CN103570521A - Preparation method of atovaquone - Google Patents
Preparation method of atovaquone Download PDFInfo
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- CN103570521A CN103570521A CN201310366325.7A CN201310366325A CN103570521A CN 103570521 A CN103570521 A CN 103570521A CN 201310366325 A CN201310366325 A CN 201310366325A CN 103570521 A CN103570521 A CN 103570521A
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- 0 **C(CC1)C**1C(*1*2C1)=CC=C2O Chemical compound **C(CC1)C**1C(*1*2C1)=CC=C2O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—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
- C07C37/16—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 by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
Abstract
The invention discloses a preparation method of atovaquone, and belongs to the drug synthesis field. The method comprises the following steps: condensing alpha-naphthol and 4-(4-chlorophenyl)cyclohexanol under acid catalysis to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1-naphthol (formula V), oxidizing the compound represented by formula V to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula IV), enabling the compound represented by the formula IV to react with bromine in additive reaction to obtain 2,3-dibromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula III), releasing a molecule of hydrogen bromide to obtain 3-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-1,4-naphthoquinone (formula II), hydrolyzing to obtain the atovaquone (formula I). Compared with the prior art, the method disclosed by the invention is simple in process, the expensive silver nitrate is prevented from using in the preparation process; and meanwhile, the yield is improved, the pollution to the environment is reduced, and the method has good popularization and application value.
Description
Technical field
The present invention relates to medicine synthetic field, specifically a kind of preparation method of atovaquone.
Background technology
Atovaquone (Atovaquone) is a kind of homologue of ubiquinone, the trouble that is applicable to tolerate SMZ-TMP is slightly to patient's AIDS of moderate Ka Shi pneumonia oral administration, but also it is active to show certain anti-malarial, its chemistry 2-(trans-4-(4-chloro-phenyl-) cyclohexyl) by name-3-hydroxyl-1,4-naphthalenedione, chemical structure is suc as formula shown in I
In prior art, the main synthetic atovaquone of following several method that adopts:
⑴
The main reference of this method is US 5053432 and EP 0362996, and the main synthesis technique that above-mentioned technique is current atovaquone is generated by the chloro-1,4-naphthoquinone of 2-(chlorinated naphthoquinone) and the condensation of 4-(4-chloro-phenyl-)-cyclohexyl-1-formic acid.Reaction be take acetonitrile as solvent, under Silver Nitrate exists, uses ammonium persulphate oxidative decarboxylation, generates the chloro-3-of (3S)-2-(4-(4-chloro-phenyl-) cyclohexyl)-Isosorbide-5-Nitrae-naphthalenedione.Under alkaline condition, hydrolysis obtains final product (3S)-2-hydroxyl-3-(4-(4-chloro-phenyl-) cyclohexyl) Isosorbide-5-Nitrae-naphthalenedione, i.e. atovaquone.The main drawback of this route is that the solvent that oxidative decarboxylation is used is acetonitrile, acetonitrile is to 2-chloro-1, the solubleness of 4-naphthoquinones (chlorinated naphthoquinone), 4-(4-chloro-phenyl-)-cyclohexyl-1-formic acid and Silver Nitrate has very big-difference, and along with adding of ammonium persulfate solution, noted phase separation phenomena is very obvious.And this reaction side reaction is more, reaction produces a lot of impurity, causes that product yield is on the low side only 20% left and right.
⑵
The main referenced patent of this method is WO 2009/122432 A2, above-mentioned technique is with 2,3-dichlone and 4-(4-chloro-phenyl-) cyclohexylenedinitrilotetraacetic acid is starting raw material, under the catalytic condition of Silver Nitrate and ammonium persulphate, there is condensation reaction, then, be hydrolyzed to obtain the finished product under the effect of alkali, the major advantage of this technique is yield ratio method (1) height, condensation reaction yield is up to 40%, and hydrolysis reaction yield reaches 95.5%.But this method has been used Silver Nitrate and ammonium persulphate equally, and production cost is higher, bad to environmental influence.
In above-mentioned two kinds of methods, all used expensive Silver Nitrate, not only cost is high and productive rate is all very low, and meanwhile, last handling process also can produce very havoc to environment.
