CN106008366A - Preparation method of rilpivirine - Google Patents
Preparation method of rilpivirine Download PDFInfo
- Publication number
- CN106008366A CN106008366A CN201610352775.4A CN201610352775A CN106008366A CN 106008366 A CN106008366 A CN 106008366A CN 201610352775 A CN201610352775 A CN 201610352775A CN 106008366 A CN106008366 A CN 106008366A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- formula
- preparation
- rilpivirine
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of rilpivirine. The method comprises the following steps: with the compounds of formulas I, II, V and VI as initial raw materials, performing a Heck reaction between the compounds of formulas I and II under the effects of a catalyst, a ligand and alkali, and dehydrating and forming hydrochloride to obtain a key intermediate 1; performing substitution and chlorination of the compounds of formulas V and VI to obtain a key intermediate 2; and performing a microwave-assisted substitution reaction between the intermediate 1 and the intermediate 2 to obtain rilpivirine 3. The preparation method disclosed by the invention has high reaction selectivity and is easy in operation; and compared with original synthesis method, the reaction time is greatly shortened, the energy consumption is reduced, the reaction yield is increased, total yield is as high as 21.4%, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the preparation method of a kind of rilpivirine.
Background technology
Rilpivirine (Rilpivirine, R278474, TMC-278), trade nameEntitled the 4-[[4-of chemistry
[[4-[(1E)-2-vinyl]-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] cyanophenyl.Yuan Yan company is beautiful
Tibotec Therapeutics company of state, on May 20th, 2011, by U.S. FDA approval listing, is continue nevirapine, dilazep Wei
Another listing non-nucleoside anti-AIDS drug after pyridine, efavirenz, etravirine.
Rilpivirine is to combine distance HIV reverse transcriptase avtive spot by noncompetitiveAllosteric hydrophobic
Property binding pocket in, in conjunction with after complex interference reverse transcriptase activity, thus reach suppress virus replication purpose.In a large number
Clinical studies show, rilpivirine has a highest activity to the Strain of wild type and saltant type, uses rilpivirine to control
Treat the incidence rate of the untoward reaction caused less than efavirenz.Grow up in the acquired immune deficiency syndrome (AIDS) not yet accepting antiretroviral therapy
In the treatment of patient, rilpivirine has that dosage is little, antiviral activity and anti-drug resistance is high, toleration and safety is good and medicine
The advantages such as thing interaction is few, in clinical practice, rilpivirine and other antiretroviral drugs are combined for never
Carrying out the treatment first of the HIV (human immunodeficiency virus) infection adult patients of antiretroviral therapy, effect is notable, for HIV sufferers
Especially acquired immune deficiency syndrome (AIDS) drug resistance patient provides new selection.
At present the synthetic method about rilpivirine is broadly divided into three parts: the synthesis of intermediate 1, the synthesis of intermediate 2,
The synthesis of rilpivirine.
One, the synthesis of intermediate 1 mainly has two:
This compound is first public in international monopoly WO2003016306, and with 4-halo-2,6-dimethylaniline is initial
Raw material prepares.Additionally also disclose in published International patent WO2004016581 with 4-halo-2,6-dimethyl benzene
Amine is two synthetic routes of initiation material:
Route 1 uses palladium and three (o-methyl-phenyl-) Phosphine ligands (P (o-Tol)3), expensive, relatively costly and
Environment is had pollution, but the use of reported in literature display palladium and three (o-methyl-phenyl-) Phosphine ligands can significantly improve trans
The productivity of isomer.Although route 2 is short compared with route 1, palladium/carbon is cheap relative to palladium, and can recycle.But solvent for use
Dimethyl acetylamide boiling point is higher, and power consumption is big；Acrylonitrile used is the organic toxic articles of B level, and toxicity is big, is managed by public security department
System, makes industrial large-scale production limited.
Two, the synthesis of intermediate 2 mainly has three:
Document (Synthetic Communacations, 27 (11), 1943-1949 (1997)) makes public for the first time with sulfur
Uracil is the synthetic route of initiation material:
This route obtains key intermediate 2 after the hydrocarbonylation of deracil, nucleophilic displacement of fluorine, chlorination.The reaction step of this route
Rapid relatively simple, total recovery is 47%, but produces poisonous and the most unpleasant methyl mercaptan in course of reaction, it is difficult to degasification completely
Taste, reaches environmental impact assessment requirement and can add the cost of industrial mass production；It addition, make solvent with diethylene glycol dimethyl ether (DME)
Reflux temperature is higher, energy consumption is relatively big, need to improve further.
