CN107540603B - The synthetic method of atazanavir - Google Patents

The synthetic method of atazanavir Download PDF

Info

Publication number
CN107540603B
CN107540603B CN201710195292.2A CN201710195292A CN107540603B CN 107540603 B CN107540603 B CN 107540603B CN 201710195292 A CN201710195292 A CN 201710195292A CN 107540603 B CN107540603 B CN 107540603B
Authority
CN
China
Prior art keywords
bases
compound
formula
amino
synthetic method
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710195292.2A
Other languages
Chinese (zh)
Other versions
CN107540603A (en
Inventor
陈建华
胡磊
黄小明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huzhou You Yan Intellectual Property Service Co.,Ltd.
Original Assignee
Nanning Xin Peptide Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanning Xin Peptide Biotechnology Co Ltd filed Critical Nanning Xin Peptide Biotechnology Co Ltd
Priority to CN201710195292.2A priority Critical patent/CN107540603B/en
Publication of CN107540603A publication Critical patent/CN107540603A/en
Application granted granted Critical
Publication of CN107540603B publication Critical patent/CN107540603B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pyridine Compounds (AREA)

Abstract

The invention discloses a kind of synthetic methods of atazanavir, including V compound of formula (S) 1 (1 diphenylphosphino ethane of (S) 2 epoxy ethyl, 2 base amino) 3, 3 dimethyl, 1 carbonyl butane, 2 ylcarbamic acid methyl ester and formula VIII compound N 1 [N (methoxycarbonyl group) L Terleus base] N 2 [4 (2 pyridyl group) benzyl] hydrazine nucleo philic substitution reaction production Ⅸ compound 1 [4 (2 pyridyl group) phenyl] 5 (S) 2 in organic solvent, 5 bis- { [N (methoxycarbonyl group) L Terleus base] amino } 46 phenyl of (S) hydroxyl, 2 aza-hexane VIII, that is atazanavir.Raw material sources of the present invention are wide, product easy purification, at low cost；Simplify synthesis step；Easy to operate, technological process is simple, to equipment without particular/special requirement, is suitable for large-scale production.

