CN109293675A - A kind of improved Du Lutewei preparation process - Google Patents
A kind of improved Du Lutewei preparation process Download PDFInfo
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- CN109293675A CN109293675A CN201811376294.2A CN201811376294A CN109293675A CN 109293675 A CN109293675 A CN 109293675A CN 201811376294 A CN201811376294 A CN 201811376294A CN 109293675 A CN109293675 A CN 109293675A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Abstract
The present invention provides the improved preparation processes of anti-AIDS drug Du Lutewei, and diastereo-isomerism synthetic intermediate 6' for Du Lutewei bulk pharmaceutical chemicals technology controlling and process research and preparation method thereof.The route that preparation process of the invention uses is simple, simplifies the purification process for intermediate, and the diastereo-isomerism synthetic intermediate 6' that furthermore present invention obtains facilitates the quality research for Du Lutewei bulk pharmaceutical chemicals preparation process.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the improved preparation process of anti-AIDS drug Du Lutewei,
And the diastereo-isomerism synthetic intermediate 6' for Du Lutewei bulk pharmaceutical chemicals technology controlling and process research.
Background technique
According to the newest report of the World Health Organization, by 2016, has more than 35,000,000 people and died of AIDS, the whole world
There are 36,700,000 people's aids infection poison.AIDS becomes serious global public health and social concern.Integrase is in HIV-1 disease
It plays an important role in poison duplication, since, without integrase and functional analogue, this enzyme is increasingly becoming inverase in human body
Ideal targets.Du Lutewei (chemical name Dolutegravir) is by Viiv Healthcare and Ge Lansu company Glaxo
SmithKline cooperative development, is second generation integrase inhibitor, is listed earliest by FDA in approval in 2013, chemical structure
It is as follows.Compared with first generation integrase inhibitor Lei Getewei (raltegravir) and Elvitegravir, Du Lutewei has
Higher drug resistance obstacle, and the clinical efficacy for the treatment of AIDS is better than Lei Getewei.
To develop imitation medicine, there is an urgent need to provide the preparation process of the Du Lutewei bulk pharmaceutical chemicals of more convenient optimization, with full
The needs of sufficient industrialized production.Ge Lansu company reports one kind by 4- methoxyl group acetoacetate in patent WO2011119566
Method of the methyl esters as starting material synthesis Du Lutewei relates generally to following eight steps reaction, is detailed in route one.
Route one
The route raw material is easy to get, and synthesis step number is few, easy to operate, is more suitble to scale industrial production.In this route
In, compound 6 contains pyrido pyridazine tricyclic precursor structure, for the key intermediate for preparing Du Lutewei；The intermediate 6 warp
It crosses and 1) is condensed with 2,4- difluorobenzylamine and 2), on removing pyridine ring obtains Du Lute after phenolic hydroxyl group ether methyl two-step reaction
Wei.
Summary of the invention
In the research of Du Lutewei preparation process, we have references to the synthetic route of document WO2011119566 offer,
And comprehensively optimize and improve to preparation process: the step of the 1st, 2,3 and 4 is reacted, and continuous four-step reaction is without other point
From and purifying, compound 4 is obtained with 36% total recovery；Step 5 does not need purification of intermediates, is handled with R-3- amino butanol
Reaction obtains the Du Lutewei key intermediate 6 comprising pyrido pyridazine tricyclic precursor structure afterwards；Literature method is turned finally to, in
Final product Du Lutewei is obtained with moderate yield after mesosome 6 and the coupling of 2,4- difluorobenzylamine and de- ether methyl.
As the crucial synthetic intermediate of Du Lutewei, compound 6 controls the optical purity of drug.On the one hand, how to change
Kind and optimization compound 6 stereoselectivity is just becoming entire industrial critical issue；On the other hand, intermediate is being prepared
Its diastereoisomer 6' may also be generated in 6 the step of.And in entire preparation process, 2,4- difluoro benzyl is participated in by compound 6'
After amine coupling reaction and subsequent demethylation, the diastereoisomer of Du Lutewei is obtained, the diastereoisomer degree of being
A contamination levels product in Lu Tewei bulk pharmaceutical chemicals technology controlling and process research.It is therefore desirable to prepare compound 6' to be used for Du Lute
Wei bulk pharmaceutical chemicals technology controlling and process and quality research.
