CN107540603A - The synthetic method of atazanavir - Google Patents
The synthetic method of atazanavir Download PDFInfo
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- CN107540603A CN107540603A CN201710195292.2A CN201710195292A CN107540603A CN 107540603 A CN107540603 A CN 107540603A CN 201710195292 A CN201710195292 A CN 201710195292A CN 107540603 A CN107540603 A CN 107540603A
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Abstract
The invention discloses a kind of synthetic method of atazanavir, including the compound of formula V (S) 1 (the base amino of 1 diphenylphosphino ethane of (S) 2 epoxy ethyl 2) 3, the ylcarbamic acid methyl ester of 3 dimethyl, 1 carbonyl butane 2 and formula VIII compound N 1 [N (methoxycarbonyl group) L Terleus base] N 2 [4 (2 pyridine radicals) benzyl] hydrazine nucleo philic substitution reaction production Ⅸ compound 1 [4 (2 pyridine radicals) phenyl] 5 (S) 2 in organic solvent, 5 pairs of aza-hexanes VIII of { [N (methoxycarbonyl group) L Terleus base] amino } 46 phenyl of (S) hydroxyl 2, that is atazanavir.Raw material sources of the present invention are wide, product easy purification, and cost is low；Simplify synthesis step；Easy to operate, technological process is simple, to equipment without particular/special requirement, suitable for large-scale production.
Description
Technical field
The present invention relates to the preparation method of protease inhibitors, in particular to a kind of synthetic method of atazanavir.
Background technology
Human immunodeficiency virus (HIV) is the pathogen for causing Immune Deficiency Syndrome (AIDS).In HIV diseases
In the infectious cycle of virion, virus protease is to play the functional enzyme that polyprotein is cut into structural proteins.Therefore, for
Virus protease becomes the effective ways for the treatment of AIDS for the inhibitor of target.
Atazanavir is the azepine peptidomimetic compound of an open chain, is a kind of novel protease inhibitors.Relative to other
Protease inhibitors, atazanavir have two remarkable advantages, and it is the protease suppression for uniquely permitting being administered one day once first
Preparation, this will greatly simplify dose schedule；Secondly, atazanavir can also increase the cholesterol and triglyceride of patient without display
Content, and this is the problem that other all protease inhibitors can all run into various degree.
Synthetic route (route 1) main process of existing atazanavir is as follows：Using p-bromobenzaldehyde as raw material, by into contracting
Aldehyde, RMgBr coupling, reduction amination forms phenylhydrazone, hydro-reduction obtains intermediate N 1- (tertbutyloxycarbonyl)-N-2- [4-
(2- pyridine radicals) benzylidene]-hydrazine, (S) -1- formyl -2- PhenethyIamino t-butyl formates react through Wittig, epoxidation
Reaction obtains (S) -1- ((R) -2- oxirane) -2- PhenethyIamino t-butyl formates, and the intermediate is previously obtained in hydrazine
Mesosome carries out out epoxy reaction, obtained ethylaminoethanol product again deprotection base, in the presence of condensing agent with methoxycarbonyl group
Terleu fragment condensation obtains final product atazanavir (Guido Bold, Alexander Fassler, Hans-Georg
Capraro etc., J.Med.Chem.1998,41,3387-3401).In the preparation method, epoxy intermediate is protected by tertbutyloxycarbonyl
The phenylpropyl alcohol ammonium aldehyde of shield reacts through Wittig to be generated, and is still had partial racemization even in substrate at -78 DEG C, is caused epoxy product pair
It is relatively low to reflect selectivity, isolates and purifies difficulty, causes yield not high.Moreover, the condensation reaction of final step uses valency in this method
The expensive condensing agent TPTU of lattice, while methoxycarbonyl group Terleu inventory is excessive, it is more difficult to reclaim, end-product is through silica gel column layer
Analysis, yield is relatively low, unsuitable industrialized production.