Summary of the invention
Technical assignment of the present invention is for above-mentioned the deficiencies in the prior art, and the preparation method of the atovaquone that a kind of production cost is low, productive rate is high is provided.
Technical assignment of the present invention is realized in the following manner: a kind of preparation method of atovaquone, is characterized in: the condensation under acid catalysis of naphthyl alcohol and 4-(4-chloro-phenyl-) hexalin obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V); Compound shown in formula V, through oxidation, obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula IV); Compound shown in formula IV and bromine generation addition reaction, obtain 2, the bromo-2-of 3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinones (formula III), then slough the hydrogen bromide of a part, obtain the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II), finally by hydrolysis reaction, obtain atovaquone (formula I).Reaction formula is as follows:
Aforesaid method comprises the following steps:
A, preparation 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V)
By naphthyl alcohol, 4-(4-chloro-phenyl-) hexalin and solvent, under 120 ~ 150 ℃, acid catalyst catalytic condition, react to raw material reaction (TLC detection) completely, obtain compound shown in formula V;
B, prepare the bromo-2-of 2,3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula III);
Under acid catalysis, with compound shown in oxygenant oxidation-type V, obtain 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula IV); Bromine simple substance reacts and obtains compound shown in formula III with compound shown in formula IV;
C, the preparation bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II)
Shown in formula III, compound reacts by elimination, removes a part hydrogen bromide, obtains compound shown in formula II;
D, preparation 3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula I)
Under the condition existing at alkali, using alcohol as solvent, compound shown in formula II is heated to reflux, and reacts complete, and washing, obtains compound shown in formula I;
Shown in described alkali and formula II, the mol ratio of compound is 1 ~ 20:1.
Further:
In steps A:
Described naphthyl alcohol and 4-(4-chloro-phenyl-) hexalin mol ratio is 1:1 ~ 4;
The mol ratio of described acid catalyst and two raw materials (naphthyl alcohol, 4-(4-chloro-phenyl-) hexalin) sum is 0.1 ~ 1:1;
Described solvent is preferably benzene, toluene or chlorobenzene;
Described acid catalyst is preferably toluenesulphonic acids, trifluoroacetic acid, acetic acid, the vitriol oil or phosphoric acid.
Step B can complete in two steps, also can a step complete, and all can reach good effect.
While completing in two steps, its detailed process is respectively:
A, compound shown in steps A gained formula V is added in solvent, under appropriate amount of acid catalyst action, with oxygenant oxidation, after completion of the reaction, obtain compound shown in formula IV;
Described solvent is preferably acetone, acetonitrile or tetrahydrofuran (THF);
Shown in described acid catalyst and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described oxygenant and formula V, the mol ratio of compound is 1 ~ 20:1;
The temperature of reaction of described oxidizing reaction is 60 ~ 90 ℃;
B, a certain amount of bromine simple substance is added shown in the formula IV being dissolved in solvent in compound, under room temperature, react complete to raw material reaction, obtain compound shown in formula III;
Shown in described bromine simple substance and formula IV, the mol ratio of compound is 1 ~ 5:1;
Described solvent is preferably tetracol phenixin, dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
When one step completes, its detailed process is:
Compound shown in steps A gained formula V and appropriate bromine simple substance are added in solvent, and under appropriate amount of acid catalyst action, with oxygenant oxidation, back flow reaction, after completion of the reaction, purifies and obtains compound shown in formula III;
Shown in described bromine simple substance and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described acid catalyst and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described oxygenant and formula V, the mol ratio of compound is 1 ~ 20:1;
The temperature of reaction of described oxidizing reaction is 60 ~ 120 ℃;
Described solvent is preferably tetracol phenixin, dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
In step B, described oxygenant is preferably hydrogen peroxide, chromic oxide, cerous sulfate, ceric ammonium nitrate, potassium permanganate, Manganse Dioxide or dichromate;
Described acid catalyst is preferably concentrated hydrochloric acid, Glacial acetic acid or the vitriol oil.
