CN114956972A - Novel synthesis method of buparvaquone - Google Patents

Novel synthesis method of buparvaquone Download PDF

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CN114956972A
CN114956972A CN202210513176.1A CN202210513176A CN114956972A CN 114956972 A CN114956972 A CN 114956972A CN 202210513176 A CN202210513176 A CN 202210513176A CN 114956972 A CN114956972 A CN 114956972A
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buparvaquone
ligand
palladium
silver
copper
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蔡岩
宫金平
王磊
苗志伟
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Cangzhou Dongen Technology Co ltd
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Abstract

The invention provides a novel synthesis method of buparvaquone, which comprises the following steps: 1, 4-naphthoquinone is taken as a raw material, and in the presence of a metal catalyst M, the 1, 4-naphthoquinone reacts with a halogen donor X to obtain a 2-halogen substituted intermediate; the 2-halogen substituted intermediate is directly subjected to oxidative decarboxylation coupling with cis-trans mixed p-tert-butylcyclohexyl acetic acid in the presence of a ligand A and an oxidant B without separation to obtain a buparvaquone precursor C with a trans configuration; and hydrolyzing the buparvaquone precursor C under the action of alkali D, and then adding acid E to adjust the pH value of the system to obtain a product buparvaquone. The method has the advantages that the configuration of the buparvaquone can be efficiently controlled in the synthetic process of the buparvaquone, the load capacity of a metal catalyst is reduced, the product yield is improved, and the problems that in the prior art, the cost of used reagents is high, the final product configuration is different, no selectivity exists, and the final product configuration is a mixture of cis-trans configurations are solved.

Description

Novel synthesis method of buparvaquone
Technical Field
The invention belongs to the technical field of new synthetic methods of raw materials of veterinary medicines, and particularly relates to a new synthetic method of buparvaquone.
Background
Buparvaquone (Buparvaquone) is a very effective drug for treating bovine tayloxiasis, and competitively inhibits energy metabolism and mitochondrial respiration of pathogenic protozoa by blocking the Q cycle of cytochrome bc1 complex on the mitochondrial inner membrane in cells of the pathogenic protozoa, thereby causing collapse of mitochondrial inner membrane potential and finally causing death of parasites. Buparvaquone is developed by Pitman-Moore company, is called as Butalex under the trade name, has a structure in which substituents on two sides of a cyclohexyl group are in a trans-configuration (formula 2), is marketed in parts of countries of Africa, the middle east and the far east in 1991, is used for treating Theileria scorchis 90-98 percent in effective rate, and can improve the immunity of cattle and the animal production performance, so the buparvaquone has high application value. At present, the global buparvaquone bulk drug is mainly produced in India and is still imported domestically, although manufacturers develop the buparvaquone bulk drug, the production cost is higher and the competitive advantage is avoided due to the complex synthesis process and particularly the difficult control of the product configuration. With the gradual expansion of the global annual dosage of the buparvaquone and the increase of the price of the current production raw material, the price of the buparvaquone rises year by year, and in addition, the raw material medicine cannot be purchased by domestic preparation manufacturers due to the restriction of import, so that the optimization and upgrade of the synthesis process of the buparvaquone are urgently needed to realize the domestic substitution of the raw material medicine.
Figure BDA0003640289320000011
The traditional synthesis method of buparvaquone has the problems of low yield, large pollution and high loading capacity of a noble metal catalyst, and EP0077550B1 reports the production method, wherein chloronaphthoquinone is used as a starting material, and the chloronaphthoquinone and trans-configuration p-tert-butylcyclohexylacetic acid 2 are subjected to oxidative decarboxylation coupling under the catalysis of silver nitrate and ammonium persulfate as an oxidant to obtain a key intermediate 3, and then the key intermediate 3 is hydrolyzed under an alkaline condition to obtain the buparvaquone (formula 3). The yield of the step of the oxidative decarboxylation coupling is less than 40%, the actual load capacity of silver nitrate is large and reaches 40% of the molar weight of raw materials, the total separation yield of the final product is less than 15%, the trans-configuration p-tert-butylcyclohexylacetic acid 2 is prepared by 4 steps of conversion after the p-tert-butylcyclohexanecarboxylic acid is resolved into the trans-configuration, and dangerous and highly toxic chemicals such as lithium aluminum hydride, potassium cyanide and the like are used in the process, so that the production method has high overall cost and large wastewater amount.
