CN112062697B - Meta-benzene polyphenol derivative and preparation method thereof - Google Patents
Meta-benzene polyphenol derivative and preparation method thereof Download PDFInfo
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- CN112062697B CN112062697B CN201910430644.7A CN201910430644A CN112062697B CN 112062697 B CN112062697 B CN 112062697B CN 201910430644 A CN201910430644 A CN 201910430644A CN 112062697 B CN112062697 B CN 112062697B
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
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- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention relates to an m-benzene polyphenol derivative and a preparation method thereof. The synthesis method can be very conveniently and widely applied to the synthesis and preparation of other derivatives and analogues of cannabidiol, greatly improves the selectivity, furthest avoids the generation of regioisomers and disubstituted byproducts, and remarkably improves the yield. The method has the advantages of low material cost, less pollutant, simple and convenient operation, easy expansion and application of the synthetic route and the like. In addition, the method specially designed by the invention can reduce byproducts, so that the method can be carried out by using a one-pot method, thereby greatly reducing the product and energy consumption during purification by a step method and greatly reducing pollutants.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to an m-benzene polyphenol derivative and a preparation method thereof.
Background
The isopolyphenols or derivatives thereof are a large family of compounds, such as resorcinol, which includes a number of natural product molecules, physiologically active molecules, pharmaceutically active ingredients and prodrug compounds thereof. One of the important members is the drug Cannabidiol (CBD). Cannabidiol (CBD) is a non-addictive component of cannabis, which does not act as a hallucinogen, and has wide application in the medical field. The application includes protecting nervous system, such as antispasmodics, anxiolytics, antiepileptics, analgesic, antiinflammatory, antirheumatic, etc. It can be used for treating various difficult and complicated diseases. In addition, a series of resorcinol compounds or derivatives thereof are also synthesized through chemical structure simulation modification of Cannabidiol (CBD). The compounds have different pharmacological activity and pharmacokinetic properties, can be used for different disease treatment and medicinal purposes, and therefore have very wide application prospects and medical values.
The series of compounds may be prepared by chemical synthesis. The chemical synthesis method comprises the condensation reaction of olive alcohol (Olivetol, OLV) and trans-menthyl-2, 8-diene-1-ol (+) - (1 s, 4R) -p-mentha-2, 8-dien-1-ol), the condensation reaction of olive alcohol benzoate and trans-menthyl-2, 8-diene-1-ol, the condensation reaction of dihalo-olive alcohol and trans-menthyl-2, 8-diene-1-ol, and other multi-step total synthesis methods.
The existing methods have certain defects, such as low reaction area selectivity, low product yield, complicated product separation and purification process, difficult route derivation and expansion application, and the like. Therefore, it is important to develop a new synthesis method of resorcinol compounds or derivatives thereof which is simpler, more efficient, lower in cost and suitable for industrial production. Meanwhile, the new method meets the requirements of an ESH management system and meets the corresponding requirements of safety and environmental protection.
Disclosure of Invention
It is an object of the present invention to provide a compound represented by the general formula II.
It is an object of the present invention to provide a compound represented by the general formula III.
It is still another object of the present invention to provide a method for preparing a compound represented by the general formula II.
It is still another object of the present invention to provide a method for preparing a compound represented by the general formula III.
It is still another object of the present invention to provide a method for preparing a compound represented by the general formula IV.
It is still another object of the present invention to provide a method for preparing a compound represented by the general formula V.
According to one aspect of the present invention, there is provided a compound represented by formula II:
in the compound represented by the general formula II, R 1 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 OR-P (=O) (OR 12 ) 2 。
Wherein, the liquid crystal display device comprises a liquid crystal display device,
R 4 to R 7 R is as follows 11 To R 12 Each independently is hydrogen, substituted or unsubstituted C 1 -C 20 Linear or branched or cyclic alkyl, substituted or unsubstitutedSubstituted benzyl, substituted or unsubstituted C 6 -C 20 An aryl group;
at R 4 To R 7 R is as follows 11 To R 12 Is substituted C 1 -C 20 Linear or branched or cyclic alkyl, substituted benzyl, or substituted C 6 -C 20 In the case of aryl, the substituents may be selected from cyano, nitro, amino, hydroxy, mercapto, halogen.
According to one aspect of the present invention, there is provided a compound represented by the general formula III:
in the compound represented by the general formula III, R 1 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 OR-P (=O) (OR 12 ) 2 。
R 2 Each independently is-C (=o) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-SiR 8 R 9 R 10 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 、-CHR 13 (OR 14 )、C-R 15 (R 16 )(R 17 ) Or a metal M.
R 4 To R 14 Each independently is hydrogen, substituted or unsubstituted C 1 -C 20 Linear or branched or cyclic alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 6 -C 20 An aryl group;
at R 4 To R 14 Is substituted C 1 -C 20 Linear or branched or cyclic alkyl, substituted benzyl, or substituted C 6 -C 20 In the case of aryl, the substituents may be selected from cyano, nitro, amino, hydroxy, mercapto, halogen.
R 15 、R 16 、R 17 Each independently selected from hydrogen, substituted or unsubstituted C 1 -C 20 Linear or branched or cyclic alkyl, C 1 -C 20 Straight-chain or branched or cyclic alkyl oxy, C 1 -C 20 Straight-chain or branched or cyclic alkylcarbonyloxy, substituted siloxyl, C 1 -C 20 Straight-chain or branched or cyclic alkylamino, C 1 -C 20 Straight-chain or branched or cyclic alkylcarbonylamino, substituted or unsubstituted benzyl, substituted or unsubstituted C 6 -C 20 Aryl groups.
At R 15 To R 17 Is substituted C 1 -C 20 Linear or branched or cyclic alkyl, substituted siloxyl, substituted benzyl, or substituted C 6 -C 20 In the case of aryl, the substituents may be selected from cyano, nitro, amino, hydroxy, mercapto, halogen.
M may be selected from lithium, sodium, potassium, cesium, magnesium, calcium, or zinc.
According to an embodiment of the present invention, there is provided a method for preparing a compound represented by the general formula II, the method comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
wherein R in the compound of formula II 1 And X is halogen as defined above.
Preferably, the reaction of step (2) above is carried out under alkaline conditions using a base reagent selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2, 6-lutidine, dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine, 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1, 8-diazabicyclo undec-7-ene (DBU), quinoline, 2-methylquinoline, 8-hydroxyquinoline.
Preferably, the solvent used in the reaction of the step (2) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide.