From the point of view of the chemical structure of compound 6', it is non-polyalcohols can be prepared from the diastereoisomer of intermediate 6'
The synthesis of enantiomter.
In order to prepare diastereoisomer 6', we first it is contemplated that diastereoisomer 6' can from compound 5 with
It is separated in the annulation of R-3- amino butanol, the 6th step reaction in route one theoretically can produce two chiralitys
Center is to get to a pair of of diastereoisomer；However, the reaction is three-dimensional as the result is shown for reaction solution HPLC and nuclear-magnetism trace analysis
Enantiomer 6, diastereoisomer ratio > 99:1 are selectively obtained.Trace is detected merely by TLC thin-layer chromatography
Diastereoisomer 6'.
Therefore, it is necessary to using other reactions could purposefully prepare compound 6', find in this research: compound 6 can
To carry out open loop and ring closure reaction under Bronsted acid and felicity condition, diastereoisomer 6'(is finally prepared for reference to route
Two).Different conversion reaction conditions are attempted, including different coupling agents, solvent and reaction temperature to optimize conversion reaction；As a result
Show to promote to convert by EDCI/DMAP in sealing tube reaction, diastereoisomer 6' obtains (ginseng with 50% conversion yield
Examine table 1, example 6).
Route two prepares intermediate 6'
A kind of mechanism is proposed to explain this conversion reaction.Acetal compound 6 hydrolyzes to form carbon sun in acid condition
The attack that the subsequent carbocation 9 of ion 9. is rolled into a ball by the OH-based from two sides (the two kinds of directions a and b), has been correspondingly made available configuration
Keep the product with configuration conversion.
The possible reaction mechanism of route two
On the one hand, the present invention provides a kind of improved Du Lutewei preparation process, synthetic method is route one, including with
Lower specific operation: 1) .4- methoxyl group methyl acetoacetate is initial feed, anti-with n,N-Dimethylformamide dimethylacetal
It answers, then replaces with 2,2- dimethoxy-ethylamine, after dimethyl oxalate cyclization, lithium hydroxide catalyzing hydrolysis obtains compound 4, wherein
The reaction of the step of 1st, 2,3 and 4, continuous four-step reaction are not necessarily to other separation and purifying, obtain compound 4；2) compound 4 is through first
After sulfonic acid hydrolysis, purification of intermediates 5 is not needed, is directly obtained in the key of Du Lutewei with R-3- amino-n-butyl alcohol cyclization
Mesosome 6；3) intermediate 6 continues that coupling reaction occurs under EDCI catalysis with 2,4- difluorobenzylamine, finally takes off ether methyl degree of obtaining
Lu Tewei.
On the other hand, the present invention provides a kind of diastereo-isomerism conjunctions for Du Lutewei bulk pharmaceutical chemicals technology controlling and process research
At intermediate 6 ', the structural formula of intermediate 6 ' is as disclosed herein.
In another aspect, the present invention provides a kind of diastereo-isomerism conjunctions for Du Lutewei bulk pharmaceutical chemicals technology controlling and process research
At the preparation method of intermediate 6 ', comprising steps of compound 6 carries out open loop and ring closure reaction under Bronsted acid and felicity condition,
Diastereo-isomerism synthetic intermediate 6' is obtained, with reference to route two.
A kind of embodiment of the preparation method of preferred diastereo-isomerism synthetic intermediate 6 ', wherein the Bronsted acid
And felicity condition is addition EDCI/DMAP as reaction promoter.
A kind of embodiment of the preparation method of preferred diastereo-isomerism synthetic intermediate 6 ', wherein the Bronsted acid
And felicity condition is addition EDCI/DMAP as reaction promoter, and 70 DEG C are heated in tube sealing.
A kind of embodiment of the preparation method of preferred diastereo-isomerism synthetic intermediate 6 ', wherein the Bronsted acid
And felicity condition is addition EDCI/DMAP as reaction promoter, and 70 DEG C are heated in tube sealing, it is molten using chloroform as reaction
Agent.
Reaction process monitors whether that the chromatography such as TLC, HPLC or GC can be selected.