Patent documentation WO2003016306 discloses with to the cyano group benzene guanidine synthetic route as initiation material:
In this route, cyano group benzene guanidine and substituted diethyl malonate carry out cyclization, then obtain intermediate 2 through chlorination.
This route first step can not directly carry out second step by purified warp " one kettle way ", and reactions steps is simple, and gross production rate is 58.5%.
But to the expensive of cyano group benzene guanidine and be difficult to obtain, limit the useful industrially of this route.
The synthetic route with uracil as initiation material is disclosed in patent documentation WO2012147091:
This route obtains intermediate 2 through uracil chlorination, nucleophilic displacement of fluorine, the reduction of methoxyl group, chlorination, but reactions steps is superfluous
Long loaded down with trivial details, productivity is relatively low, and gross production rate is only 7%, and uses the reagent phosphorus oxychloride that toxicity is bigger, industrialization expanding production for twice
Environmental pollution is serious.The whole piece route reaction time is longer, and power consumption is big, is not suitable for industrialized production.
Three, the synthesis of rilpivirine:
When patent documentation WO2003016306 and patent documentation WO2004016581 discloses using acetonitrile as solvent, profit
The synthetic route of Wei Lin:
This route is substituted reaction using acetonitrile as reaction dissolvent, intermediate 1 and intermediate 2 and obtains rilpivirine.This is anti-
Though should be fairly simple, the response time is longer, and the prolongation industrialization cyclic production time causes the abrasion of equipment, and reduces
Productivity and the quality of product.
Patent documentation WO2013038425 discloses and synthesizes rilpivirine using N-Methyl pyrrolidone as solvent:
This route is using N-Methyl pyrrolidone as solvent, and 90 DEG C of reaction 16h obtain end-product rilpivirine.W-response
Time is the longest.Additionally solvent for use N-Methyl pyrrolidone boiling point is higher, and industrial recovery is more difficult, adds industry raw
The cost produced.
In sum, in the synthetic route of rilpivirine, there is reaction temperature height, initiation material costliness is difficult to obtain, instead
Answer step redundant and complicated to cause reaction yield is relatively low, the response time is long etc. problem.Therefore, carry out rilpivirine synthesis work
Skill research, finds a kind of more efficient and has the method for industrial production value to synthesize rilpivirine, speeding up to it
Domestic industry, for alleviating the present situation of China's HIV sufferers " medication is difficult, and medication is expensive ", significant.
Summary of the invention
For the deficiencies in the prior art, the present invention provide a kind of easy and simple to handle, total recovery is high, have industrial production value
The preparation method of rilpivirine.
Technical scheme is as follows:
The preparation method of rilpivirine shown in a kind of formula 3,
Compound of formula I and Formula II compound occur Heck to react under the effect of catalyst, part and alkali, then dehydration,
Hydrochloric acid salt obtains key intermediate 1；
Formula V compound and Formula IV compound are substituted, after chlorination key intermediate 2；
Intermediate 1 and intermediate 2 finally utilize microwave reaction generation replacement to obtain rilpivirine 3.
Catalyst, part and alkali used in the described synthesis preparing intermediate 1 is palladium, three (adjacent first respectively
Base phenyl) phosphine and sodium acetate；
Described prepare intermediate 2 during substitution reaction select frit reaction to carry out；The chlorination reagent of chlorination reaction
For phosphorus oxychloride.