Preferably, in the step (2), the molar ratio of the compound of formula I, the esterifying reagent and the alkali reagent is 1.05 (1.0-1.5): (1.0-1.51), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, more preferably-30-10 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
According to an embodiment of the present invention, there is provided a method for preparing a compound represented by the general formula III, the method comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
(3) When R is 2 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 When the compound of formula II is combined with an esterifying reagent XR 2 Or R is 2 OR 2 Obtaining a compound of a formula III through reaction; when R is 2 is-SiR 8 R 9 R 10 、C-R 15 (R 16 )(R 17 ) or-CHR 13 (OR 14 ) When the compound of formula II is combined with an esterifying reagent XR 2 Obtaining a compound of a formula III through reaction; when R is 2 In the case of metal M, the compound of formula II reacts with a base reagent of metal M to obtain a compound of formula III,
wherein R1 in the compound of formula II is defined, R in the compound of formula III 1 And R is 2 Wherein X is halogen,
wherein steps (1) and (2) are as described above,
preferably, in the step (3), when R 2 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 、-SiR 8 R 9 R 10 Or C-R 15 (R 16 )(R 17 ) When the reaction of the above step (3) is carried out under alkaline conditions using a catalyst selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium phosphate, potassium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2, 6-dimethylpyridine, p-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine, 1, 4-diazabicyclo [ 2.2.2.2 ]]Octane (DABCO), 1, 8-diazabicyclo undec-7-ene (DBU), quinoline, 2-methylquinoline, 8-hydroxyquinoline, or a mixture of several kinds.
Preferably, in the step (3), when R 2 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 、-SiR 8 R 9 R 10 Or C-R 15 (R 16 )(R 17 ) The solvent used in the reaction in the step (3) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and C 4 -C 12 Straight-chain or branched or cyclic alkane, benzene,Toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide.
Preferably, in the step (3), when R 2 is-COR 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 、-SiR 8 R 9 R 10 Or C-R 15 (R 16 )(R 17 ) The molar ratio of the compound of formula II, the esterifying reagent and the alkali reagent is 1.0:2.0-3.0:2.0-3.0, the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, more preferably-30-10 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
Preferably, in the step (3), when R 2 is-CHR 13 (OR 14 ) When the reaction in the step (3) is carried out under an acidic condition, the acidic reagent is selected from one or a mixture of a plurality of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic Lewis acids and inorganic Lewis acids; more preferably, it comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride.
Preferably, in the step (3), when R 2 is-CHR 13 (OR 14 ) The solvent used in the reaction in the step (3) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, acetonitrile, acetone, N-dimethylformamide, dimethyl sulfoxide and water.
Preferably, in the step (3), when R 2 is-CHR 13 (OR 14 ) When the formula IIThe molar ratio of the compound to the reactant to the acid is 1.0:2.0-3.0:0.01-2.0, the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, more preferably-30-10 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
Preferably, in the step (3), when R 2 In the case of the metal M, the reaction in the step (3) is carried out in the presence of an alkali reagent selected from the group consisting of an alkyl lithium or aryl lithium reagent such as lithium carbonate, lithium hydroxide, lithium t-butoxide, and n-butyllithium, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium monohydrogen phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, potassium monohydrogen phosphate, potassium methoxide, potassium ethoxide, potassium t-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium t-butoxide, magnesium isopropoxide, and the like, a Grignard reagent such as calcium carbonate, calcium hydroxide, calcium phosphate, calcium oxide, calcium methoxide, calcium ethoxide, calcium isopropoxide, calcium t-butoxide, zinc oxide, zinc ethoxide, zinc t-butoxide, an alkyl or aryl zinc reagent.
Preferably, in the step (3), when R 2 In the case of metal M, the solvent used in the reaction in the step (3) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, methyl tertiary butyl ether, N-dimethylformamide, dimethyl sulfoxide and water.
Preferably, in the step (3), when R 2 In the case of metal M, the molar ratio of the compound of formula II, the esterifying reagent and the alkali reagent is 1.0 (2.0-3.0): (2.0-3.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, more preferably-30-10 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
Preferably, steps (2) and (3) of the process may be carried out using a one pot process.
According to an embodiment of the present invention, there is provided a method for preparing a compound represented by the general formula IV, the method comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
(3) When R is 2 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 When the compound of formula II is combined with an esterifying reagent XR 2 Or R is 2 OR 2 Obtaining a compound of a formula III through reaction; when R is 2 is-SiR 8 R 9 R 10 、C-R 15 (R 16 )(R 17 ) or-CHR 13 (OR 14 ) Reacting the compound of formula II with a reagent to obtain a compound of formula III; when R is 2 In the case of metal M, the compound of formula II reacts with a base reagent of metal M to obtain a compound of formula III,
(4) Reacting the compound of formula III with a coupling reagent to obtain a compound of formula IV,
wherein the substituents of formulae I to IV are the same as described above,
wherein steps (1) to (3) are the same as described above,
preferably, the reaction in step (4) is carried out in the presence of a transition metal catalyst selected from palladium acetate, palladium dichloride, palladium on charcoal, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (tricyclohexylphosphine) palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (di-tert-butylphosphine) palladium dichloride, tris [ dibenzylideneacetone ] dipalladium, bis [ dibenzylideneacetone ] palladium, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl complex with palladium salt, 2-dicyclohexylphosphine-2 ', a complex of 6' -diisopropyloxy-biphenyl and palladium salt, a complex of 2-dicyclohexylphosphine-2 ' -dimethylamino-biphenyl and palladium salt, a complex of 2-di-tert-butylphosphine biphenyl and palladium salt, a complex of 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl and immobilized palladium, a complex of 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-biphenyl and immobilized palladium, a complex of 2-dicyclohexylphosphine-2 ' -dimethylamino-biphenyl and immobilized palladium, a complex of 2-di-tert-butylphosphine biphenyl and immobilized palladium, ferric trichloride, ferrous chloride, ferrous acetate, ferrous bromide, ferrous sulfate, ferric nitrate, ferric (acetylacetonate), a complex of nickel salt and a ligand, wherein the nickel salt is selected from nickel difluoride, nickel dichloride, nickel dibromide, nickel diiodide, nickel acetate, nickel trifluoroacetate, nickel acetylacetonate, bis (hexafluoroacetylacetonate) nickel and hydrates of the nickel salts, and the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1 '-bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2', 6 '-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 6 '-diisopropyloxybiphenyl, 2-dicyclohexylphosphine-2' -dimethylamino-biphenyl, 2-di-tert-butylphosphine biphenyl, 2 '-bipyridine, 1,10' -phenanthroline.