Figure BDA0003640289320000021
In 2008, patent CN101265172A reports a new improved synthesis method of buparvaquone, in which chlorinated naphthoquinone is replaced by 2-ethoxy-1, 4-naphthoquinone 4, and the oxidative decarboxylation coupling is performed using silver nitrate as a catalyst and ammonium persulfate as an oxidant to obtain intermediate 5, and then the ethyl group is removed under an alkaline condition to obtain buparvaquone (formula 4), the yield of the coupling reaction step is slightly improved, the total reaction yield is 21%, and since the whole reaction strategy is not greatly changed, and 2-ethoxy-1, 4-naphthoquinone needs to be prepared from 2-hydroxy-1, 4-naphthoquinone, the preparation cost is still high, most importantly, the oxidative coupling step has no selectivity, and the obtained intermediate 5 is a mixed product with cis-trans configuration.
Figure BDA0003640289320000022
In 2013, patent CN103483176A reports a synthesis method of buparvaquone, which uses 1, 4-benzopyranedione 6 as a raw material, and condenses with p-tert-butylcyclohexyl acetaldehyde 7 under the catalysis of morpholine-acetic acid to obtain an intermediate 8, then ring-opening rearrangement is performed under the action of sodium methoxide to obtain buparvaquone (formula 5), the total reaction yield is increased to 65%, but the two raw materials of 1, 4-benzopyranedione and p-tert-butylcyclohexyl acetaldehyde are not easy to purchase and prepare, so that the cost is greatly increased, and in addition, due to poor stability of the intermediate 8, a byproduct of ester exchange is easily generated during the last step of rearrangement reaction, so that the product is not easy to purify, so that the purity of the prepared product is low, and most importantly, the final product configuration is not selective, and is a mixture with cis-trans configuration.
Figure BDA0003640289320000031
In 2015, patent CN105198718A reports a new synthesis method of buparvaquone, which uses 1, 4-naphthoquinone as a raw material, performs an addition reaction with p-tert-butylcyclohexylacetic acid-2-thiopyridone-N-oxide ester 9 to obtain an intermediate 10, and then hydrolyzes under the action of potassium phosphate to obtain buparvaquone (formula 6), wherein the total reaction yield is 41%, the reaction strategy avoids the use of silver nitrate as a noble metal catalyst, the yield is improved as a whole, but thionyl chloride and 2-thiopyridone-N-oxide are used in the preparation of the intermediate 9, which causes a large amount of odor in the operation environment and complicated operation, and a large amount of phosphorus-containing wastewater is generated in the final hydrolysis step, which causes poor environmental protection of the process, increases the production cost, and most importantly, the configuration of the final product has no selectivity, is a mixture of cis and trans configurations.
Figure BDA0003640289320000041
2018, patent CN110734368A reports a synthesis method of buparvaquone, 4-tert-butylcyclohexyl formaldehyde is used as a starting material, an intermediate 11 is obtained by condensation under the action of piperidine-acetic acid, then a carbon-carbon double bond in a reduction product is hydrogenated to obtain an intermediate 12, the obtained product is condensed with methyl phthalate under an alkaline condition to obtain a key intermediate 13, bromine addition is carried out on the double bond in the obtained product, then in-situ hydrolysis is carried out to obtain an intermediate 14, the obtained product is finally subjected to alkaline hydrolysis to obtain buparvaquone (formula 7), although the reaction strategy avoids the use of a noble metal catalyst of silver nitrate, the reaction steps are longer, the 4-tert-butylcyclohexyl formaldehyde as the raw material is not easy to obtain and the preparation cost is higher, when the intermediate 13 is prepared, side reactions are more and the product is difficult to purify, so that the reaction process cost is still high, most importantly, the configuration of the final product is not selective and is a mixture of cis-trans configurations.
Figure BDA0003640289320000042
From the above description, it can be seen that the existing production of buparvaquone has the problems of low yield, difficult control of product configuration, need of noble metal catalyst and large loading capacity, so the invention provides a solution to the existing problems of buparvaquone, and aims to solve the problems of configuration control, large loading capacity of metal catalyst and low yield in the production process of buparvaquone.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing buparvaquone, and effectively solves the problems of low yield, difficult control of product configuration, need of a noble metal catalyst and large loading capacity in the existing production of buparvaquone.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a novel synthesis method of buparvaquone comprises the following steps:
1, 4-naphthoquinone is taken as a raw material, and in the presence of a metal catalyst M, the 1, 4-naphthoquinone reacts with a halogen donor X to obtain a 2-halogen substituted intermediate;
the 2-halogen substituted intermediate is directly subjected to oxidative decarboxylation coupling with cis-trans mixed p-tert-butylcyclohexyl acetic acid in the presence of a ligand A and an oxidant B without separation to obtain a buparvaquone precursor C with trans configuration; wherein the structure of the buparvaquone precursor C is shown as the following formula (1):
Figure BDA0003640289320000051
and hydrolyzing the buparvaquone precursor C under the action of alkali D, and then adding acid E to adjust the pH value of the system to obtain a product buparvaquone.