Description

The synthetic method of atazanavir
Technical field
The present invention relates to the preparation methods of protease inhibitors, in particular to a kind of synthetic method of atazanavir.
Background technology
Human immunodeficiency virus (HIV) is the pathogen for leading to 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 is the effective ways that the inhibitor of target becomes treatment AIDS.
Atazanavir is the azepine peptidomimetic compound of an open chain, is a kind of novel protease inhibitors.Relative to other Protease inhibitors, there are two remarkable advantages for atazanavir tool, it is the protease suppression for uniquely permitting being administered one day once first Preparation, this will greatly simplify dose schedule；Secondly, there are no the cholesterol and triglycerides that display can increase patient for atazanavir Content, and this is the problem that other all protease inhibitors can all encounter in various degree.
Synthetic route (route 1) main process for having atazanavir is as follows：Using p-bromobenzaldehyde as raw material, by contracting Aldehyde, Grignard Reagent coupling, reduction amination forms phenylhydrazone, hydro-reduction obtains intermediate N 1- (tertbutyloxycarbonyl)-N-2- [4- (2- pyridyl groups) benzylidene]-hydrazine, (S) -1- formyls -2- PhenethyIaminos t-butyl formate is through Wittig reactions, epoxidation (S) -1- ((R) -2- ethylene oxide) -2- PhenethyIamino t-butyl formates are obtained by the reaction, which is previously obtained in hydrazine Mesosome carries out out epoxy reaction, obtained ethylaminoethanol product again deprotection base, under the action of condensing agent and 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 is reacted through Wittig to be generated, even if substrate still has partial racemization at -78 DEG C, leads to 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 valence in this method The condensing agent TPTU of lattice costliness, while methoxycarbonyl group Terleu inventory is excessive, it is more difficult to it recycles, final product is through silica gel column layer Analysis, yield is relatively low, unsuitable industrialized production.
By improving, another process route (route 2) is using p-bromophenyl boric acid as raw material, by Suzuki couplings, reduction Ammonification forms phenylhydrazone, hydro-reduction obtains intermediate N 1- (tertbutyloxycarbonyl) N-2- [4- (2- pyridyl groups) benzylidene]-hydrazine, Another synthesis segment 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 protecting group and highly basic act on Lower formation epoxy, obtains (S) -1- ((R) -2- ethylene oxide) -2- PhenethyIamino t-butyl formates, the intermediate with The hydrazine intermediate of above-mentioned preparation carries out out epoxy reaction, deprotection base, equally under the action 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 as former route when this skeleton, but chiral epoxy intermediate passes through by the chiral diol of higher price through protection base strategy Prepared by the reaction of 4 steps, which improves the optical purity of intermediate compared with former route, but synthesis step is more, is produced into This is higher.
Therefore, a kind of synthetic method of efficient atazanavir of research and development seems very necessary.
Invention content
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, simplifies production technology and reduce production cost.
In order to solve the above technical problems, the synthetic method of atazanavir provided by the present invention, includes the following steps：
A kind of synthetic method of atazanavir, includes the following steps：
V compound of formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyls Base butane -2- bases-methyl carbamate and formula VIII compound N -1- [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridyl groups)-benzyl] hydrazine Ⅸ compound 1- of nucleo philic substitution reaction production [4- (2- pyridyl groups) benzene in organic solvent Base] bis- { [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 The mixed solvent of one or more of alkene.
Further, V compound of formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- bis- The synthetic method of methyl-1-carbonyl butane-2- bases-methyl carbamate includes 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 II compound of an accepted way of doing sth (S) -1- ((S)-phenylpropionic acid -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-amino first Sour methyl esters；
2) II compound of formula 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) III compound of formula (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 IV compound of biological enzyme production (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) IV compound of formula (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, sour agent is gone 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 the condensation reaction addition is 3- (diethoxy phosphoryl oxy)- The mixture of 1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides DECI；It is described Organic solvent is the mixed solvent of one or more of isopropanol, tetrahydrofuran, hexane, hexamethylene, acetone, dichloromethane.
Further, in the step 1), the condensing agent of the condensation reaction addition is 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 2 ︰, 2 ︰ 1 compositions in mass ratio.
Further, in the step 2), the organic solvent is acetonitrile, isopropanol, pyridine, phenol, tetrahydrofuran, two The mixed solvent of one or more of chloromethanes；After II compound of the formula reacts 0.5~1h with isobutyl chlorocarbonate, to anti- It answers after adding 4~6h of diazomethane reaction in system, then 1~1.5h of reaction of hydrogen bromide is added to get formula III into reaction system Compound.
Further, in the step 3), the biological enzyme is the carbonyl reductase for coming from Candida parapsilosis Genetic engineering bacterium clasmatosis enzyme solution；The biological enzyme and the mass ratio of III compound of formula are no more than 2%.
Further, described to go sour agent for sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, hydrogen in the step 4) Lithia, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium alkoxide, triethylamine, diisopropyl ethyl The mixture of one or more of amine, pyridine, 2 hydroxy pyrimidine, piperidines, N- methyl piperidines, morpholine or N-methylmorpholine.
Further, VIII compound N -1- of formula [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridyl groups) - Benzyl] synthetic method of hydrazine includes the following steps：
The tertiary bright aminocarbonyl hydration hydrazine hydrochlorides of VI compound N of formula-methoxycarbonyl group-L- and VII compound 4- (2- pyridines of formula Base)-benzaldehyde is through VIII compound N -1- of reduction amination production [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- Pyridyl group)-benzyl] hydrazine；
Reaction equation is as follows：
Further, the reducing agent added is LiAlH4。
Biological enzyme is the genetic engineering bacterium clasmatosis enzyme solution 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. be CN101717745B (application No. is 200910263147.9) Chinese invention patent announce method.Carrying out ultrasonic bacteria breaking is collected by centrifugation from Candida parapsilosis Carbonyl reductase genetic engineering bacterium clasmatosis enzyme solution.Biological 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, 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 for Large-scale production.
Specific implementation mode
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
V compound of formula (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 includes the following steps：
1) type I compound L-phenylalanine (74.6g, 451.9mmol) and N- methoxycarbonyl groups-S-Leucine (90.8g, It 480.0mmol) is reacted in 1000ml dichloromethane, uses condensing agent for 3- (the diethoxy phosphinylidyne oxygen of (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, and reaction carries out 6~10h at 0~20 DEG C, obtains II compound of formula (S) -1- ((S)-phenylpropionic acid -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate (138.6g, 412.1mmol)；
2) II compound of 138.6g formulas first adds isobutyl chlorocarbonate in ice in the in the mixed solvent of tetrahydrofuran and ether Bath is lower to react 20min, diazomethane reaction 3h is then added, then add hydrogen bromide and react 40min 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 III compound of 144.0g formulas (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 solution be biological enzyme catalyst, using NADPH as coenzyme, the phosphoric acid buffer for being 6.5 in ph values is molten IV compound of production (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) IV compound of 140.6g formulas (S) -1- (the bromo- 3- hydroxyls -1- phenyl butanes -2- bases-amino of (S) -4-) -3,3- bis- Methyl-1-carbonyl butane-2- bases-methyl carbamate adds HOBt, N- methyl in the saturation ethanol solution of potassium hydroxide Quinoline carries out V compound (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3 of epoxidation reaction production, 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 ethyl alcohol (500mL) solution of (77.2g, 380.0mmol), it is small to be stirred at room temperature 1 When, ethyl alcohol (250ml) solution dissolved with formula VII compound 4- (2- pyridyl groups)-benzaldehydes (65.1g, 355.6mmol) is added, Flow back 5h at 45 DEG C, is cooled to room temperature, and LiAlH is added4(8g, 0.25mol), normal pressure hydrogenation 12 hours.Filtering, filtrate concentration, The crude product of gained is obtained into VIII compound N -1- of formula [N- (methoxycarbonyl group)-S-Leucine base]-N- with recrystallisation from isopropanol 2- [4- (2- pyridyl groups)-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 VIII compound N -1- of (122.2g, 330.0mmol) formula [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridyl groups)-benzyl] hydrazine is dissolved in 500ml isopropanols, at 90 DEG C Lower reflux 12h, it is cooling, it is slowly added to 1000ml distilled water, stirs 2h, is stood, is filtered, washing, then recrystallized with ethanol water, very Sky is dry, and liquid phase detection obtains Ⅸ compound 1- of 201.3g formulas [4- (2- pyridyl groups) phenyl] bis- { [N- (methoxies of -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 belongs to the prior art well known to those skilled in the art.