In the context of this application, common some contractings in the abbreviation and chemistry experiment report of chemical reagent have been used
WriteMode, comprising: d refers to day, and h refers to hour, and min or mins refer to minute, and r.t. refers to room temperature, and TLC refers to thin-layer chromatography
Chromatography, HPLC refer to high performance liquid chromatography, and GC refers to gas chromatography, and NMR refers to that nuclear magnetic resonance method, EDCI refer to 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride, DCI refer to 4,5-
Dicyanoimidazole, DMAP refer to that 4-dimethylaminopyridine, AcOEt refer to that ethyl acetate, 2N HCl refer to
The HCL aqueous solution of 2mol/L.
The invention has the beneficial effects that: the present invention provides a kind of improved Du Lutewei preparation processes.With 4- methoxy
Base methyl acetoacetate is raw material, has synthesized the Du Lutewei comprising pyrido pyridazine tricyclic precursor structure by six-step process and has closed
Key intermediate 6；Overall yield is 18.7%；Average each step yield is up to 75%.In six-step process, only in the 4th step and the 6th step
Simple operations by washing filter cake have purified target product, remaining step is all made of crude product and feed intake in next step, greatly
Ground simplifies operation.By having carried out recrystallization purifying behaviour to bulk pharmaceutical chemicals penultimate stride intermediary 7 and Du Lutewei final product
Make, the purity of Du Lutewei bulk pharmaceutical chemicals is improved, to be conducive to industrial-scale production.The present invention provides one kind for spending
The diastereo-isomerism synthetic intermediate 6 ' and preparation method thereof of Lu Tewei bulk pharmaceutical chemicals technology controlling and process research.
Specific embodiment
The present invention will be further described below in conjunction with specific embodiments.
4- methoxyl group methyl acetoacetate, N used in the present invention, N-dimethylformamide dimethylacetal (DMF-
DMA), aminoacetaldehyde dimethyl acetal, dimethyl oxalate, lithium hydride, anhydrous lithium hydroxide, methane sulfonic acid, R-3- amino -1- fourth
Alcohol, N, N- carbonyl dimidazoles, glycol dimethyl ether, 2,4- difluorobenzylamine, anhydrous magnesium bromide MgBr2(analyzing pure, Chinese medicines group)；
Glacial acetic acid, petroleum ether, ether, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran (analyzing pure, Chongqing Chuan Dong chemical industry)；NaOH,
Na2CO3(analyzing pure, Solution on Chemical Reagents in Shanghai factory)；Column silica gel for chromatography (200~300 mesh of granularity, Haiyang Chemical Plant, Qingdao), silica gel
Lamellae (Haiyang Chemical Plant, Qingdao)；Distilled water (self-control).
The synthetic method of Du Lutewei
Referenced patent document WO2011119566, using 4- methoxyl group methyl acetoacetate as initial feed, with N, N- diformazan
The reaction of base formamide dimethylacetal, then replace, after dimethyl oxalate cyclization with 2,2- dimethoxy-ethylamine, lithium hydroxide catalytic water
Solution obtains compound 4,4 and obtains the key intermediate 6 of Du Lutewei with R-3- amino-n-butyl alcohol cyclization after sour water solution.6 continue
Coupling reaction occurs under EDCI catalysis with 2,4- difluorobenzylamine, finally deprotection obtains Du Lutewei I (route one).