Further, in the step of preparing the buparvaquone precursor C, the 2-halogen substituted intermediate undergoes a coupling reaction in a solvent F; wherein, the solvent F is one or more of acetonitrile, tetrahydrofuran, DMF, acetone and toluene.
Further, the mass ratio of the solvent F to the 1, 4-naphthoquinone is 10: 1-2: 1.
further, the molar ratio of the metal catalyst M to the 1, 4-naphthoquinone is 0.01: 1-0.1: 1; the molar ratio of the halogen donor X to the 1, 4-naphthoquinone is 1: 1-2: 1.
Further, the molar ratio of the metal catalyst M to the ligand A is 1: 1-1: 2; the molar ratio of the oxidant B to the 1, 4-naphthoquinone is 1: 1-5: 1.
Further, in the hydrolysis process of the buparvaquone precursor C, the hydrolysis is carried out in a solvent G; wherein the solvent G is one or more of water, dimethyl sulfoxide, ethyl acetate, ethanol and methanol.
Further, the mass ratio of the solvent G to the 1, 4-naphthoquinone is 10: 1-2: 1.
further, the metal catalyst M is one or more of copper salt, silver salt, palladium salt, nickel salt, iron salt, rhodium salt and cobalt salt.
Further, the metal catalyst M is preferably one or more of copper salt, silver salt and palladium salt; wherein,
the copper salt comprises: one or more of cuprous chloride, cuprous bromide, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, copper trifluoromethanesulfonate, copper tetraacetonitrile trifluoromethanesulfonate, copper isooctanoate, copper acetate, copper acetylacetonate, copper trifluoroacetylacetonate, copper tartrate, copper ethylacetoacetate and copper bis (tert-butylacetoacetate);
the silver salt comprises one or more of silver nitrate, silver carbonate, silver chloride, silver oxide, silver sulfate, silver methylsulfonate, silver trifluoroacetate, silver bromide, silver trifluoromethylsulfonate, silver p-toluenesulfonate, silver tetrakis (acetyl cyanide) l (I) tetrafluoroborate, silver lactate and silver pivalate;
the palladium salt comprises one or more of bis (diphenylphosphinophenyl ether) palladium dichloride, bis (triphenylphosphine) palladium dichloride, di-bromo-bis (tri-tert-butylphosphino) dipalladium, palladium acetate, bis (benzonitrile) palladium chloride, bis (3,5,3 ', 5' -dimethoxydibenzylideneacetone) palladium, bis (tri-tert-butylphosphino) palladium, triphenylphosphine palladium acetate, palladium trifluoroacetate, bis [ tris (2-tolyl) phosphine ] palladium, tris (dibenzylideneacetone) dipalladium, bis (acetylacetone) palladium, palladium pivalate, (1, 5-cyclooctadiene) palladium dichloride, bis (triethylphosphine) palladium dichloride, palladium hexafluoroacetylacetonate and palladium benzoate.
Further, the halogen donor X is one or more of chlorine, bromine, iodine simple substance, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), phosphorus trichloride, phosphorus tribromide, thionyl chloride and carbon tetrachloride.
Further, the ligand A is one or more of oxazoline ligand, N-heterocyclic carbene ligand, bipyridine ligand, porphyrin ligand, monodentate phosphine ligand, bidentate phosphine ligand, phosphine-nitrogen ligand, ferrocene-phosphine ligand, nitrogen donor ligand and oxygen donor ligand.