The detailed process of step C is:
Compound shown in step B gained formula III is dissolved in solvent, under 60 ~ 90 ℃ of conditions, reacts 2 ~ 24h, be washed to and occur precipitation, obtain compound shown in formula II.
Or compound shown in step B gained formula III is dissolved in solvent, adds appropriate sodium acetate to make catalyzer, back flow reaction is to reacting completely, the compound shown in formula II of purifying to obtain;
Shown in described sodium acetate and formula III, the mol ratio of compound is 1 ~ 10:1.
In step C, described solvent is preferably dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
In step D, described alkali is preferably sodium hydroxide, potassium hydroxide, hydrated barta, lithium hydroxide, carbonate or supercarbonate; Described alcohol is preferably one or more the mixture in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
The preparation method of atovaquone of the present invention compared with prior art has following outstanding beneficial effect:
(1) catalyzer is changed to the acid catalyst being easy to get, avoids using expensive Silver Nitrate, reduced production cost, can, better for industrial production, meanwhile, reduce the detrimentally affect for environment;
(2) adopting naphthyl alcohol and 4-(4-chloro-phenyl-) hexalin is raw material, synthetic important intermediate 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V), productive rate is enhanced compared with other techniques, and atovaquone production cost is further minimized.
Embodiment
With specific embodiment, the preparation method of atovaquone of the present invention is described in detail below.
Embodiment mono-:
The preparation of A, 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V)
Under nitrogen protection; by 4-(4-chloro-phenyl-) hexalin 2.9g, naphthyl alcohol 2g, tosic acid 2.63g adds in 30ml toluene; 140 ℃ of back flow reaction 3h; TLC monitoring reaction is carried out, and after reacting completely, organic phase washes with water; phase-splitting dewaters; organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, crystallization obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols.
B, 2, the preparation of the bromo-2-of 3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula III)
(a), the preparation of 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula IV)
Add 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols 2.98g in 15ml acetonitrile, then drip successively 4ml concentrated hydrochloric acid (38%, v/v), 16ml hydrogen peroxide (30%, v/v), stirring reaction 3h at 100 ℃, TLC detection reaction progress, after reacting completely, concentrating under reduced pressure, adds 20ml chloroform, and organic layer washes with water, separate organic layer, condensing crystal, obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone.
(b), 2, the preparation of the bromo-2-of 3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula III)
The bromine simple substance of 60ul is added in the acetic acid of 1ml, the acetic acid solution of bromine is dropped to 2-(4-(4-chloro-phenyl-) cyclohexyl)-1 in 15min, in the mixed system that 4-naphthoquinones 2.24g and acetic acid 5ml form, stirring at room 45min, pours into the reaction solution obtaining in frozen water, has Precipitation, suction filtration, obtain the bromo-2-of 2,3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone.
The preparation of the bromo-2-of C, 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II)
The bromo-2-of 2,3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone 5g is dissolved in 25mlDMSO, 60 ℃ of reaction 2h, TLC detection reaction is carried out, after reacting completely, be washed to and occur precipitation, obtain the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone.
The preparation of D, 3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula I)
By the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinones 2.145g and sodium hydroxide 1.6g are dissolved in 65ml methyl alcohol, back flow reaction, TLC detection reaction progress, reacts complete, adjust pH2 ~ 3, the concentrated methyl alcohol of removing, with ethyl acetate extraction, vacuum concentration, low temperature crystallization obtains target compound atovaquone (3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone).
Embodiment bis-:
The preparation of A, 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V)
In the there-necked flask of 100ml, add chlorobenzene 30ml, naphthyl alcohol 2g, 4-(4-chloro-phenyl-) hexalin 4.65g and tosic acid 0.8g, back flow reaction 3h, TLC monitors reaction, react complete, concentrating under reduced pressure, adds chloroform extraction, washing, separate organic layer, boil off solvent, obtain product 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols.
