I prepared in the S1 and (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol to prepare an intermediate II; n = 1-8 in the intermediate II, and R is any one of methyl, ethyl, propyl and butyl;
s3, hydrolyzing the intermediate II at high temperature under the action of sodium hydroxide for decarboxylation, and finally obtaining the cannabidiol.
2. A method of synthesizing cannabidiol as claimed in claim 1, wherein: the S1 includes the following steps:
s11, taking methyl 2, 4-dihydroxy-6-pentylbenzoate as a raw material to react with N, N-dialkyl hydramine under the action of potassium hydroxide through nitrogen protection;
s12, adding an acid solution, adjusting the pH value of the solution to acidity, and extracting for the first time;
s13, adding alkali to adjust the pH value of the solution to be alkaline, and extracting again;
s14, washing with water, drying, and concentrating under reduced pressure to obtain an intermediate I.
3. A method of cannabidiol synthesis as claimed in claim 2, wherein: and adjusting the pH of the solution in the S12 to be 2-3.
4. A method of cannabidiol synthesis as claimed in claim 2, wherein: and adjusting the pH of the solution to 10 in the S13.
5. A method of cannabidiol synthesis as claimed in claim 2, wherein: the pH was adjusted in S13 by adding a basic solid.
6. The method of claim 5, wherein the cannabidiol is selected from the group consisting of: the S13 is sodium carbonate solid by adding alkaline solid.
7. A method of synthesizing cannabidiol as claimed in claim 1, wherein: the S2 includes the following steps:
s21, carrying out a condensation reaction on the intermediate I and (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol under the catalysis of anhydrous zinc chloride;
s22, adding acid after the reaction is finished, and purifying by an acid-base extraction method to obtain a crude product of the intermediate II which has the purity of at least 90% and can be recrystallized;
s23, recrystallizing the crude product of the intermediate II by using a solvent to synthesize the key intermediate II of the bulk drug with high purity.
8. The method of claim 7, wherein the cannabidiol is selected from the group consisting of: the acid in the S22 is any one of hydrochloric acid, sulfuric acid, acetic acid, oxalic acid and citric acid.
9. The method of claim 7, wherein the cannabidiol is selected from the group consisting of: the solvent in the S23 is any one of petroleum ether, n-pentane, n-hexane and n-heptane.
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| ES2909350T3 (en) * | 2017-06-20 | 2022-05-06 | Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd | Compositions of esters of cannabidiolic acid and uses thereof |
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| EP3864000A4 (en) | 2018-10-10 | 2022-08-10 | Treehouse Biosciences, Inc. | Synthesis of cannabigerol |
| JP2022524780A (en) | 2019-03-12 | 2022-05-10 | イーピーエム（アイピー）， インコーポレイテッド | Cannabinoid acid ester composition and its use |
| CN111943813B (en) * | 2019-05-17 | 2023-04-14 | 上海特化医药科技有限公司 | Preparation method of cannabidiol compound |
| CN112062697B (en) * | 2019-05-22 | 2023-09-01 | 上海特化医药科技有限公司 | Meta-benzene polyphenol derivative and preparation method thereof |
| CN112047815B (en) * | 2020-10-10 | 2023-01-31 | 成都海博为药业有限公司 | Preparation method of cannabidiol compound |
| CN115504864A (en) * | 2021-06-07 | 2022-12-23 | 南通新世元生物科技有限公司 | Method for obtaining high-purity cannabidiol from industrial cannabis sativa |
| CN113603568A (en) * | 2021-07-19 | 2021-11-05 | 厦门朝阳生物工程有限公司 | Preparation method of cannabidiol |
| CN114634403A (en) * | 2022-03-10 | 2022-06-17 | 南京康立瑞生物科技有限公司 | Preparation method of 3, 6-dimethyl-1, 2-benzenediol |
| CN115583933B (en) * | 2022-10-31 | 2024-02-06 | 暨明医药科技（苏州）有限公司 | Preparation method of high-purity tetrahydrocannabinoid homolog |
| CN115677456B (en) * | 2022-11-11 | 2023-12-08 | 暨明医药科技（苏州）有限公司 | Preparation method of cannabidiol |
| CN119613231B (en) * | 2025-02-17 | 2025-05-23 | 山东新华制药股份有限公司 | Preparation method of cannabidiol |
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