Further, the ligand A is preferably one or more of oxazoline ligand, nitrogen heterocyclic carbene ligand, bipyridine ligand, bidentate phosphine ligand and phosphine-nitrogen ligand, wherein,
the oxazoline ligand has the following structure:
Figure BDA0003640289320000071
wherein R in the oxazoline-based ligand 1 Can be hydrogen atom, methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl, benzyl, aromatic heterocycle; r 2 Can be hydrogen atom, methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl, benzyl, aromatic heterocycle; r 3 Can be one or more of hydrogen atom, methyl, ethyl, propyl, butyl and benzyl;
the N-heterocyclic carbene ligand has the following structure:
Figure BDA0003640289320000081
wherein R in the N-heterocyclic carbene ligand 1 Can be one or more of methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl and benzyl;
the bipyridine ligand has the following structure:
Figure BDA0003640289320000082
wherein R in the bipyridine ligand 1 Can be one or more of methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl, benzyl, methoxyl, halogen, cyano, carboxyl, ester group and alcoholic hydroxyl;
the bidentate phosphine ligand has the following structure:
Figure BDA0003640289320000091
wherein R in the bidentate phosphine ligand 1 Can be methyl, methoxy, halogen, tertiary butyl; r is 2 Can be phenyl, cyclopentyl, cyclohexyl, methyl, tertiary butyl; r 3 Can be one or more of hydrogen atom, methyl and tertiary butyl;
the phosphine-nitrogen ligand has the following structure:
Figure BDA0003640289320000101
wherein R in the phosphine-nitrogen-based ligand 1 Can be one or more of hydrogen atom, methyl, ethyl, isopropyl, phenyl and aromatic heterocycle.
Further, the oxidant B is one or more of sodium persulfate, potassium persulfate, ammonium persulfate, oxygen, potassium permanganate, sodium hypochlorite and hydrogen peroxide.
Further, the acid E is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and acetic acid.
Further, the acid E adjusts the pH of the system to 2-3.
Further, the base D is one or more of sodium hydride, potassium carbonate, triethylamine, 4-Dimethylaminopyridine (DMAP), n-butyllithium, LiHMDS, sodium hydroxide and potassium hydroxide.
By adopting the technical scheme, 1, 4-naphthoquinone is used as a raw material, firstly, the 1, 4-naphthoquinone reacts with a halogen donor in the presence of a metal catalyst to obtain a 2-halogen substituted intermediate, the product is directly subjected to oxidative decarboxylation coupling with cis-trans mixed p-tert-butylcyclohexyl acetic acid in the presence of a ligand and an oxidant without separation to obtain a buparvaquone precursor with trans configuration, and then the buparvaquone precursor is hydrolyzed under the action of alkali to obtain a product-buparvaquone with single trans configuration; according to the scheme, the combined use of the metal catalyst and the ligand is adopted, the configuration of the product of the oxidative decarboxylation coupling reaction is controlled to be trans, the configuration of buparvaquone can be efficiently controlled in the synthesis process, the loading capacity of the metal catalyst is reduced, the product yield is improved, and the problems that in the prior art, the cost of the used reagent is high, the final product configuration is different, the selectivity is absent, and the mixture is cis-trans configured are solved.
Drawings
FIG. 1 shows a buparvaquone precursor in a novel method for synthesizing buparvaquone in an embodiment of the invention 1 H-NMR spectrum
FIG. 2 is an HPLC chromatogram of a buparvaquone precursor in the novel synthesis method of buparvaquone in the embodiment of the invention
FIG. 3 shows the product buparvaquone obtained by the novel method for synthesizing buparvaquone in the embodiment of the invention 1 H-NMR spectrum
FIG. 4 is the MS spectrum of buparvaquone product in the new synthesis method of buparvaquone in the embodiment of the invention
FIG. 5 is an HPLC spectrogram of buparvaquone in the new synthesis method of buparvaquone
FIG. 6 is an HPLC chromatogram of a prior art imported standard of buparvaquone
Detailed Description
The invention is further illustrated by the following examples and figures:
unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments and comparative examples only and is not intended to limit the scope of the present invention. It should be specifically noted that there may be many names for the same organic structure, as long as the structure is within the scope of the present patent.
Unless otherwise defined, the raw materials, reagents and the like in the following examples and comparative examples are commercially available or prepared according to reported methods.
The invention provides a novel synthesis method of buparvaquone, in particular to a method for efficiently controlling the configuration of buparvaquone in the synthesis process, which is specifically shown as a formula (8):
s1: 1, 4-naphthoquinone is used as a raw material, firstly, in the presence of a metal catalyst M, the 1, 4-naphthoquinone reacts with a halogen donor X to obtain a 2-halogen substituted intermediate, the product is directly subjected to oxidative decarboxylation coupling with cis-trans mixed p-tert-butylcyclohexyl acetic acid in the presence of a ligand A and an oxidant B without separation, and a buparvaquone precursor C with trans configuration is obtained;
s2: and hydrolyzing the buparvaquone precursor C under the action of a base D, and then adding an acid E to adjust the pH value of the system to obtain the buparvaquone.