Claims (9)

1. a kind of synthetic method of atazanavir, which is characterized in that include the following steps：V compound of formula (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- pyridyl groups)-benzyl] hydrazine passes through in organic solvent Bis- { [N- (the methoxycarbonyl group)-L- uncles of Ⅸ compound 1- of nucleophilic substitution production [4- (2- pyridyl groups) phenyl] -5 (S) -2,5- Leucine base] amino } -4 (S)-hydroxyl -6- phenyl -2- aza-hexanes, i.e. atazanavir；
Reaction equation is as follows：
V compound of the formula (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 includes the following steps：
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) II compound of formula is changed with isobutyl chlorocarbonate, diazomethane, reaction of hydrogen bromide production III successively in organic solvent Close object (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) III compound of formula (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 IV compound of biological enzyme production (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) IV compound of formula (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, sour agent is gone to carry out cyclization reaction V chemical combination of production in organic solvent Object (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：
2. the synthetic method of atazanavir according to claim 1, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate With VIII compound N -1- of the formula [N- (methoxycarbonyl group)-S-Leucine base]-N-2- [4- (2- pyridyl groups)-benzyl] hydrazine reaction Used organic solvent is isopropanol, tetrahydrofuran, dichloromethane, N-methylmorpholine, triethylamine, ethylene glycol ether, three The mixed solvent of one or more of vinyl chloride, styrene.
3. the synthetic method of atazanavir according to claim 1, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate Synthetic method step 1) in, the organic solvent be isopropanol, tetrahydrofuran, hexane, hexamethylene, acetone, dichloromethane One or more of mixed solvent, the condensing agent of condensation reaction addition is 3- (diethoxy phosphoryl oxy) -1,2, The mixture of 3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides EDCI.
4. the synthetic method of atazanavir according to claim 1, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate Synthetic method step 1) in, the organic solvent is that isopropanol, tetrahydrofuran, acetone are that 2 ︰, 2 ︰ 1 are formed in mass ratio The condensing agent of mixed solvent, the condensation reaction addition is 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone DEPBT and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides EDCI is the mixture of 3 ︰ 1 compositions in mass ratio.
5. the synthetic method of atazanavir according to claim 4, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate Synthetic method step 2) in, the organic solvent be acetonitrile, isopropanol, pyridine, phenol, tetrahydrofuran, in dichloromethane One or more of mixed solvents, after II compound of the formula reacts 0.5~1h with isobutyl chlorocarbonate, into reaction system After adding 4~6h of diazomethane reaction, then 1~1.5h of reaction of hydrogen bromide is added to get III compound of formula into reaction system.
6. the synthetic method of atazanavir according to claim 5, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate Synthetic method step 3) in, the biological enzyme is the genetic engineering bacterium for the carbonyl reductase for coming from Candida parapsilosis Clasmatosis enzyme solution；The biological enzyme and the mass ratio of III compound of formula are no more than 2%.
7. the synthetic method of atazanavir according to claim 6, which is characterized in that V compound of the formula (S) -1- ((S) -2- epoxy ethyl -1- diphenylphosphino ethanes -2- bases-amino) -3,3- dimethyl -1- carbonyl butane -2- bases-methyl carbamate Synthetic method step 4) in, it is described go sour agent be sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, lithium hydroxide, hydrogen Sodium oxide molybdena, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium alkoxide, triethylamine, diisopropyl ethyl amine, pyridine, 2- The mixture of one or more of pyridone, piperidines, N- methyl piperidines, morpholine and N-methylmorpholine.
8. the synthetic method of atazanavir according to claim 1, which is characterized in that VIII compound N -1- [N- (methoxies of formula Carbonyl)-S-Leucine base] synthetic method of-N-2- [4- (2- pyridyl groups)-benzyl] hydrazine includes 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- pyridyl groups)-benzene Formaldehyde is under the action of reducing agent through VIII compound N -1- of reduction amination production [N- (methoxycarbonyl group)-S-Leucine Base]-N-2- [4- (2- pyridyl groups)-benzyl] hydrazine；
Reaction equation is as follows：
9. the synthetic method of atazanavir according to claim 8, which is characterized in that VI compound N of formula-methoxycarbonyl group- The tertiary bright aminocarbonyl hydration hydrazine hydrochlorides of L- react added reducing agent with formula VII compound 4- (2- pyridyl groups)-benzaldehyde and are LiAlH4。
CN201710195292.2A 2017-03-29 2017-03-29 The synthetic method of atazanavir Active CN107540603B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710195292.2A CN107540603B (en) 2017-03-29 2017-03-29 The synthetic method of atazanavir