B, 2, the preparation of the bromo-2-of 3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula III)
In 30ml tetracol phenixin, add 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols 3.36g, Br
21.6g, 30% superoxol 1.2ml, 98% vitriol oil 0.6ml, reaction solution backflow 20min, concentrate and be cooled to 0 ℃, after suction filtration, retain solid, in filtrate, add suitable quantity of water, by extracted with diethyl ether, concentrate to obtain thick product, the thick product of two portions merges recrystallization and obtains the bromo-2-of 2,3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone.
The preparation of the bromo-2-of C, 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II)
By 2,3-dibromo 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone 0.3g is dissolved in the acetic acid of 10ml, adds the sodium acetate of 0.2g, back flow reaction 1h, TLC monitoring, adds 5ml water in reaction solution, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone.
The preparation of D, 3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula I)
By the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinones 2.2g and sodium carbonate 3.18g join in 45ml Virahol, reflux, react complete, filtration under diminished pressure, the concentrated Virahol of removing, with ethyl acetate, extract, vacuum concentration, low temperature crystallization obtains target compound atovaquone (3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone).
Claims (10)
1. a preparation method for atovaquone, is characterized in that, the condensation under acid catalysis of naphthyl alcohol and 4-(4-chloro-phenyl-) hexalin obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V); Compound shown in formula V, through oxidation, obtains 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula IV);
Compound shown in formula IV and bromine generation addition reaction, obtain 2, the bromo-2-of 3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinones (formula III), then slough the hydrogen bromide of a part, obtain the bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II), finally by hydrolysis reaction, obtain atovaquone (formula I).
2. the preparation method of atovaquone according to claim 1, is characterized in that, comprises the following steps:
A, preparation 2-(4-(4-chloro-phenyl-) cyclohexyl)-1-naphthols (formula V)
By naphthyl alcohol, 4-(4-chloro-phenyl-) hexalin and solvent, under 120 ~ 150 ℃, acid catalyst catalytic condition, react, obtain compound shown in formula V;
B, prepare the bromo-2-of 2,3-bis-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula III);
At 60 ~ 90 ℃, under acid catalysis, with compound shown in oxygenant oxidation-type V, obtain 2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula IV); At room temperature, bromine simple substance reacts and obtains compound shown in formula III with compound shown in formula IV;
C, the preparation bromo-2-of 3-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula II)
Shown in formula III, compound reacts by elimination, at 60 ~ 90 ℃, removes hydrogen bromide, obtains compound shown in formula II;
D, preparation 3-hydroxyl-2-(4-(4-chloro-phenyl-) cyclohexyl)-1,4-naphthoquinone (formula I)
Shown in formula II, compound is usingd alcohol as solvent, under the condition existing, is heated to reflux at alkali, reacts complete, and washing, obtains compound shown in formula I;
Shown in described alkali and formula II, the mol ratio of compound is 1 ~ 20:1.
3. the preparation method of atovaquone according to claim 2, is characterized in that: in steps A,
Described naphthyl alcohol and 4-(4-chloro-phenyl-) hexalin mol ratio is 1:1 ~ 4;
The mol ratio of described acid catalyst and two raw material sums is 0.1 ~ 1:1;
Described solvent is benzene, toluene or chlorobenzene;
Described acid catalyst is toluenesulphonic acids, trifluoroacetic acid, acetic acid, the vitriol oil or phosphoric acid.
4. the preparation method of atovaquone according to claim 2, is characterized in that, the detailed process of step B is:
A, compound shown in steps A gained formula V is added in solvent, at 60 ~ 90 ℃ with under appropriate amount of acid catalyst action with oxygenant oxidation, after completion of the reaction, obtain compound shown in formula IV;
Described solvent is acetone, acetonitrile or tetrahydrofuran (THF);
Shown in described acid catalyst and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described oxygenant and formula V, the mol ratio of compound is 1 ~ 20:1;
B, a certain amount of bromine simple substance is added shown in the formula IV being dissolved in solvent in compound, react complete to raw material reaction, obtain compound shown in formula III;
Shown in described bromine simple substance and formula IV, the mol ratio of compound is 1 ~ 5:1;
Described solvent is tetracol phenixin, dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
5. the preparation method of atovaquone according to claim 2, is characterized in that, the detailed process of step B is:
Compound shown in steps A gained formula V and appropriate bromine simple substance are added in solvent, and under appropriate amount of acid catalyst action, with oxygenant oxidation, back flow reaction, after completion of the reaction, purifies and obtains compound shown in formula III;
Shown in described bromine simple substance and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described acid catalyst and formula V, the mol ratio of compound is 1 ~ 5:1;
Shown in described oxygenant and formula V, the mol ratio of compound is 1 ~ 20:1;
The temperature of reaction of described oxidizing reaction is 60 ~ 120 ℃;
Described solvent is tetracol phenixin, dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
6. according to the preparation method of the atovaquone described in claim 4 or 5, it is characterized in that:
Described oxygenant is hydrogen peroxide, chromic oxide, cerous sulfate, ceric ammonium nitrate, potassium permanganate, Manganse Dioxide or dichromate;
Described acid catalyst is concentrated hydrochloric acid, Glacial acetic acid or the vitriol oil.