Figure BDA0003640289320000121
In step S1, the 2-halo substituted intermediate undergoes a coupling reaction in solvent F; wherein the solvent F is one or more of acetonitrile, tetrahydrofuran, DMF, acetone and toluene, and the mass ratio of the solvent F to the 1, 4-naphthoquinone is 10: 1-2: 1.
in step S1, the preparation of buparvaquone precursor C is carried out in two small steps,
s11: heating a system of 1, 4-naphthoquinone and a halogen donor X to 70-80 ℃ in the presence of a metal catalyst M to react for 5-7h to obtain a 2-halogen substituted intermediate, wherein the molar ratio of the metal catalyst M to the 1, 4-naphthoquinone is 0.01: 1-0.1: 1; the molar ratio of the halogen donor X to the 1, 4-naphthoquinone is 1: 1-2: 1;
s12: directly carrying out oxidative decarboxylation coupling on the 2-halogen substituted intermediate and p-tert-butylcyclohexyl acetic acid with cis-trans mixed configuration in the presence of a ligand A and an oxidant B, heating the system to reflux, continuously reacting for 4-6h, subsequently removing the solvent, and recrystallizing the residue to obtain a buparvaquone precursor C with trans configuration; wherein the molar ratio of the ligand A to the metal catalyst M is 1: 1-1: 2; the molar ratio of the oxidant B to the 1, 4-naphthoquinone is 1: 1-5: 1.
In step S2, hydrolyzing in a solvent G, heating the system to 70-80 ℃ for reacting for 2-4h, adding an acid E to adjust the pH value of the system to 2-3 after the reaction is finished, and then extracting and recrystallizing to obtain a product, namely buparvaquone; wherein the solvent G is one or more of water, dimethyl sulfoxide, ethyl acetate, ethanol and methanol; and the mass ratio of the solvent G to the 1, 4-naphthoquinone is 10: 1-2: 1.
the selection types and preferred structures of the specific relevant metal catalyst M, the halogen donor X, the ligand a, the oxidant B, the base D and the acid F are listed in the above summary of the invention, and include, but are not limited to, the above listed structures, and will not be described in detail herein.
The reagents used in the method are all easily available and low-cost reagents, and due to the generation of the 2-halogen substituted intermediate and the addition of the ligand, the p-tert-butylcyclohexylacetic acid 2 with cis-trans mixed configuration can be used in the intermediate process, and the buparvaquone product with single trans configuration can be obtained without configuration screening, so that the intermediate configuration screening steps are reduced, the cost is saved, the production time is also saved, the configuration is efficiently controlled in the synthesis process, the loading capacity of the metal catalyst can be reduced, and the corresponding yield can be improved.
Several specific examples are listed below:
example 1
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 101g of NCS and 3.1g of cuprous chloride are added, the system is heated to 75 ℃ to react for 6 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 12g of CO3 in oxazoline ligand is added, stirring is carried out for 30 minutes at room temperature continuously, 150g of p-tert-butylcyclohexylacetic acid in a cis-trans mixing configuration is added, 513g of potassium persulfate and 1L of water are added finally, the system is heated to reflux reaction for 5 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, a solvent is removed by a rotary evaporator, ethanol is used for recrystallization of residues to obtain light orange yellow solid, 165g of product, namely a buparvaquone precursor C is obtained after drying, and the yield is 76%. The synthetic route 1 is shown as follows:
Figure BDA0003640289320000141
as shown in figure 1, the buparvaquone precursor in the novel synthesis method of buparvaquone 1 The data for buparvaquone precursor C in example 1, shown by the H-NMR spectrum and the HPLC spectrum of buparvaquone precursor in the new method for synthesizing buparvaquone in fig. 2, are: 97.3 percent of HPLC; 1 H NMR(600MHz,Chloroform-d):δ8.17–8.19(m,1H),8.12–8.15(m,1H),7.73–7.81(m,2H),2.91(d,J＝7.3Hz,2H),2.16(s,1H),1.61–1.68(m,3H),1.58–1.60(m,1H),1.47–1.54(m,2H),1.34–1.42(m,2H),0.98–1.04(m,1H),0.91(s,9H)。
example 2
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 135g of NBS and 4.5g of cuprous bromide are added, the system is heated to 75 ℃ to react for 6 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 12g of ligand CO3 is added, stirring is continued at room temperature for 30 minutes, 150g of p-tert-butylcyclohexyl acetic acid in a cis-trans mixing configuration is added, 513g of potassium persulfate and 1L of water are added, the system is heated to reflux reaction for 5 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, a solvent is removed by a rotary evaporator, residues are recrystallized by ethanol to obtain light orange yellow solid, and 177g of a product, namely buparvaquone precursor C, is obtained after drying, and the yield is 81%. The synthetic route 2 is shown as follows:
Figure BDA0003640289320000151
example 3