The preparation of 1. compound 4 of embodiment
By 4- methoxyl group methyl acetoacetate (8ml, 61.8mmol), n,N-Dimethylformamide dimethylacetal 9.6ml
1.5h is stirred at room temperature in (abbreviation DMF-DMA, 72.26mmol) in the round-bottomed flask of 150ml, and solution is gradually become pale brown by yellow
Color, reaction obtain compound 1 (Rf=0.14, TLC solvent: AcOEt/petroleum ether=5/1).In reaction solution
20ml methanol dilution is added and is added aminoacetaldehyde dimethyl acetal 6.68ml (61.31mmol), 1h is stirred at room temperature, solution becomes
Claret, reaction obtain compound 2 (Rf=0.56, TLC solvent: AcOEt).Reaction solution is concentrated under reduced pressure to give comprising centre
Methanol 45.2ml and dimethyl oxalate (18.34g, 155.34mmol) is added, to oxalic acid in the rufous oily liquids of 2 crude product of body
Temperature is controlled after dimethyl ester is completely dissolved, under ice-water bath, and LiH (0.86g, 108.67mmol), solution are added portionwise at 25 DEG C or less
At brownish red suspension, reaction solution is placed under 40 DEG C of bath temperatures after charging and reacts 14h, solution becomes brick red by suspension
Color solution, reaction obtain compound 3 (Rf=0.23, TLC solvent: AcOEt).Reaction solution is cooled to 3-5 DEG C and nothing is added
Water LiOH (5.94g, 123.8mmol) the reaction was continued 2h, reaction solution become yellow-orange suspension by brick-red, and reaction obtains chemical combination
2N HCl (146.8ml) quenching reaction is added in ice-water bath for object 3 (Rf=0.12, TLC solvent: AcOEt).Gained reaction solution
Middle addition 180ml ethyl acetate, filtering discard solid.It collects liquid phase and carries out liquid separation, 90ml water, decompression are added in organic phase
After organic solvent is evaporated off in concentration, a large amount of white solids are precipitated, filter, filter cake is washed with a small amount, is obtained after 50 DEG C of vacuum drying
6.93g compound 4 (Rf=0.44, TLC solvent: CH2Cl2/MeOH=40/1+0.5%HOAc) is colorless solid, total to receive
Rate 36%.1H NMR(400MHz,CDCl3) δ=8.40-8.42 (m, 1H), 4.49-4.53 (m, 1H), 4.10-4.14 (m, 2H),
3.98(s,3H),3.97(s,3H),3.38(s,3H),3.37(s,3H)；13C NMR(100MHz,CDCl3) δ=174.86,
165.99,161.60,148.65,145.47,136.59,116.53,102.31,60.97,57.26,55.97,53.77。
The preparation of 2. key intermediate 6 of embodiment
Compound 4 (3.38g, 107.24mmol) is dissolved in 33ml acetonitrile, at room temperature be added glacial acetic acid (3ml) and
Methanesulfonic acid (0.21ml, 3.24mmol) is heated to 60 DEG C of reaction 19h in the round-bottomed flask of 150ml；Obtain compound 5.It will
(R) -3- amino-n-butyl alcohol (1.44ml, 1.34g are dissolved in 2.25ml CH3CN) is slowly added dropwise into the above reaction solution, continues
60 DEG C are stirred to react 18h, obtain white suspension.Concentrate is obtained after reaction solution is concentrated to dryness, and 25ml CH2Cl2 is added
And 1N HCl (25ml), liquid separation and collected organic layer, water layer CH2Cl2(25ml x 2) extraction merges organic layer and depressurizes dense
It is reduced to and dry obtains 6 2.2g of crude product.The crude product is recrystallized using MeOH/petroleum ether=6/1 solvent 15ml, is crossed and is filtered dry
Faint yellow solid product 1.72g (Rf=0.42, the TLC solvent: CH2Cl2/MeOH=20/1+ of compound 6 is obtained after dry
0.5%HOAc), yield 52%, HPLC purity are 95.3%.1H NMR(400MHz,CDCl3) δ=15.02 (d, J=
16.7Hz, 1H), 8.42 (d, J=11.8Hz, 1H), 5.29 (dd, J=5.4,3.9Hz, 1H), 4.97 (p, J=6.4Hz, 1H),
4.52 (t, J=4.5Hz, 1H), 4.43 (dd, J=13.6,3.5Hz, 1H), 4.26 (dd, J=13.6,5.8Hz, 1H), 4.13