By improving, another process route (route 2) is coupled by Suzuki, reduced using p-bromophenyl boric acid as raw material
Ammonification forms phenylhydrazone, hydro-reduction obtains intermediate N 1- (tertbutyloxycarbonyl) N-2- [4- (2- pyridine radicals) benzylidene]-hydrazine,
Another synthesis fragment is set out from optically pure (2S, 3S) -3,4- dihydroxy -1- phenyl butane -2- t-butyl carbamates, through primary
Hydroxyl is protected with tert-butyldimethyl silyl ether, secondary hydroxyl introduces methane sulfonyl, removing primary hydroxyl protection group and highly basic act on
The lower formation step such as epoxy, obtains (S) -1- ((R) -2- oxirane) -2- PhenethyIamino t-butyl formates, the intermediate with
The hydrazine intermediate of above-mentioned preparation carries out out epoxy reaction, deprotection base, equally in the presence of condensing agent with methoxycarbonyl group uncle
Leucine be condensed to yield final product atazanavir (Zhongmin Xu, Janak Singh, Mark D.Schwinden etc.,
Organic Process Research＆Development, 2002,6,323-328).The preparation method is in structure compound base
It is identical with former route during this skeleton, but chiral epoxy intermediate passes through by the higher chiral diol of price through protection group strategy
Prepared by the reaction of 4 steps, the route improves the optical purity of intermediate compared with former route, but synthesis step is more, is produced into
This is higher.
Therefore, research and develop a kind of synthetic method of efficient atazanavir and seem very necessary.
The content of the invention
Problem to be solved by this invention seeks to provide a kind of synthetic method of atazanavir, and this method is ensureing high turn
On the basis of rate, simplify production technology and reduce production cost.
In order to solve the above technical problems, the synthetic method of atazanavir provided by the present invention, comprises the following steps：
A kind of synthetic method of atazanavir, comprises the following steps：
The compound of formula V (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyls
Base butane -2- bases-methyl carbamate and the compound N -1- of formula VIII [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4-
(2- pyridine radicals)-benzyl] the hydrazine compound 1- of nucleo philic substitution reaction production Ⅸ [4- (2- pyridine radicals) benzene in organic solvent
Base] double { [N- (methoxycarbonyl group)-S-Leucine base] amino } -4 (S)-hydroxyl -6- phenyl -2- aza-hexanes of -5 (S) -2,5-
VIII, i.e. atazanavir；
Reaction equation is as follows：
Preferably, organic solvent is isopropanol, tetrahydrofuran, dichloromethane, ethylene glycol ether, trichloro ethylene, benzene second
One or more of mixed solvents in alkene.
Further, the compound of formula V (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- bis-
The synthetic method of methyl isophthalic acid-carbonyl butane -2- bases-methyl carbamate comprises the following steps：
1) type I compound L-phenylalanine is given birth to through condensation reaction in organic solvent with N- methoxycarbonyl groups-S-Leucine
The compound of an accepted way of doing sth II (S) -1- ((S)-phenylpropionic acid -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-amino first
Sour methyl esters；
2) compound of formula II in organic solvent successively with isobutyl chlorocarbonate, diazomethane, reaction of hydrogen bromide production
III compound (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -1- carbonyl butane -2-
Base-methyl carbamate；
3) compound of formula III (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -
1- carbonyl butane -2- bases-methyl carbamate passes through the compound of biological enzyme production IV (S) -1- (bromo- 3- hydroxyls of (S) -4-
Base -1- phenyl butanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate；
4) compound of formula IV (S) -1- (the bromo- 3- hydroxyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -
1- carbonyl butane -2- bases-methyl carbamate adds condensing agent, goes sour agent to carry out cyclization reaction production V in organic solvent
Compound (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases -
Methyl carbamate；
Reaction equation is as follows：
Further, in the step 1), the condensing agent of condensation reaction addition for 3- (diethoxy phosphoryl oxy)-
1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides DECI mixture；It is described
Organic solvent is one or more of mixed solvents in isopropanol, tetrahydrofuran, hexane, hexamethylene, acetone, dichloromethane.
Further, in the step 1), the condensing agent of condensation reaction addition for 3- (diethoxy phosphoryl oxy)-
1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides DECI is 3 ︰ 1 in mass ratio
The mixture of composition；The organic solvent is the mixed solvent that isopropanol, tetrahydrofuran, acetone are the ︰ 1 of 2 ︰ 2 compositions in mass ratio.
Further, in the step 2), the organic solvent is acetonitrile, isopropanol, pyridine, phenol, tetrahydrofuran, two
One or more of mixed solvents in chloromethanes；After the compound of formula II and isobutyl chlorocarbonate react 0.5~1h, to anti-
Answer after adding 4~6h of diazomethane reaction in system, then 1~1.5h of reaction of hydrogen bromide is added into reaction system, produce formula III
Compound.