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 101g of NCS and 4.5g of silver chloride are added, the system is heated to 75 ℃ to react for 6h, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 16.7g of ligand PN7 is added, stirring is continued at room temperature for 30min, 150g of p-tert-butylcyclohexyl acetic acid in a cis-reverse mixing configuration is added, 513g of potassium persulfate and 1L of water are added, the system is heated to reflux reaction for 5h, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, a solvent is removed by a rotary evaporator, and the remainder is recrystallized by ethanol to obtain light orange yellow solid, 153g of a product, namely the buparvaquone precursor C, is obtained after drying, and the yield is 70%. The synthetic route 3 is shown as follows:
Figure BDA0003640289320000152
example 4
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 101g of NCS and 5.4g of silver nitrate are added, the system is heated to 75 ℃ to react for 6 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 16.7g of ligand PN7 is added, stirring is continued at room temperature for 30 minutes, 150g of p-tert-butylcyclohexyl acetic acid in a cis-trans mixing configuration is added, 513g of potassium persulfate and 1L of water are added, the system is heated to reflux reaction for 5 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, a solvent is removed by a rotary evaporator, ethanol is used for recrystallization to obtain light orange yellow solid, 185g of a product, namely the buparvaquone precursor C is obtained after drying, and the yield is 85%. The synthetic route 4 is shown as follows:
Figure BDA0003640289320000161
example 5
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 101g of NCS and 5.4g of silver nitrate are added, the system is heated to 75 ℃ to react for 6h, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 16.7g of ligand PN7 is added, stirring is continued at room temperature for 30min, 150g of p-tert-butylcyclohexyl acetic acid in a cis-reverse mixing configuration is added, 433g of ammonium persulfate and 1L of water are added finally, the system is heated to reflux reaction for 5h, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, then a solvent is removed by using a rotary evaporator, the remainder is recrystallized by using ethanol to obtain light orange yellow solid, and 174g of product, namely buparvaquone precursor C is obtained after drying, and the yield is 80%. The synthetic route 5 is shown as follows:
Figure BDA0003640289320000162
example 6
Preparation of buparvaquone precursor C: 100g of 1, 4-naphthoquinone is placed in 1L of acetonitrile to be stirred, 101g of NCS and 22g of bis triphenylphosphine palladium dichloride are added, the system is heated to 75 ℃ to react for 6 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 29.6g of ligand BP9 is added, then stirring is carried out continuously at room temperature for 30 minutes, 150g of p-tert-butylcyclohexyl acetic acid in a cis-reverse mixing configuration is added, 433g of ammonium persulfate and 1L of water are added finally, the system is heated to reflux reaction for 5 hours, TLC detection is carried out to complete reaction, the system is cooled to room temperature, 1L of ethyl acetate is added for extraction, an organic extraction phase is collected, then a solvent is removed by a rotary evaporator, the residue is recrystallized by ethanol to obtain light orange yellow solid, 135g of a product is obtained after drying, namely the buparvaquone precursor C, and the yield is 62%. The synthetic route 6 is shown as follows:
Figure BDA0003640289320000171
example 7
Preparation of buparvaquone product: 100g of buparvaquone precursor C is placed in 1L of ethanol, 49g of potassium hydroxide and 1L of water are added, the system is heated to 75 ℃ to react for 3 hours, TLC detection reaction is complete, then the system is placed in an ice-water bath to be cooled, 6M hydrochloric acid is gradually added to adjust the pH value of the system to 2-3, dichloromethane is added to extract, an organic extraction phase is collected, a solvent is removed by a rotary evaporator, the residue is recrystallized by ethanol to obtain yellow crystalline solid, and 81g of product, namely buparvaquone is obtained after drying, with the yield of 86%. The synthetic route 7 is shown as follows:
Figure BDA0003640289320000172
as shown in fig. 3 to 5, the buparvaquone 1H-NMR spectrum, MS spectrum and HPLC spectrum of the product of the new synthesis method of buparvaquone are as follows: 99.3 percent of HPLC; 1 H-NMR(600MHz,Chloroform-d)：δ8.14(dd,J＝7.7,1.2Hz,1H),8.10(dd,J＝7.5,1.3Hz,1H),7.77(td,J＝7.6,1.4Hz,1H),7.70(td,J＝7.5,1.3Hz,1H),7.33(s,1H),2.53(d,J＝7.2Hz,2H),1.71–1.86(m,4H),1.54–1.60(m,1H),1.03–1.12(m,2H),0.94–0.99(m,3H),0.83(s,9H)；MS：calcd.For:C 21 H 25 O 3 ,[M-H] - 325.43,Found[M-H] - 325.39. comparing the HPLC chromatogram of the buparvaquone imported standard of the prior art of FIG. 6, the liquid phase data of the buparvaquone prepared in this example and the imported buparvaquone standard and 1 H-NMR data can confirm that the buparvaquone prepared in the embodiment is completely consistent with the imported standard in configuration and main impurity distribution, and the product buparvaquone obtained in the embodiment is a usable standard.