(d, J=4.5Hz, 1H), 4.05 (d, J=13.0Hz, 2H), 3.98 (d, J=2.2Hz, 3H), 3.96 (d, J=2.9Hz, 1H),
3.39 (s, 3H), 2.22-2.09 (m, 1H), 1.52 (dd, J=13.9,1.6Hz, 1H), 1.35 (d, J=7.0Hz, 2H)；13C
NMR(100MHz,CDCl3) δ=173.23,164.17,162.24,149.45,144.64,135.03,130.77,130.73,
130.67,119.35,111.34,111.30,111.13,111.09,103.81,102.73,60.78,56.81,55.72,
53.47,36.60,36.56。
The preparation of 3. compound 7 of embodiment
By compound 6 (0.6g, 1.95mmol), 1- ethyl-(3- dimethylaminopropyl) carbonic acid diimmonium salt hydrochlorate
Acetonitrile (10ml) solution of (EDCI, 0.51g, 2.65mmol), 2,4- difluorobenzylamine (0.29ml, 2.44mmol) is heated to 80 DEG C
5h is reacted, 6ml water quenching reaction is added, lower layer is at thick yellow oily liquid, upper layer suspension milky white granules.It is evaporated under reduced pressure
Acetonitrile solvent is removed, filters, obtains solid crude product 1.06g, crude product AcOEt/petroleum ether=4/1 solvent 15ml
It is recrystallized to give 7 0.66g of compound (Rf=0.25, TLC solvent: AcOEt), yield 78%.1H NMR(400MHz,
CDCl3) δ=10.36 (t, J=5.7Hz, 1H), 8.45 (s, 1H), 7.33-7.25 (m, 1H), 6.81-6.71 (m, 2H), 5.17
(dd, J=4Hz, 4Hz, 1H), 4.97 (t, J=8Hz, 1H), 4.58 (d, J=4Hz, 2H), 4.30 (dd, J=16Hz, 4Hz,
1H), 4.12 (dd, J=12Hz, 8Hz, 1H), 3.99 (s, 3H), 3.88-3.93 (m, 2H), 2.1-2.2 (m, 1H), 1.47 (dd,
J=16Hz, 4Hz, 1H), 1.30 (d, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3) δ=174.49,163.95,
155.63,154.57,142.21,130.63,130.57,130.54,130.48,129.38,118.90,111.41,111.37,
111.20,111.16,104.10,103.85,103.60,76.13,62.44,61.08,53.37,44.51,36.51,29.33,
15.97。
The preparation of 4. Du Lutewei I of embodiment
Compound 7 (480mg, 1.11mmol) is dissolved in the acetonitrile of 9.12ml and be added anhydrous MgBr2 (470mg,
2.55mmol), mixture is placed in 50 DEG C of oil bath pans and stirs 30h, reaction solution is at white suspension.The hydrochloric acid of 11.4ml is added
Quenching reaction is carried out, reaction solution becomes clarification, and reaction solution is diluted with CH2Cl2 and pH is adjusted to 1 or so, liquid separation is collected organic
Phase, water layer are extracted twice with 11.4ml CH2Cl2 again, merge organic phase, and concentration is evaporated under reduced pressure, and 3ml AcOEt is added to dissolve, and are taken out
Filter, a small amount of ethyl acetate washing, drying obtain the colorless solid product 0.37g of compound I；Crude product ethyl acetate and ethyl alcohol
It is recrystallized to give Du Lutewei I 0.18g (Rf=0.46, TLC solvent: CH2Cl2/MeOH=40/1+0.5%HOAc), is
White solid, yield 43%；HPLC purity is 98.5%.IR(KBr,cm-1): λ 3467 (s), 3420 (s), 3244 (m), 2930
(s),2348(w),2107(w),1731(m),1426(s),1399.9(s),1303(w)；1H NMR(400MHz,CDCl3) δ=
3.18 (s, 2H), 5.47 (s, 2H), 6.58 (s, 2H)；13C NMR(100MHz,CDCl3) δ=174.23,170.89,164.35,
164.15,162.22,155.74,153.63,142.92,140.43,130.58,130.07,121.65,116.88,116.80,
115.52,115.42,110.99,110.77,103.51,103.26,102.99,76.43,76.28,62.36,62.01,
60.34,53.07,52.04,48.08,45.05,44.85,36.00,29.12,14.74,14.27。
The preparation of 5. diastereoisomer 6' of embodiment
Compound 6 can carry out open loop and ring closure reaction under Bronsted acid and felicity condition, finally be prepared for diastereomeric different
Structure body 6'(refers to route two).Different conversion reaction conditions are attempted, including different coupling agents, solvent and reaction temperature with excellent
Change conversion reaction；The result shows that promoting to convert by EDCI/DMAP in sealing tube reaction, diastereoisomer 6' is with 50%
Conversion yield obtains (table 1, example 6).