Preferably, the coupling reagent used in step (4) above is selected from the group consisting of a lithium reagent, a magnesium reagent, a zinc reagent, or a complex salt thereof, substituted alkyl, and a substituted boric acid or borate compound, or a substituted trifluoroborate, or a substituted organotin reagent; more preferably, the coupling reagent comprises R 3 Magnesium chloride (R) 3 MgCl)、R 3 Magnesium bromide (R) 3 MgBr)、R 3 Magnesium iodide radical (R) 3 MgI)、R 3 Zinc chloride (R) 3 ZnCl)、R 3 Zinc monobromide (R) 3 ZnCBr)、R 3 Zinc iodide (R) 3 ZnI)、R 3 Magnesium chloride-lithium chloride based complex (R) 3 MgCl·LiCl)、R 3 Magnesium bromide-lithium chloride based complexes (R) 3 MgBr·LiCl)、R 3 Magnesium iodide-lithium chloride based complex (R) 3 MgI·LiCl)、R 3 Zinc chloride-lithium chloride based complex (R 3 ZnCl·LiCl)、R 3 Zinc bromide-lithium chloride based compositeObject (R) 3 ZnBr·LiCl)、R 3 Zinc iodide-lithium chloride based complex (R) 3 ZnI·LiCl)、R 3 Substituted boric acids or esters, trialkylboron ((R) 3 ) 3 B)、R 3 Substituted potassium fluoroborate (R) 3 BF 3 )、R 3 One or a mixture of several substituted organotin.
Preferably, the solvent used in the reaction in the step (4) is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide.
Preferably, in the step (4), the molar ratio of the compound of formula III, the transition metal catalyst and the coupling agent is 1.0 (0.001-0.5): (0.8-2.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-100 ℃, more preferably-30 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
According to an embodiment of the present invention, there is provided a method for preparing a compound represented by the general formula V, the method comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
(3) When R is 2 is-C (=O) R 4 、-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-C(＝O)-OR 11 、-P(＝O)(OR 12 ) 2 When the compound of formula II is combined with an esterifying reagent XR 2 Or R is 2 OR 2 Obtaining a compound of a formula III through reaction; when R is 2 is-SiR 8 R 9 R 10 、C-R 15 (R 16 )(R 17 ) or-CHR 13 (OR 14 ) When in use, the method comprises the steps ofII Compounds and esterifying Agents XR 2 Obtaining a compound of a formula III through reaction; when R is 2 In the case of metal M, the compound of formula II reacts with a base reagent of metal M to obtain a compound of formula III,
(4) Reacting the compound of formula III with a coupling reagent to obtain a compound of formula IV,
(5) The compound of formula IV undergoes a deprotection reaction to give the compound of formula V.
Wherein the substituents of formulae I to V are as described above,
wherein steps (1) to (4) are the same as described above,
preferably, in the step (5), when R 2 is-C (=O) R 4 、-SiR 8 R 9 R 10 、-C(＝O)(OR 11 ) In the case of using an alkaline reagent or an acidic reagent as the reaction reagent,
in the above step (5), when R 2 is-SO 2 R 5 、-C(＝O)-NR 6 R 7 、-P(＝O)(OR 12 ) 2 In the case of this, the only reagents used are alkaline reagents,
in the above step (5), when R 2 is-CHR 13 (OR 14 ) Or C-R 15 (R 16 )(R 17 ) In the case of the reaction reagent used is only an acidic reagent,
wherein the alkaline reagent is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, tetrabutylammonium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tri-sec-butylborohydride, potassium triisooxyborohydride, potassium tri-sec-butylborohydride, tetrabutylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, zinc fluoride, magnesium fluoride, calcium fluoride.
Wherein the acidic reagent is selected from one or a mixture of a plurality of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic Lewis acids and inorganic Lewis acids; more preferably, it comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride.
Preferably, the solvent used in the reaction in the above step (5) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, methanol, ethanol, isopropanol, n-butanol, tertiary butanol, ethylene glycol and water.
Preferably, in the step (5), the molar ratio of the compound of formula IV, the alkaline reagent or the acidic reagent is 1.0 (2.0 to 10.0), the concentration of the solution is 0.05 to 2.0mol/L, the reaction temperature is-60 to 30 ℃, more preferably-30 to-10 ℃, and the reaction time is 2 to 10 hours, more preferably 3 to 4 hours.
Preferably, steps (4) and (5) of the process may be carried out using a one pot process.
According to an embodiment of the present invention, there is provided a method for preparing a compound represented by the general formula V, the method comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
(3') reacting the compound of formula II with a coupling reagent to obtain a compound of formula V,
Wherein the substituents of formulae I to II are the same as described above,
wherein steps (1) to (2) are the same as described above,
preferably, the reaction in step (3 ') is carried out in the presence of a transition metal catalyst selected from palladium acetate, palladium dichloride, palladium on charcoal, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (tricyclohexylphosphine) palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (di-tert-butylphosphine) palladium dichloride, tris [ dibenzylideneacetone ] dipalladium, bis [ dibenzylideneacetone ] palladium, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl complex with palladium salt, 2-dicyclohexylphosphine-2 ', a complex of 6' -diisopropyloxy-biphenyl and palladium salt, a complex of 2-dicyclohexylphosphine-2 '-dimethylamino-biphenyl and palladium salt, a complex of 2-di-tert-butylphosphine biphenyl and palladium salt, a complex of 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl and immobilized palladium, a complex of 2-dicyclohexylphosphine-2', 6 '-diisopropyloxy-biphenyl and immobilized palladium, a complex of 2-dicyclohexylphosphine-2' -dimethylamino-biphenyl and immobilized palladium, a complex of 2-di-tert-butylphosphine biphenyl and immobilized palladium, ferric trichloride, ferrous chloride, ferrous acetate, ferrous bromide, ferrous sulfate, ferric nitrate, ferric (acetylacetonate), a complex of nickel salt and a ligand, wherein the nickel salt is selected from nickel difluoride, nickel dichloride, nickel dibromide, nickel diiodide, nickel acetate, nickel trifluoroacetate, nickel acetylacetonate, bis (hexafluoroacetylacetonate) nickel and hydrates of the nickel salts, and the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1 '-bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2', 6 '-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 6 '-diisopropyloxybiphenyl, 2-dicyclohexylphosphine-2' -dimethylamino-biphenyl, 2-di-tert-butylphosphine biphenyl, 2 '-bipyridine, 1,10' -phenanthroline.