Further, in the step 3), the biology enzyme is the carbonyl reductase for coming from Candida parapsilosis
Genetic engineering bacterium clasmatosis enzyme liquid；The biology enzyme and the mass ratio of the compound of formula III are no more than 2%.
Further, it is described to go sour agent as sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, hydrogen in the step 4)
Lithia, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium alkoxide, triethylamine, diisopropyl ethyl
One or more of mixtures in amine, pyridine, 2 hydroxy pyrimidine, piperidines, N- methyl piperidines, morpholine or N-methylmorpholine.
Further, the compound N -1- of formula VIII [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridine radicals) -
Benzyl] synthetic method of hydrazine comprises the following steps：
The tertiary bright aminocarbonyl hydration hydrazine hydrochlorides of VI compound N of formula-methoxycarbonyl group-L- and compound 4- (the 2- pyridines of formula VII
Base)-benzaldehyde is through the compound N -1- of reduction amination production VIII [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2-
Pyridine radicals)-benzyl] hydrazine；
Reaction equation is as follows：
Further, the reducing agent added is LiAlH4。
Biology enzyme is the genetic engineering bacterium clasmatosis enzyme liquid for the carbonyl reductase for coming from Candida parapsilosis, carbonyl
The preparation method of the genetic engineering bacterium of reductase such as Authorization Notice No. is CN101717745B (Application No.
200910263147.9) Chinese invention patent announce method.Carrying out ultrasonic bacteria breaking, it is collected by centrifugation from Candida parapsilosis
Carbonyl reductase genetic engineering bacterium clasmatosis enzyme liquid.Biology enzyme can also be commercially available carbonyl reductase.
Advantages of the present invention is mainly reflected in following several respects：
First, raw material sources of the present invention it is wide, it is cheap, be not required to separately prepare, condensation reaction condition is easy, and product is easily pure
Change, so as to reduce cost.
Second, present invention eliminates tertbutyloxycarbonyl protection, synthesis step is simplified.
Third, easily-controlled reaction conditions of the present invention, easy to operate, technological process is simple, to equipment without particular/special requirement, is suitable to
Large-scale production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, but the embodiment should not be construed pair
The limitation of the present invention, it is only for example.Simultaneously by illustrating that advantages of the present invention will become clearer and be readily appreciated that.
Embodiment 1
The compound of formula V (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyls
The synthetic method of base butane -2- bases-methyl carbamate comprises the following steps：
1) type I compound L-phenylalanine (74.6g, 451.9mmol) and N- methoxycarbonyl groups-S-Leucine (90.8g,
480.0mmol) reacted in 1000ml dichloromethane, use 3- (diethoxy phosphinylidyne oxygen of the condensing agent for (150g, 0.5mol)
Base) -1,2,3- phentriazine -4- ketone DEPBT and (50g, 0.26mol) 1- (3- dimethylamino-propyls) -3- ethyls carbon two it is sub-
The mixture of amine DECI compositions, adds 20ml triethylamines, reacts 6~10h of progress at 0~20 DEG C, obtains the compound of formula II
(S) -1- ((S)-phenylpropionic acid -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate
(138.6g, 412.1mmol)；
2) compound of 138.6g formulas II first adds isobutyl chlorocarbonate in ice in the in the mixed solvent of tetrahydrofuran and ether
The lower reaction 20min of bath, then adds diazomethane reaction 3h, then adds hydrogen bromide and 40min is reacted at -20 DEG C, obtains formula III
Compound (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -1- carbonyl butane -2-
Base-methyl carbamate (144.0g, 348.3mmol)；
3) with the compound of 144.0g formulas III (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3-
Dimethyl -1- carbonyl butane -2- bases-methyl carbamate is substrate, adds the carbonyl reductase of 2.16g Candida parapsilosis
Genetic engineering bacterium clasmatosis enzyme liquid be biological enzyme catalyst, using NADPH as coenzyme, ph values be 6.5 phosphoric acid buffer it is molten
The compound of production IV (S) -1- (bromo- 3- hydroxyls -1- phenyl butanes -2- bases-ammonia of (S) -4- is reacted by biological enzyme in liquid
Base) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate (140.6g, 338.5mmol)；Wherein, biocatalyst
It is further selected from commercially available carbonyl reductase；
4) compound of 140.6g formulas IV (S) -1- (the bromo- 3- hydroxyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- bis-
Methyl isophthalic acid-carbonyl butane -2- bases-methyl carbamate adds HOBt, N- methyl in the saturation ethanol solution of potassium hydroxide