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710195292.2A CN107540603B (en) 2017-03-29 2017-03-29 The synthetic method of atazanavir

Publications (2)

Publication Number Publication Date
CN107540603A CN107540603A (en) 2018-01-05
CN107540603B true CN107540603B (en) 2018-09-21

Family

ID=60966728

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710195292.2A Active CN107540603B (en) 2017-03-29 2017-03-29 The synthetic method of atazanavir

Country Status (1)

Country Link
CN (1) CN107540603B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101391978B (en) * 2007-09-19 2010-12-01 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
CN102911113B (en) * 2011-08-05 2015-08-19 浙江九洲药业股份有限公司 A kind of preparation method of Reyataz R
CN104356054B (en) * 2014-09-30 2017-04-19 东北制药集团股份有限公司 Method for preparing atazanavir monomer

Also Published As

Publication number Publication date
CN107540603A (en) 2018-01-05

Similar Documents

Publication Publication Date Title
TWI438188B (en) Production method of intermediate compound for synthesizing medicament
CN107540603B (en) The synthetic method of atazanavir
WO2014101690A1 (en) Method for preparing ezetimibe chiral intermediate
CN101391978B (en) Novel synthetic method of HIV-1 protease inhibitor atazanavir
CS205085B2 (en) Method of producing hydroxy-and oxoderivatives of arylthio-perhydro-aza-heterocycles
CN1137095C (en) The preparation of i(N)-substituted-hydroxycycloalkylamine derivatives
JPH0772167B2 (en) Process for producing 4-amino-3-hydroxybutyric acid derivative
CN108530402B (en) Preparation method of (R) -3-propyl-gamma-butyrolactone
CN102134208B (en) [R,R]-methylphenidate intermediate and analogue thereof and their synthesis and application
JP5301676B2 (en) Process for producing (3S, 4S) -4-((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone and novel intermediate used therefor
CN101092342A (en) Chemical process for the preparation of intermediates to obtain n-formyl hydroxy-lamine compounds
JP3819532B2 (en) Piperidine derivatives and method for producing the same
MX2015004593A (en) Macrocyclic ketoamide immunoproteasome inhibitors.
KR100915551B1 (en) Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof
CN100360520C (en) Synthesis of 4-(piperidyl)(2-pyridy)methanone-(e)-o-methyloxime and its salts
CN108329332A (en) A method of preparing Glecaprevir
KR100879120B1 (en) Method of Preparing Donepezil and Its Intermediate
JP4027539B2 (en) Process for producing N-benzyl-4-formylpiperidine
US5688985A (en) Process for producing keto nitrile derivative
CN113149891B (en) Preparation method of 2-amino-2- (1-methyl-4-piperidinyl) ethanol
CN111393346B (en) Synthesis method of N-Boc-Dolaprine and Boc-Dap DCHA
KR102152445B1 (en) Production method of intermediate compound for synthesizing medicament
JPH01228946A (en) Synthesis of beta-hydroxyphenetylamines
US6921832B2 (en) Optically active fluorine-containing compounds and processes for their production
CN107827811B (en) Method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20201225

Address after: 313000 room 1020, science and Technology Pioneer Park, 666 Chaoyang Road, Nanxun Town, Nanxun District, Huzhou, Zhejiang.

Patentee after: Huzhou You Yan Intellectual Property Service Co.,Ltd.

Address before: 530000 No.2, East 4th Road, Keyuan Avenue, Nanning, Guangxi Zhuang Autonomous Region

Patentee before: NANNING SCD BIO PHARMACEUTICALS, Inc.

TR01 Transfer of patent right