Route two prepares intermediate 6'
Table 1 optimizes conversion condition to prepare intermediate 6'
By compound 6 (67.6mg, 0.23mmol), EDCI (155.5mg, 0.81mmol) and DMAP (11.9mg,
Chloroform (15ml) solution 0.1mmol) is heated to 70 DEG C in seal pipe, keeps 3d.After being cooled to room temperature, it is added water (5ml)
To reaction mixture.Organic phase is separated, water phase is extracted with methylene chloride (2 × 20ml), by combined organic phase MgSO4It is dry
It is dry.After removing solvent, residue is analyzed by HPLC, and the content ratio of compound 6 and its diastereoisomer 6' are 1:1, is passed through
Chromatography uses DCM:CH3OH=97:3 as eluant, eluent by silica gel column purification, obtain title product (6', 27.2mg,
It 40.24%), is light yellow solid.Rf=0.23 (DCM:CH3OH=97:3) .m.p.86.2 DEG C of [α] 25=-28.38 (c=
4.96,CH3OH) δ=7.97 (s, 1H) .1H NMR (400MHz, CDCl3), 5.20 (s, 1H), 4.97-4.81 (m, 1H),
4.33-4.10 (m, 3H), 3.99 (dd, J=13.3,6.1Hz, 1H), 3.92 (s, 4H), 2.30 (d, J=9.5Hz, 1H), 2.08
(dt, J=11.6,6.8Hz, 1H), 1.27 (dt, J=9.3,4.6Hz, 5H) .13C NMR (101MHz, CDCl3) δ=
172.29,164.55,155.84,143.33,128.06,117.71,76.10,62.44,60.88,53.35,44.35,
29.66,15.98,14.29.
Claims (6)
1. a kind of improved Du Lutewei preparation process, synthetic method is route one, including operation in detail below: 1) .4- first
Oxygroup methyl acetoacetate be initial feed, reacted with n,N-Dimethylformamide dimethylacetal, then with 2,2- dimethoxy second
Amine replaces, after dimethyl oxalate cyclization, and lithium hydroxide catalyzing hydrolysis obtains compound 4, wherein the step of the 1st, 2,3 and 4 is reacted, continuously
Four-step reaction is not necessarily to other separation and purifying, obtains compound 4；2) compound 4 does not need to purify after methanesulfonic acid hydrolyzes
Intermediate product 5 directly obtains the key intermediate 6 of Du Lutewei with R-3- amino-n-butyl alcohol cyclization；3) intermediate 6 continue with
Under EDCI catalysis coupling reaction occurs for 2,4- difluorobenzylamines, finally takes off ether methyl and obtains Du Lutewei.
2. according to claim 1, the diastereo-isomerism synthetic intermediate 6 ', 6 ' for Du Lutewei bulk pharmaceutical chemicals technology controlling and process research
Structural formula it is as follows:
3. according to claim 2, the preparation method of intermediate 6 ', comprising steps of compound 6 under Bronsted acid and felicity condition into
Row open loop and ring closure reaction obtain diastereo-isomerism synthetic intermediate 6', with reference to following route
4. the preparation method of intermediate 6 ' according to claim 3, wherein the Bronsted acid and felicity condition are addition
EDCI/DMAP is as reaction promoter.
5. the preparation method of intermediate 6 ' according to claim 3, wherein the Bronsted acid and felicity condition are addition
EDCI/DMAP is heated to 70 DEG C as reaction promoter in tube sealing.
6. the preparation method of intermediate 6 ' according to claim 3, wherein the Bronsted acid and felicity condition are addition
EDCI/DMAP is heated to 70 DEG C as reaction promoter in tube sealing, using chloroform as reaction dissolvent.
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| CN110128448A (en) * | 2019-05-22 | 2019-08-16 | 博诺康源(北京)药业科技有限公司 | The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material and intermediate |
| CN111620891A (en) * | 2020-05-27 | 2020-09-04 | 上海启讯医药科技有限公司 | Totiravi key intermediate solvate polymorph and preparation method and application thereof |
| CN113461607A (en) * | 2021-05-21 | 2021-10-01 | 上海迪赛诺药业股份有限公司 | Method for preparing DTG-4-2 as intermediate of doriravir based on continuous flow micro-reaction technology |
| CN115572257A (en) * | 2021-06-21 | 2023-01-06 | 江西帝劢药业有限公司 | Synthesis method of pyridone compound |
| CN114213432A (en) * | 2021-12-31 | 2022-03-22 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir |
| CN114213432B (en) * | 2021-12-31 | 2023-02-17 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir |
| CN114605437A (en) * | 2022-04-01 | 2022-06-10 | 遵义医科大学 | Synthesis process for preparing three telaprevir medicaments by continuous one-pot method |
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