Quinoline carries out compound (the S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3 of epoxidation reaction production V,
3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate (102.0g, 305.0mmol)；
Reaction equation is as follows：
Embodiment 2
Under nitrogen protection, hydrazine hydrochloride is hydrated dissolved with the tertiary bright aminocarbonyls of VI compound N of formula-methoxycarbonyl group-L- at one
Triethylamine (21.9mL, 158.5mmol) is added in ethanol (500mL) solution of (77.2g, 380.0mmol), it is small to be stirred at room temperature 1
When, ethanol (250ml) solution dissolved with compound 4- (2- the pyridine radicals)-benzaldehydes of formula VII (65.1g, 355.6mmol) is added,
Flow back 5h at 45 DEG C, is cooled to room temperature, adds LiAlH4(8g, 0.25mol), normal pressure hydrogenation 12 hours.Filtering, filtrate concentration,
The crude product of gained is obtained into the compound N -1- of formula VIII [N- (methoxycarbonyl group)-S-Leucine base]-N- with recrystallisation from isopropanol
2- [4- (2- pyridine radicals)-benzyl] hydrazine (122.2g, 330.0mmol)；
Reaction equation is as follows：
Embodiment 3
(102.0g, 305.0mmol) formula V compound (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-ammonia
Base) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate and the compound N -1- of (122.2g, 330.0mmol) formula VIII
[N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridine radicals)-benzyl] hydrazine is dissolved in 500ml isopropanols, at 90 DEG C
Lower backflow 12h, cooling, 1000ml distilled water is slowly added to, stirs 2h, stood, filtered, washing, then recrystallized with ethanol water, very
Sky is dried, liquid phase detection, obtains the double { [N- (methoxies of the compound 1- of 201.3g formulas Ⅸ [4- (2- pyridine radicals) phenyl] -5 (S) -2,5-
Carbonyl)-S-Leucine base] amino } -4 (S)-hydroxyl -6- phenyl -2- aza-hexanes VIII, as atazanavir.
Reaction equation is as follows：
The content not being described in detail in this specification, belong to prior art known to those skilled in the art.
Claims (10)
1. a kind of synthetic method of atazanavir, it is characterised in that comprise the following steps：The compound of formula V (S) -1- ((S) -2-
Epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate and formula VIII
Compound N -1- [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridine radicals)-benzyl] hydrazine passes through in organic solvent
Double { [N- (the methoxycarbonyl group)-L- uncles of the compound 1- of nucleophilic substitution production Ⅸ [4- (2- pyridine radicals) phenyl] -5 (S) -2,5-
Leucine base] amino } -4 (S)-hydroxyl -6- phenyl -2- aza-hexanes VIII, i.e. atazanavir；
Reaction equation is as follows：
2. the synthetic method of atazanavir according to claim 1, it is characterised in that the organic solvent be isopropanol,
Tetrahydrofuran, dichloromethane, N-methylmorpholine, triethylamine, ethylene glycol ether, trichloro ethylene, one kind in styrene or several
The mixed solvent of kind.
3. the synthetic method of atazanavir according to claim 1, it is characterised in that the compound of formula V (S) -1- ((S) -
2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate conjunction
Comprise the following steps into method：
1) type I compound L-phenylalanine and N- methoxycarbonyl groups-S-Leucine are in organic solvent through condensation reaction production
II compound (S) -1- ((S)-phenylpropionic acid -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-carbamic acid first
Ester；
2) compound of formula II is changed with isobutyl chlorocarbonate, diazomethane, reaction of hydrogen bromide production III successively in organic solvent
Compound (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -1- carbonyl butane -2- bases -
Methyl carbamate；
3) compound of formula III (S) -1- (the bromo- 3- carbonyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -1- carbonyls
Base butane -2- bases-methyl carbamate passes through the compound of biological enzyme production IV (S) -1- (bromo- 3- hydroxyls -1- of (S) -4-
Phenyl butane -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate；
4) compound of formula IV (S) -1- (the bromo- 3- hydroxyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- dimethyl -1- carbonyls
Base butane -2- bases-methyl carbamate adds condensing agent, goes sour agent to carry out the cyclization reaction chemical combination of production V in organic solvent
Thing (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-amino
Methyl formate；
Reaction equation is as follows：
4. the synthetic method of atazanavir according to claim 3, it is characterised in that in the step 1), the condensation
The condensing agent of reaction addition is 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamine
Base propyl group) -3- ethyl carbodiimides DECI mixture；The organic solvent be isopropanol, tetrahydrofuran, hexane, hexamethylene,
One or more of mixed solvents in acetone, dichloromethane.