It should be noted that the above-mentioned contents are only some embodiments of the present invention, and those produced by suitable modifications and alterations of the main idea and related contents of the present invention by those skilled in the art shall also fall into the protection scope of the claims of the present invention. And the technical terms and other materials referred to in the present invention are only for clearly illustrating the advantages and effects of the present invention and should not be taken as limitations to the inventive idea.
The embodiments of the present invention have been described in detail, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims (16)

1. A novel synthesis method of buparvaquone comprises the following steps:
1, 4-naphthoquinone is taken as a raw material, and in the presence of a metal catalyst M, the 1, 4-naphthoquinone reacts with a halogen donor X to obtain a 2-halogen substituted intermediate;
the 2-halogen substituted intermediate is directly subjected to oxidative decarboxylation coupling with cis-trans mixed p-tert-butylcyclohexyl acetic acid in the presence of a ligand A and an oxidant B without separation to obtain a buparvaquone precursor C with trans configuration; wherein the structure of the buparvaquone precursor C is shown as the following formula (1):
Figure FDA0003640289310000011
and hydrolyzing the buparvaquone precursor C under the action of alkali D, and then adding acid E to adjust the pH value of the system to obtain a product buparvaquone.
2. The novel method for synthesizing buparvaquone as claimed in claim 1, wherein: in the step of preparing the buparvaquone precursor C, the 2-halogen substituted intermediate is subjected to coupling reaction in a solvent F; wherein, the solvent F is one or more of acetonitrile, tetrahydrofuran, DMF, acetone and toluene.
3. The novel method for synthesizing buparvaquone as claimed in claim 2, wherein: the mass ratio of the solvent F to the 1, 4-naphthoquinone is 10: 1-2: 1.
4. the novel method for synthesizing buparvaquone as claimed in claim 1, wherein: the molar ratio of the metal catalyst M to the 1, 4-naphthoquinone is 0.01: 1-0.1: 1; the molar ratio of the halogen donor X to the 1, 4-naphthoquinone is 1: 1-2: 1.
5. The novel method for synthesizing buparvaquone as claimed in claim 4, wherein the method comprises the following steps: the molar ratio of the metal catalyst M to the ligand A is 1: 1-1: 2; the molar ratio of the oxidant B to the 1, 4-naphthoquinone is 1: 1-5: 1.
6. The novel method for synthesizing buparvaquone as claimed in claim 1, wherein: in the hydrolysis process of the buparvaquone precursor C, the hydrolysis is carried out in a solvent G; wherein the solvent G is one or more of water, dimethyl sulfoxide, ethyl acetate, ethanol and methanol.
7. The novel method for synthesizing buparvaquone as claimed in claim 6, wherein: the mass ratio of the solvent G to the 1, 4-naphthoquinone is 10: 1-2: 1.
8. the novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the metal catalyst M is one or more of copper salt, silver salt, palladium salt, nickel salt, iron salt, rhodium salt and cobalt salt.
9. The novel synthesis method of buparvaquone as claimed in claim 8, wherein: the metal catalyst M is preferably one or more of copper salt, silver salt and palladium salt; wherein,
the copper salt comprises: one or more of cuprous chloride, cuprous bromide, tetraacetonitrile copper hexafluorophosphate, tetraacetonitrile copper tetrafluoroborate, copper trifluoromethanesulfonate, tetraacetonitrile copper trifluoromethanesulfonate, copper isooctanoate, copper acetate, copper acetylacetonate, copper trifluoroacetylacetonate, copper tartrate, copper ethylacetoacetate and copper bis (tert-butylacetoacetate);
the silver salt comprises one or more of silver nitrate, silver carbonate, silver chloride, silver oxide, silver sulfate, silver methanesulfonate, silver trifluoroacetate, silver bromide, silver trifluoromethanesulfonate, silver p-toluenesulfonate, silver tetrakis (acetyl nitrile) tetrafluoroborate, silver lactate and silver pivalate;
the palladium salt comprises one or more of bis (diphenylphosphinophenyl ether) palladium dichloride, bis (triphenylphosphine) palladium dichloride, di-bromo-bis (tri-tert-butylphosphino) dipalladium, palladium acetate, bis (benzonitrile) palladium chloride, bis (3,5,3 ', 5' -dimethoxydibenzylideneacetone) palladium, bis (tri-tert-butylphosphino) palladium, triphenylphosphine palladium acetate, palladium trifluoroacetate, bis [ tris (2-tolyl) phosphine ] palladium, tris (dibenzylideneacetone) dipalladium, bis (acetylacetone) palladium, palladium pivalate, (1, 5-cyclooctadiene) palladium dichloride, bis (triethylphosphine) palladium dichloride, palladium hexafluoroacetylacetonate and palladium benzoate.