Preferably, in the above stepThe coupling reagent used in (3') is selected from a lithium reagent, a magnesium reagent, a zinc reagent, or a complex salt thereof, substituted boric acid or a borate compound, or a substituted trifluoroborate, or a substituted organotin reagent; more preferably, the coupling reagent comprises R 3 Magnesium chloride radical, R 3 Magnesium bromide radical R 3 Magnesium iodide radical, R 3 Zinc chloride radical, R 3 Zinc monobromide, R 3 Zinc iodide radical R 3 Magnesium chloride-lithium chloride based complex, R 3 Magnesium bromide-lithium chloride based complex, R 3 Magnesium iodide-lithium chloride compound, R 3 Zinc chloride-lithium chloride based complex, R 3 Zinc bromide-lithium chloride based complex, R 3 Zinc iodide-lithium chloride based complex, R 3 Boric acid, R 3 Boric anhydride, R 3 Pinacol ester of phenylboronic acid, R 3 T-amyl alcohol ester of phenylboronic acid, R 3 Ethylene glycol monoboronate, R 3 Propylene glycol ester of Ylboronic acid, tri R 3 Boron radicals, R 3 Potassium trifluoroborate radical R 3 Tin trichloride, tetraR 3 One or a mixture of several of the base tin.
Preferably, the solvent used in the reaction in the step (3') is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide.
Preferably, in the step (3'), the molar ratio of the compound of formula II, the transition metal catalyst and the coupling agent is 1.0 (0.001-0.5): (0.8-2.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, more preferably-30-10 ℃, and the reaction time is 2-10 hours, more preferably 3-4 hours.
Preferably, the process is carried out using a one-pot process.
Advantageous effects
The invention takes phloroglucinol which is an industrially available chemical or basic chemical raw material as a starting material, prepares phloroglucinol derivatives through known condensation reaction and characteristic high-selectivity monoesterification reaction, and conveniently obtains resorcinol compounds or derivatives thereof with application significance through characteristic cross-coupling reaction and the like, wherein the resorcinol compounds or derivatives thereof comprise Cannabidiol (CBD) which has pharmacological actions such as antiepileptic, antispasmodic, anxiolytic and the like, and derivatives, analogues, prodrug compounds and the like thereof.
In the synthetic route of the synthetic method, the terpene ring substituent fragment, the aromatic ring fragment containing the diphenol hydroxyl and the substituent fragment at the para position of the terpene ring are synthesized and introduced into the final molecular structure in steps, so that the synthetic method can be very conveniently and widely applied to the synthesis and preparation of other derivatives and analogues of cannabidiol. The method greatly improves the selectivity, avoids the generation of regioisomers and disubstituted byproducts to the maximum extent, and obviously improves the yield. The method has the advantages of low material cost, less pollutant, simple and convenient operation, easy expansion and application of the synthetic route and the like.
The method specially designed by the invention can reduce byproducts, so that the method can be carried out by a one-pot method, thereby greatly reducing the product and energy consumption during purification by a step-by-step method and greatly reducing pollutants.
Detailed Description
Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details set forth in the following examples, as other variations will be known and apparent to those of ordinary skill in the art in light of the present disclosure.
Example 1: preparation of Compound I-1
Phloroglucinol (50.4 g,400 mmol) was added to a reaction flask with a constant pressure funnel. Air was removed under vacuum and replaced three times with nitrogen, solvent tetrahydrofuran (150 mL) was added and stirred well until the solid dissolved and clear. Boron trifluoride-diethyl etherate (2.85 g,20 mmol) was then added to the solution and stirred well before the reaction was cooled to-5 ℃. A solution of trans-menthyl-2, 8-dien-1-ol (4.04 g,40 mmol) in tetrahydrofuran (50 mL) was then slowly added dropwise to the mixture from a constant pressure funnel with stirring at-5-5℃and allowed to react for 4 hours at-5℃to 5 ℃. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (20 mL) and the reaction mixture was warmed to 20℃to 25℃and stirred for half an hour. The aqueous phase was discarded, the organic phase was concentrated by distillation under reduced pressure, and the reaction mixture was purified by silica gel column chromatography to give 43.3g of a pure product as a yellow-orange viscous oil with a yield of 83%.
1 H NMR(CDCl 3 400MHz):1.65(s,3H),1.71-1.80(m,5H),2.05-2.24(m,2H),2.34-2.40(m,1H),3.83-3.85(m,1H),4.50(s,1H),4.58(s,1H),5.51(s,1H),5.95(s,br,3H),6.19(s,br,2H).LR-MS(ESI)m/z:259(M-H) - ,261(M+H) + .
Example 2: preparation of Compound II-1
Compound I-1 (37.2 g,143 mmol) and methylene chloride (80 mL) were added to a reaction flask with a constant pressure funnel, 2, 6-lutidine (16.7 g,156 mmol) was added and stirred well at room temperature. Trifluoromethanesulfonic anhydride (36.6 g,130 mmol) and dichloromethane (80 mL) were added to the constant pressure funnel and mixed well. Slowly dripping the trifluoro methane sulfonic anhydride solution into the reaction under the stirring of minus 20 ℃ to minus 15 ℃ for about 1 hour, then heating the reaction to 0 ℃ to 5 ℃ and continuing the reaction for 3 to 4 hours. The reaction mixture was warmed to room temperature of 20-25 ℃, quenched by adding dilute hydrochloric acid (1 m,35 ml) with stirring and adjusted to pH 1-2. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. The organic phase was washed once with water, then toluene (80 mL) was added, concentrated by distillation under reduced pressure to remove the vast majority of the dichloromethane, and then slowly cooled to room temperature. The toluene phase was washed twice with 2-3% aqueous potassium hydroxide (50 mL), and the organic phase was washed once with dilute hydrochloric acid (1M, 10 mL) and once with water. The organic phase was concentrated to remove most of toluene to obtain an oily solid residue, which was purified by silica gel column chromatography to obtain 43.3g of pure compound II-1 in 85% yield.
1 H NMR(CDCl 3 ,400MHz):1.65(s,3H),1.65-1.88(m,5H),2.10-2.25(m,2H),2.32-2.38(m,1H),3.86-3.89(m,1H),4.50(s,1H),4.65(s,1H),5.24(s,br,1H),5.54(s,1H),6.30(s,br,1H),6.36(s,br,2H).LR-MS(ESI)m/z:391(M-H) - ,410(M+NH 4 ) + .