5. the synthetic method of atazanavir according to claim 4, it is characterised in that in the step 1), the condensation
The condensing agent of reaction addition is 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamine
Base propyl group) -3- ethyl carbodiimides DECI in mass ratio for 3 ︰ 1 composition mixture；The organic solvent is isopropanol, tetrahydrochysene
Furans, acetone are in mass ratio the mixed solvent of the ︰ 1 of 2 ︰ 2 compositions.
6. the synthetic method of atazanavir according to claim 5, it is characterised in that described organic in the step 2)
Solvent is one or more of mixed solvents in acetonitrile, isopropanol, pyridine, phenol, tetrahydrofuran, dichloromethane；The formula
After II compound reacts 0.5~1h with isobutyl chlorocarbonate, after adding 4~6h of diazomethane reaction into reaction system, then to
1~1.5h of reaction of hydrogen bromide is added in reaction system, produces the compound of formula III.
7. the synthetic method of atazanavir according to claim 6, it is characterised in that in the step 3), the biology
Enzyme is the genetic engineering bacterium clasmatosis enzyme liquid for the carbonyl reductase for coming from Candida parapsilosis；The biology enzyme and formula III
The mass ratio of compound is no more than 2%.
8. the synthetic method of atazanavir according to claim 7, it is characterised in that described to remove acid in the step 4)
Agent is sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrogen-oxygen
Change magnesium, barium hydroxide, sodium alkoxide, triethylamine, diisopropyl ethyl amine, pyridine, 2 hydroxy pyrimidine, piperidines, N- methyl piperidines, morpholine
With one or more of mixtures in N-methylmorpholine.
9. the synthetic method of atazanavir according to claim 1, it is characterised in that the compound N -1- [N- (methoxies of formula VIII
Carbonyl)-S-Leucine base] synthetic method of-N-2- [4- (2- pyridine radicals)-benzyl] hydrazine comprises the following steps：
The tertiary bright aminocarbonyl hydration hydrazine hydrochlorides of VI compound N of formula-methoxycarbonyl group-L- and formula VII compound 4- (2- pyridine radicals)-benzene
Formaldehyde is in the presence of reducing agent through the compound N -1- of reduction amination production VIII [N- (methoxycarbonyl group)-S-Leucine
Base]-N-2- [4- (2- pyridine radicals)-benzyl] hydrazine；
Reaction equation is as follows：
10. the synthetic method of atazanavir according to claim 9, it is characterised in that the reducing agent added is
LiAlH4。
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| CN109988789A (en) * | 2019-04-29 | 2019-07-09 | 上海健康医学院 | The method that carbonyl reductase CLEAs catalyzes and synthesizes atazanavir intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101391978A (en) * | 2007-09-19 | 2009-03-25 | 中国科学院上海药物研究所 | Novel synthetic method of HIV-1 protease inhibitor atazanavir |
| WO2009130534A1 (en) * | 2008-04-24 | 2009-10-29 | Oxyrane (Pty) Ltd. | Process for synthesizing atazanavir |
| CN102911113A (en) * | 2011-08-05 | 2013-02-06 | 浙江九洲药业股份有限公司 | Method for preparing atazanavir |
| CN104356054A (en) * | 2014-09-30 | 2015-02-18 | 东北制药集团股份有限公司 | Novel method for preparing atazanavir monomer |
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2017
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101391978A (en) * | 2007-09-19 | 2009-03-25 | 中国科学院上海药物研究所 | Novel synthetic method of HIV-1 protease inhibitor atazanavir |
| WO2009130534A1 (en) * | 2008-04-24 | 2009-10-29 | Oxyrane (Pty) Ltd. | Process for synthesizing atazanavir |
| CN102911113A (en) * | 2011-08-05 | 2013-02-06 | 浙江九洲药业股份有限公司 | Method for preparing atazanavir |
| CN104356054A (en) * | 2014-09-30 | 2015-02-18 | 东北制药集团股份有限公司 | Novel method for preparing atazanavir monomer |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988789A (en) * | 2019-04-29 | 2019-07-09 | 上海健康医学院 | The method that carbonyl reductase CLEAs catalyzes and synthesizes atazanavir intermediate |
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