10. The novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the halogen donor X is one or more of chlorine, bromine, iodine simple substance, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), phosphorus trichloride, phosphorus tribromide, thionyl chloride and carbon tetrachloride.
11. The novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the ligand A is one or more of oxazoline ligand, nitrogen heterocyclic carbene ligand, bipyridine ligand, porphyrin ligand, monodentate phosphine ligand, bidentate phosphine ligand, phosphine-nitrogen ligand, ferrocene-phosphine ligand, nitrogen donor ligand and oxygen donor ligand.
12. The novel method for synthesizing buparvaquone according to claim 11, which is characterized in that: the ligand A is preferably one or more of oxazoline ligand, nitrogen heterocyclic carbene ligand, bipyridine ligand, bidentate phosphine ligand and phosphine-nitrogen ligand, wherein,
the oxazoline ligand has the following structure:
Figure FDA0003640289310000031
wherein R in the oxazoline-based ligand 1 Can be hydrogen atom, methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl, benzyl, aromatic heterocycle; r 2 Can be hydrogen atom, methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl, benzyl, aromatic heterocycle; r 3 Can be one or more of hydrogen atom, methyl, ethyl, propyl, butyl and benzyl;
the N-heterocyclic carbene ligand has the following structure:
Figure FDA0003640289310000041
wherein R in the N-heterocyclic carbene ligand 1 Can be one or more of methyl, ethyl, propyl, butyl, tertiary butyl, isobutyl, phenyl and benzyl;
the bipyridine ligand has the following structure:
Figure FDA0003640289310000042
wherein R in the bipyridine ligand 1 Can be one or more of methyl, ethyl, propyl, butyl, tert-butyl, isobutyl, phenyl, benzyl, methoxyl, halogen, cyano, carboxyl, ester group and alcoholic hydroxyl;
the bidentate phosphine ligand has the following structure:
Figure FDA0003640289310000051
wherein R in the bidentate phosphine ligand 1 Can be methyl, methoxy, halogen, tert-butyl; r 2 Can be phenyl, cyclopentyl, cyclohexyl, methyl, tertiary butyl; r is 3 Can be one or more of hydrogen atom, methyl and tertiary butyl;
the phosphine-nitrogen ligand has the following structure:
Figure FDA0003640289310000061
wherein R in the phosphine-nitrogen-based ligand 1 Can be one or more of hydrogen atom, methyl, ethyl, isopropyl, phenyl and aromatic heterocycle.
13. The novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the oxidant B is one or more of sodium persulfate, potassium persulfate, ammonium persulfate, oxygen, potassium permanganate, sodium hypochlorite and hydrogen peroxide.
14. The novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the acid E is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and acetic acid.
15. The novel method for synthesizing buparvaquone as claimed in claim 14, wherein: the acid E adjusts the pH value of the system to 2-3.
16. The novel method for synthesizing buparvaquone according to any one of claims 1 to 7, wherein: the alkali D is one or more of sodium hydride, potassium carbonate, triethylamine, 4-Dimethylaminopyridine (DMAP), n-butyl lithium, LiHMDS, sodium hydroxide and potassium hydroxide.
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CN103483176A (en) * 2013-08-23 2014-01-01 山东鲁抗舍里乐药业有限公司 Preparation method of buparvaquone
CN105198718A (en) * 2015-10-27 2015-12-30 山东川成医药股份有限公司 Preparation method for buparvaquone
CN110734368A (en) * 2018-07-19 2020-01-31 新发药业有限公司 Preparation method of buparvaquone
CN114426441A (en) * 2021-11-29 2022-05-03 南京师范大学 Method for catalyzing chlorination of quinone compounds by iron

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4485117A (en) * 1981-10-16 1984-11-27 Hudson Alan T Antiprotozoal compounds
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CN103483176A (en) * 2013-08-23 2014-01-01 山东鲁抗舍里乐药业有限公司 Preparation method of buparvaquone
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