Example 3: preparation of Compound III-1
Compound II-1 (3.92 g,10 mmol) and dichloromethane (10 mL) were added to a reaction flask with a constant pressure funnel at room temperature and stirred until the solution was clear, and then N, N-dimethylaminopyridine (122 mg,1 mmol) and triethylamine (3.03 g,30 mmol) were added and stirred uniformly. Pivaloyl chloride (3.01 g,25 mmol) and dichloromethane (80 mL) were added to a constant pressure funnel and mixed well. The pivaloyl chloride solution was slowly added dropwise to the reaction under stirring at room temperature for about 1 hour, and then the reaction was continued at room temperature for 10 to 12 hours. Dilute hydrochloric acid (1 m,15 ml) was added under stirring to quench the reaction and the pH was adjusted to 1-2. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. The organic phase was washed once with saturated aqueous sodium bicarbonate (20 mL) and once with water. The organic phase was concentrated to remove the solvent to give crude compound III-1 as a clear bright yellow oil, 5.3g, 95% yield.
1 H NMR(CDCl 3 ,400MHz):1.33-1.34(m,20H),1.53(s,3H),1.62(s,3H),1.66-2.12(m,5H),2.66-2.71(m,1H),3.59-3.61(m,1H),4.51(s,1H),4.55(s,1H),5.21(s,1H),6.79(s,2H).LR-MS(ESI)m/z:578(M+NH 4 ) + .
Example 4: preparation of Compound IV-1
Anhydrous zinc chloride (102 mg,0.75 mmol) was added to the reaction tube, dried under vacuum to remove water and oxygen, and nitrogen was vented. Anhydrous tetrahydrofuran (1 mL) was added under nitrogen and stirred until dissolved and clear. N-pentylmagnesium bromide solution (0.75 mL,1M, THF) was added dropwise to zinc chloride solution under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour.
Compound III-1 (280 mg,0.5 mmol) and Pd (dppf) Cl as a catalyst 2 (3.7 mg,0.005 mmol) and tetrahydrofuran (2 mL) were added to the flask at room temperature and stirred well until dissolved and clarified, and nitrogen was replaced 3 times. The prepared tetrahydrofuran solution of n-amyl zinc chloride is added into the reaction at one time under the stirring of room temperature, and then the reaction is continued for 3 to 4 hours at the temperature of 50 to 55 ℃. After the reaction was cooled to room temperature, the reaction was quenched by adding a saturated aqueous ammonium chloride solution (5 mL) under stirring, and extracted with ethyl acetate (5 mL). The aqueous phase was discarded by pipetting. The organic phase was concentrated to remove the solvent to give a brown yellow oil, which was purified by silica gel column chromatography to give pure product IV-1 as a colorless transparent oil, 217mg, yield 90%.
1 H NMR(CDCl 3 ,400MHz):0.88(t,J＝8Hz,3H),1.29-1.33(m,22H),1.54(s,3H),1.60(s,3H),1.54-1.80(m,4H),1.94-2.19(m,2H),2.52(t,J＝8Hz,2H),2.64-2.69(m,1H),3.50-3.53(m,1H),4.55(s,2H),5.25(s,1H),6.58(s,2H).LR-MS(ESI)m/z:500(M+NH 4 ) + .
Example 5: preparation of Compound V-1
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Compound IV-1 (96 mg,0.2 mmol), dichloromethane (4 mL), methanol (0.5 mL) and potassium hydroxide (56 mg,1 mmol) were added to the reaction flask at room temperature, stirred well until dissolved and clarified, and replaced with nitrogen 3 times. The reaction is carried out for 10 to 12 hours under stirring at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (5 mL), and extracted with n-heptane (5 mL) with stirring. The aqueous phase was discarded after standing and separating. The organic phase was concentrated to remove the solvent to give a bright yellow oil, which was purified by silica gel column chromatography to give pure product of the bright yellow oily compound V-1, 58mg, yield 91%.
1 H NMR(CDCl 3 ,400MHz):0.90(t,J＝8Hz,3H),1.22-1.33(m,7H),1.53-1.60(m,2H),1.65(s,3H),1.78(s,3H),2.00-2.21(m,2H),2.38-2.46(m,3H),3.89-3.92(m,1H),4.55(s,1H),4.66(s,1H),4.96(s,br,1H),5.57(s,1H),6.01(s,br,1H),6.20(s,br,2H).LR-MS(ESI)m/z:313(M-H) - ,315(M+H) + .
Example 6: preparation of Compound II-2
Compound I-1 (6.9 g,26.5 mmol) and methylene chloride (20 mL) were added to a reaction flask with a constant pressure funnel, triethylamine (2.95 g,29.0 mmol) was added and stirred well at room temperature. P-toluenesulfonyl chloride (5.1 g,26.5 mmol) and methylene chloride (20 mL) were added to the constant pressure funnel and mixed well. Slowly dripping the p-toluenesulfonyl chloride solution into the reaction under the stirring of 0+/-2 ℃ for about half an hour, and then heating the reaction to 20-25 ℃ for continuous reaction for 5 hours. Dilute hydrochloric acid (1 m,10 ml) was added under stirring to quench the reaction and the pH was adjusted to 1-2. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. The organic phase is washed once by saturated sodium bicarbonate aqueous solution, the water phase is discarded after liquid separation, then the water is used for washing once, the organic phase obtained by liquid separation is concentrated by reduced pressure distillation to obtain oily solid residue, and the oily solid residue is separated and purified by silica gel column chromatography to obtain a pure product of the compound II-2, which is light yellow syrup solid, 9.5g, and the yield is 87%.
1 H NMR(CDCl 3 ,400MHz):1.62(s,3H),1.73-1.87(m,8H),2.07-2.34(m,4H),2.43(s,3H),3.74-3.77(m,1H),3.83-3.85(m,1H),4.39(s,1H),4.58(s,1H),5.32(s,br,1H),5.50(s,1H),6.02(s,br,1H),6.14(s,br,2H),7.28(d,J＝8Hz,2H),7.69(d,J＝8Hz,2H).LR-MS(ESI)m/z:413(M-H) - ,432(M+NH 4 ) + .
Example 7: preparation of Compound V-1
Anhydrous zinc chloride (1.36 g,10.0 mmol) and anhydrous lithium chloride (425 mg,10.0 mmol) were added to the reaction tube, dried under vacuum to remove water and oxygen, and purged with nitrogen. Anhydrous tetrahydrofuran (5 mL) was added under nitrogen and stirred until dissolved and clear. N-pentylmagnesium bromide solution (10 mL,1M, THF) was added dropwise to the zinc chloride-lithium chloride solution under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour.