7. the preparation method of atovaquone according to claim 2, is characterized in that, the detailed process of step C is:
Compound shown in step B gained formula III is dissolved in solvent, under 60 ~ 90 ℃ of conditions, reacts 2 ~ 24h, be washed to and occur precipitation, obtain compound shown in formula II.
8. the preparation method of atovaquone according to claim 2, is characterized in that, the detailed process of step C is:
Compound shown in step B gained formula III is dissolved in solvent, adds appropriate sodium acetate to make catalyzer, back flow reaction is to reacting completely, the compound shown in formula II of purifying to obtain;
Shown in described sodium acetate and formula III, the mol ratio of compound is 1 ~ 10:1.
9. according to the preparation method of the atovaquone described in claim 7 or 8, it is characterized in that: described solvent is dimethyl sulfoxide (DMSO), dimethyl formamide, acetic acid or acetonitrile.
10. the preparation method of atovaquone according to claim 2, is characterized in that: in step D,
Described alkali is sodium hydroxide, potassium hydroxide, hydrated barta, lithium hydroxide, carbonate or supercarbonate;
Described alcohol is one or more the mixture in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069845A (en) * | 2018-01-18 | 2018-05-25 | 大连理工大学 | An a kind of one step preparation method of bromo 1,4- naphthoquinones |
| CN110734369A (en) * | 2018-07-19 | 2020-01-31 | 新发药业有限公司 | Preparation method of atovaquones |
| CN111099981A (en) * | 2019-12-31 | 2020-05-05 | 日照巴洛特药业有限公司 | Synthetic method of derivatives based on atovaquone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009007991A2 (en) * | 2007-04-19 | 2009-01-15 | Ipca Laboratories Limited | A new process for preparation of atovaquone and novel intermediates thereof |
| WO2012153162A1 (en) * | 2011-05-12 | 2012-11-15 | Lupin Limited | Novel method for preparation of atovaquone |
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2013
- 2013-08-21 CN CN201310366325.7A patent/CN103570521A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009007991A2 (en) * | 2007-04-19 | 2009-01-15 | Ipca Laboratories Limited | A new process for preparation of atovaquone and novel intermediates thereof |
| WO2012153162A1 (en) * | 2011-05-12 | 2012-11-15 | Lupin Limited | Novel method for preparation of atovaquone |
Non-Patent Citations (1)
| Title |
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| 丘坤元: "消除反应", 《化学通报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069845A (en) * | 2018-01-18 | 2018-05-25 | 大连理工大学 | An a kind of one step preparation method of bromo 1,4- naphthoquinones |
| CN108069845B (en) * | 2018-01-18 | 2020-04-14 | 大连理工大学 | One-step preparation method of bromo-1, 4-naphthoquinone |
| CN110734369A (en) * | 2018-07-19 | 2020-01-31 | 新发药业有限公司 | Preparation method of atovaquones |
| CN110734369B (en) * | 2018-07-19 | 2022-08-12 | 新发药业有限公司 | Preparation method of atovaquone |
| CN111099981A (en) * | 2019-12-31 | 2020-05-05 | 日照巴洛特药业有限公司 | Synthetic method of derivatives based on atovaquone |
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Application publication date: 20140212 |