Compound II-1 (784 mg,2 mmol), palladium acetate (4.5 mg,0.02 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (16.4 mg,0.04 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask at room temperature, stirred well until dissolved and clarified, and nitrogen was replaced 3 times. The prepared tetrahydrofuran solution of n-amyl zinc chloride-lithium chloride is transferred out by a syringe under stirring at room temperature and slowly added into the reaction in a dropwise manner, and then the reaction is continued for 2-3 hours at 25-30 ℃. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) with stirring at room temperature, and extracted with ethyl acetate (5 mL). The aqueous phase was discarded by pipetting. The organic phase was concentrated to remove the solvent to give a brown yellow oil, which was purified by silica gel column chromatography to give pure product of V-1 as a colorless transparent oil, 217mg, yield 30%.
1 H NMR(CDCl 3 ,400MHz):0.90(t,J＝8Hz,3H),1.22-1.33(m,7H),1.53-1.60(m,2H),1.65(s,3H),1.78(s,3H),2.00-2.21(m,2H),2.38-2.46(m,3H),3.89-3.92(m,1H),4.55(s,1H),4.66(s,1H),4.96(s,br,1H),5.57(s,1H),6.01(s,br,1H),6.20(s,br,2H).LR-MS(ESI)m/z:313(M-H) - ,315(M+H) + .
Example 8: preparation of Compound III-2
Compound II-1 (7.84 g,20 mmol) and methylene chloride (50 mL) were added to the reaction flask at room temperature and stirred well until dissolved and clarified, and then N, N-dimethylaminopyridine (244 mg,2 mmol) and triethylamine (6.06 g,60 mmol) were added and stirred well. Partoluenesulfonyl chloride (9.53 g,50 mmol) was added slowly in portions to the reaction with stirring at room temperature, over 1 hour, and the reaction was continued at room temperature for 5-6 hours. Dilute hydrochloric acid (1 m,15 ml) was added under stirring to quench the reaction and the pH was adjusted to 1-2. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. The organic phase was washed twice with saturated aqueous sodium bicarbonate (20 mL) and the organic phase was washed once with water. The organic phase was concentrated to remove the solvent to give crude compound III-2 as a pale yellow oil, 113.7g, yield 98%.
1 H NMR(CDCl 3 ,400MHz):1.49(s,3H),1.54(s,3H),1.56-1.82(m,4H),2.40-2.45(m,1H),2.47(s,6H),3.59-3.62(m,1H),4.23(s,1H),4.41(s,1H),4.49(s,1H),7.06(s,br,2H),7.36(d,J＝8Hz,4H),7.75(d,J＝8Hz,4H).LR-MS(ESI)m/z:718(M+NH 4 ) + .
Example 9: preparation of Compound IV-2
Anhydrous zinc chloride (210 mg,1.5 mmol) was added to the reaction tube, dried under vacuum to remove water and oxygen, and nitrogen was vented. Anhydrous tetrahydrofuran (3 mL) was added under nitrogen and stirred until dissolved and clear. N-pentylmagnesium bromide solution (1.5 mL,1M, THF) was added dropwise to zinc chloride solution under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour.
Compound III-2 (700 mg,1 mmol), catalyst Pd (dppf) Cl 2 (7 mg,0.01 mmol) and tetrahydrofuran (3 mL) were added to the flask at room temperature and stirred well until dissolved and clarified, and nitrogen was replaced 3 times. The prepared tetrahydrofuran solution of n-amyl zinc chloride is added into the reaction at one time under the stirring of room temperature, and then the reaction is continued for 3 to 4 hours at the temperature of 50 to 55 ℃. After the reaction was cooled to room temperature, the reaction was quenched by adding a saturated aqueous ammonium chloride solution (10 mL) under stirring, and extracted with ethyl acetate (10 mL). The aqueous phase was discarded by pipetting. The organic phase was concentrated to remove the solvent to give a brown yellow oil, which was purified by silica gel column chromatography to give pure product of pale yellow compound IV-2, 490mg, yield 80%.
1 H NMR(CDCl 3 ,400MHz):0.90(t,J＝8Hz,3H),1.20-1.34(m,4H),1.44-1.58(m,11H),1.68-1.75(m,1H),2.39-2.48(m,9H),3.51-3.53(m,1H),4.31(s,1H),4.41(s,1H),4.51(s,1H),6.92(s,br,2H),7.33(d,J＝8Hz,4H),7.74(d,J＝8Hz,4H).LR-MS(ESI)m/z:640(M+NH 4 ) + .
Example 10: preparation of Compound III-3
Compound II-1 (500 mg,1.28 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask at room temperature and stirred well until dissolved and clarified, and then N, N-dimethylaminopyridine (19 mg,0.13 mmol) and diisopropylethylamine (495mg, 3.83 mmol) were added and stirred well. Di-tert-butyl dicarbonate (696 mg,3.19 mmol) was added slowly in portions to the reaction with stirring at room temperature, over half an hour, and the reaction was continued at room temperature for 5-6 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (20 mL) with stirring and the pH was adjusted to 5-6. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. The organic phase was washed twice more with water. The organic phase was concentrated to remove the solvent to give crude compound III-3 as an off-white solid, 644mg, in 85% yield.
1 H NMR(CDCl 3 ,400MHz):1.53(s,18H),1.59(s,3H),1.68(s,3H),1.72-1.80(m,2H),1.97-2.01(m,1H),2.19-2.26(m,1H),2.64-2.71(m,1H),3.72-3.74(m,1H),4.40(s,1H),4.51(s,1H),5.18(s,1H),6.98(s,2H).LR-MS(ESI)m/z:610(M+NH 4 ) + .
Example 11: preparation of Compound III-3 (continuous feed)
Compound I-1 (260 mg,1 mmol) and toluene (3 mL) were added to a reaction flask with a constant pressure funnel, 2, 6-lutidine (128 mg,0.12 mmol) was added and stirred well at room temperature. To a constant pressure funnel was added trifluoromethanesulfonic anhydride (282 mg,1 mmol). Slowly dripping the trifluoro methane sulfonic anhydride solution into the reaction under the stirring of minus 25 ℃ to minus 20 ℃ for about 1 hour, then heating the reaction to 0 ℃ to 5 ℃ and continuing the reaction for 3 to 4 hours. The reaction mixture was warmed to room temperature (20-25 ℃) and quenched by the addition of dilute hydrochloric acid (1 m,3 ml) with stirring and the pH adjusted to 1-2. After fully stirring, standing and separating liquid, and discarding the water phase from the separated liquid. 10-15% aqueous potassium carbonate (5 mL) was added to the mixture to wash the toluene phase thoroughly, and the aqueous phase was discarded after standing and separation. N, N-dimethylaminopyridine (12.2 mg,0.1 mmol) and potassium carbonate (345 mg,2.5 mmol) and acetonitrile (1 mL) were added to the organic phase and stirred well. Di-tert-butyl dicarbonate (490 mg,2.25 mmol) was added slowly in portions to the reaction with stirring at room temperature, over half an hour, and the reaction was continued at room temperature for 5-6 hours. 10mL of water is added for quenching reaction, and after full stirring, the mixture is kept stand for liquid separation, and the water phase is discarded. The organic phase was concentrated to remove most of toluene to give an oily solid residue, which was purified by silica gel column chromatography to give 520mg of pure compound III-3 in 88% yield.
1 H NMR(CDCl 3 ,400MHz):1.53(s,18H),1.59(s,3H),1.68(s,3H),1.72-1.80(m,2H),1.97-2.01(m,1H),2.19-2.26(m,1H),2.64-2.71(m,1H),3.72-3.74(m,1H),4.40(s,1H),4.51(s,1H),5.18(s,1H),6.98(s,2H).LR-MS(ESI)m/z:610(M+NH 4 ) + .
Example 12: preparation of Compound V-1 (continuous feeding)
Anhydrous zinc chloride (100 mg,0.75 mmol) and anhydrous lithium chloride (33 mg,0.75 mmol) were added to the reaction tube, dried under vacuum to remove water and oxygen, and purged with nitrogen. Anhydrous tetrahydrofuran (2 mL) was added under nitrogen and stirred until dissolved and clear. N-pentylmagnesium bromide solution (0.75 mL,1M, THF) was added dropwise to zinc chloride solution with stirring at room temperature, and stirring was completed for 0.5 hours at room temperature until complete dissolution and clarification. Compound III-3 (300 mg,0.5 mmol), catalyst Pd (dppf) Cl 2 (4 mg,0.005 mmol) was added to the zinc reagent solution under nitrogen flow protection with stirring at room temperature, followed by 55. Mu.mThe reaction is carried out for 3 to 4 hours at the temperature of 60 ℃. After the reaction was cooled to room temperature, the reaction was quenched by adding a saturated aqueous ammonium chloride solution (5 mL) under stirring, and extracted with toluene (3 mL). After fully stirring, standing for layering, separating liquid and discarding water phase. Saturated aqueous sodium bicarbonate (5 mL) was added to the organic phase, the mixture was allowed to stand for separation, and the aqueous phase was discarded. The organic phase was concentrated to remove the solvent, then methanol (5 mL) and potassium hydroxide (140 mg,2.5 mmol) were added, stirred well until dissolved and clear, and replaced 3 times with nitrogen. Reacting for 4-5 hours at reflux temperature. After cooling to room temperature, n-heptane (5 mL) and saturated aqueous ammonium chloride solution (5 mL) were added to quench the reaction, and the pH was adjusted to 4 to 5. After fully stirring, standing, separating liquid and discarding the water phase. The organic phase was concentrated to remove the solvent, and purified by silica gel column chromatography to give pure product of the bright yellow oily compound V-1, 135mg, yield 86%.
1 H NMR(CDCl 3 ,400MHz):0.90(t,J＝8Hz,3H),1.22-1.33(m,7H),1.53-1.60(m,2H),1.65(s,3H),1.78(s,3H),2.00-2.21(m,2H),2.38-2.46(m,3H),3.89-3.92(m,1H),4.55(s,1H),4.66(s,1H),4.96(s,br,1H),5.57(s,1H),6.01(s,br,1H),6.20(s,br,2H).LR-MS(ESI)m/z:313(M-H) - ,315(M+H) + .
Claims (20)
1. A compound represented by formula II:
in the compound represented by the general formula II, R 1 Is trifluoromethanesulfonyl or p-toluenesulfonyl.
2. A compound represented by formula III:
in the compound represented by the general formula III, R 1 Is trifluoromethanesulfonyl or p-toluenesulfonyl,
R 2 to pair(s)Tosyl, pivaloyl, or t-butoxycarbonyl.
3. A process for preparing a compound represented by formula II, the process comprising:
(1) The phloroglucinol and trans-menthyl-2, 8-diene-1-alcohol undergo condensation reaction to obtain a compound of the formula I,
(2) Compounds of formula I and esterifying reagent XR 1 Or R is 1 OR 1 The reaction is carried out to obtain the compound of the formula II,
wherein R in the compound of formula II 1 R in claim 1 1 X is halogen as defined in the specification.
4. A method according to claim 3, wherein
The reaction in the step (2) is carried out under alkaline conditions, and the alkaline reagent used is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2, 6-dimethylpyridine, p-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine, 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1, 8-diazabicyclo undec-7-ene (DBU), quinoline, 2-methylquinoline and 8-hydroxyquinoline,
The solvent used in the reaction in the step (2) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, acetonitrile, acetone, N-dimethylformamide, dimethyl sulfoxideThe mixture of the species is used to produce a seed,
in the step (2), the mol ratio of the compound shown in the formula I, the esterifying reagent and the alkali reagent is 1.05 (1.0-1.5) (1.0-1.51), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is minus 60-30 ℃, and the reaction time is 2-10 hours.
5. The method of claim 4, wherein,
in the step (2), the reaction temperature is-30 to-10 ℃ and the reaction time is 3 to 4 hours.
6. A process for preparing a compound represented by formula III, the process comprising:
(1) And (2) preparing a compound of formula II according to the process of any one of claims 3-5,
(3) Compounds of formula II and esterifying reagent XR 2 Or R is 2 OR 2 Obtaining a compound of a formula III through reaction;
wherein R in the compound of formula II 1 Definition of (3) R in the compound of formula III 1 And R is 2 R in claim 2 1 And R is 2 X is halogen as defined in the specification.
7. The method of claim 6, wherein,
in the above step (3), the reaction is carried out under alkaline conditions using one or more selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2, 6-lutidine, p-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine, 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1, 8-diazabicyclo undec-7-ene (DBU), quinoline, 2-methylquinoline, 8-hydroxyquinoline,
in the step (3), the solvent used in the reaction is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, acetonitrile, acetone, N-dimethylformamide, dimethyl sulfoxide,
In the step (3), the mol ratio of the compound of the formula II, the esterifying reagent and the alkali reagent is 1.0:2.0-3.0:2.0-3.0, the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is minus 60-30 ℃, and the reaction time is 2-10 hours.
8. The method of claim 7, wherein,
the reaction temperature is-30 to-10 ℃, and the reaction time is 3-4 hours.
9. The method according to any one of claims 6-8, wherein,
steps (2) and (3) of the process are carried out using a one-pot process.
10. A process for preparing a compound represented by formula IV, the process comprising:
(1), (2) and (3) preparing a compound of formula III according to the method of any one of claims 6-9,
(4) Reacting the compound of formula III with a coupling reagent to obtain a compound of formula IV,
wherein the substituents of the formulae I to IV are as defined in claim 6,
wherein, at the upper partThe coupling reagent used in step (4) is selected from R 3 Magnesium chloride radical, R 3 Magnesium bromide radical R 3 Magnesium iodide radical, R 3 Zinc chloride radical, R 3 Zinc monobromide, R 3 One or a mixture of several zinc iodide, R is as follows 3 Is alkyl.
11. The method of claim 10, wherein
The reaction in step (4) is carried out in the presence of a transition metal catalyst selected from palladium acetate, palladium dichloride, palladium on carbon, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (tricyclohexylphosphine) palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (di-tert-butylphosphine) palladium dichloride, tris [ dibenzylideneacetone ] dipalladium, bis [ dibenzylideneacetone ] palladium, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2 ' -dimethylamino-biphenyl with palladium salt, 2-di-tert-butylphosphine biphenyl with palladium salt, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2 ' -diisopropyloxy-biphenyl with palladium salt with ferric iron, ferric chloride with ferric chloride, ferric chloride or ferric chloride, wherein the nickel salt is selected from nickel difluoride, nickel dichloride, nickel dibromide, nickel diiodide, nickel acetate, nickel trifluoroacetate, nickel acetylacetonate, bis (hexafluoroacetylacetonate) nickel and hydrates of the above nickel salts, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1 '-bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2', 6 '-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 6 '-diisopropyloxybiphenyl, 2-dicyclohexylphosphine-2' -dimethylamino-biphenyl, 2-di-tert-butylphosphine biphenyl, 2 '-bipyridine, 1,10' -phenanthroline,
The solvent used in the reaction in the step (4) is selected from one or a mixture of more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide,
in the step (4), the mol ratio of the compound of the formula III, the transition metal catalyst and the coupling reagent is 1.0 (0.001-0.5): (0.8-2.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is minus 60-100 ℃, and the reaction time is 2-10 hours.
12. The method of claim 11, wherein
In the step (4), the reaction temperature is-30 to 30 ℃ and the reaction time is 3 to 4 hours.
13. A process for preparing a compound represented by formula V, the process comprising:
(1), (2), (3) and (4) preparing a compound of formula IV according to the method of any one of claims 10-12,
(5) The compound of formula IV undergoes a deprotection reaction to give a compound of formula V,
wherein the substituents of formula I to formula V are the same as described in claim 10.
14. The method of claim 13, wherein
In the above step (5), when R 2 In the case of pivaloyl or t-butoxycarbonyl, the reaction reagent used is an alkaline reagent or an acidic reagent,
In the above step (5), when R 2 In the case of p-toluenesulfonyl, the reagent used is only an alkaline reagent,
wherein the alkaline reagent is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, tetrabutylammonium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tri-sec-butylborohydride, potassium triisooxyborohydride, potassium tri-sec-butylborohydride, tetrabutylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, zinc fluoride, magnesium fluoride, calcium fluoride,
wherein the acidic reagent is selected from one or a mixture of more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride,
The solvent used in the reaction in the step (5) is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and C 4 -C 12 Straight-chain or branched-chain or cyclic alkane, benzene, toluene, xylene, methylene chloride, chloroform, methyl tertiary butyl ether, methanol, ethanol, isopropanol, n-butanol, tertiary butanol, ethylene glycol, water or a mixture of several of them,
in the step (5), the molar ratio of the compound of formula IV to the alkaline reagent or the acidic reagent is 1.0 (2.0-10.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is-60-30 ℃, and the reaction time is 2-10 hours.
15. The method of claim 14, wherein
In the step (5), the reaction temperature is-30 to-10 ℃ and the reaction time is 3 to 4 hours.
16. The method of any one of claims 13-15, wherein
Steps (4) and (5) of the method are performed using a one-pot process.
17. A process for preparing a compound represented by formula V, the process comprising:
(1) And (2) preparing a compound of formula II according to the process of any one of claims 3-5,
(3') reacting the compound of formula II with a coupling reagent to obtain a compound of formula V,
Wherein the substituents of formulae I to II are the same as described in claim 3,
wherein the coupling reagent used in the above step (3') is selected from R 3 Magnesium chloride radical, R 3 Magnesium bromide radical R 3 Magnesium iodide radical, R 3 Zinc chloride radical, R 3 Zinc monobromide, R 3 One or a mixture of several zinc iodide, R is as follows 3 Is alkyl.
18. The method of claim 17, wherein
The reaction in step (3 ') is carried out in the presence of a transition metal catalyst selected from palladium acetate, palladium dichloride, palladium on carbon, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (tricyclohexylphosphine) palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, [1, 2-bis (diphenylphosphino) ethane ] palladium dichloride, bis (di-tert-butylphosphine) palladium dichloride, tris [ dibenzylideneacetone ] dipalladium, bis [ dibenzylideneacetone ] palladium, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2 '-dimethylamino-biphenyl with palladium salt, 2-di-tert-butylphosphine biphenyl with palladium salt, 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl with palladium salt, 2-dicyclohexylphosphine-2' -diisopropyloxy-biphenyl with palladium salt with ferric iron, iron (ferric) chloride, ferric chloride with ferric chloride, ferric chloride or ferric chloride with ferric chloride, wherein the nickel salt is selected from nickel difluoride, nickel dichloride, nickel dibromide, nickel diiodide, nickel acetate, nickel trifluoroacetate, nickel acetylacetonate, bis (hexafluoroacetylacetonate) nickel and hydrates of the above nickel salts, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1 '-bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2', 6 '-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 6 '-diisopropyloxybiphenyl, 2-dicyclohexylphosphine-2' -dimethylamino-biphenyl, 2-di-tert-butylphosphine biphenyl, 2 '-bipyridine, 1,10' -phenanthroline,
The solvent used in the reaction in the step (3') is selected from one or a mixture of more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetonitrile, acetone, N-dimethylformamide and dimethyl sulfoxide,
in the step (3'), the molar ratio of the compound of the formula II, the transition metal catalyst and the coupling reagent is 1.0 (0.001-0.5): (0.8-2.0), the concentration of the solution is 0.05-2.0 mol/L, the reaction temperature is minus 60-30 ℃, and the reaction time is 2-10 hours.
19. The method of claim 18, wherein
In the step (3'), the reaction temperature is-30 to-10 ℃ and the reaction time is 3 to 4 hours.
20. The method of any one of claims 17-19, wherein
The method is carried out using a one-pot process.
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