The present invention is more detailed, the preparation method of a kind of rilpivirine, and step is as follows:
(1) initiation material compound of formula I and Formula II compound dissolution are in non-protonic solvent, catalyst acetic acid palladium,
Heck reaction, then hydrochloric acid in ethanol solution hydrochloride is there is under the effect of part three (o-methyl-phenyl-) phosphine and alkali sodium acetate
Salt generates intermediate 1；Wherein, compound I: compound II: palladium: three (o-methyl-phenyl-) phosphine: the mol ratio of sodium acetate is
1.0:1.0-1.1:0.1-0.3:0.1-0.3:1.5, reaction dissolvent is Isosorbide-5-Nitrae-dioxane, N-Methyl pyrrolidone, N, N-bis-
Methylformamide or N,N-dimethylacetamide, reaction temperature is 80-130 DEG C；
(2) intermediate V and cyano-aniline VI occurs under melting condition the nucleophilic displacement of fluorine of first sulfydryl of intermediate V anti-
Should, then under conditions of phosphorus oxychloride is as chlorination reagent, chlorination generates intermediate 2；Wherein, compound V: to cyano-aniline
The mol ratio of VI is 1.0:1.0-1.1, and reaction temperature is 150-180 DEG C；
(3) joining in polar reaction solvent by intermediate 1 and intermediate 2, reaction obtains rilpivirine；Wherein, middle
The molar ratio of body 1 and intermediate 2 is 1.0:1.0-1.1；Reaction dissolvent is N-Methyl pyrrolidone, dioxane or second
Nitrile, reaction temperature 100-150 DEG C, the response time is 5-120min.
According to the invention it is preferred to,
Compound I described in step (1): compound II: palladium: three (o-methyl-phenyl-) phosphine: sodium acetate mole
Ratio is 1.0:1.0:0.3:0.3:1.5；Reaction temperature preferably 130 DEG C；The preferred DMAC N,N' dimethyl acetamide of reaction dissolvent.
In step (2), compound V: the mol ratio to cyano-aniline VI is 1.0:1.0, and reaction temperature is preferably 160-180
DEG C, 160 DEG C of reaction 2h, then rise high-temperature and react 2h to 180 DEG C.
In step (3), intermediate 1 and intermediate 2 are joined microwave reactor carries out microwave reaction；Wherein said
The preferred reaction dissolvent of microwave reaction is acetonitrile；Preferred 140-150 DEG C of temperature；Response time preferred 90-120min.
In step (3), the molar ratio of intermediate 1 and intermediate 2 is 1.0:1.0.
The present invention prepares rilpivirine with compound I and compound II and compound V and compound VI for initial feed.
Comprise the steps: that compound I and compound II occur Heck to react under the effect of catalyst and part and alkali, then take off
Water, hydrochloric acid salt obtain key intermediate 1；Compound V and compound VI is substituted, after chlorination key intermediate 2；Intermediate
1 and intermediate 2 finally utilize microwave reaction to obtain product rilpivirine 3 after replacing.
Synthetic route of the present invention is as follows:
Reagent and condition: (i) palladium, three (o-methyl-phenyl-) phosphine, sodium acetate, N,N-dimethylacetamide, N2, 130
DEG C, 24h；(ii) phosphorus oxychloride, 40 DEG C, 1h；(iii) ethanol, acidic alcohol, 30min；(iv) melted, 160 DEG C, 2h；180 DEG C,
2h；(v) phosphorus oxychloride, backflow, 1h；(vi) microwave, acetonitrile, 140 DEG C, 90min.
The invention provides a kind of new method synthesizing rilpivirine and synthesizing rilpivirine with microwave reactor, this method
Reaction selectivity is high, simple to operate, and significantly shortens the response time compared to original synthetic method, wherein, and intermediate 1
Substitution reaction is occurred to generate in the step of rilpivirine, by the reaction in original patent documentation WO2004016581 with intermediate 2
69h shortens to 90min, reduces energy resource consumption, and overall yield of reaction has been brought up to 21.4% by original 18.5%, is suitable for industry
Metaplasia is produced.
Below in conjunction with the case study on implementation of detailed description of the invention, the present invention will be further described.
Detailed description of the invention
Embodiment 1:
(1) synthesis of intermediate 1
By bromo-for 4-2,6 dimethylaniline I (50mmol, 10g), acrylamide II (50mmol, 3.7g), sodium acetate
(75mmol, 6.15g), palladium (15mmol, 3.4g) and three (o-methyl-phenyl-) phosphine (15mmol, 4.6g) are placed in round-bottomed flask
In, under nitrogen protection, N,N-dimethylacetamide being slowly added in above-mentioned round-bottomed flask, oil bath is heated to 130 DEG C of reaction 24h.
Reaction is cooled to room temperature after terminating, kieselguhr filters, and evaporated under reduced pressure solvent is subsequently adding water, and ethyl acetate extracts three times, merges
Organic facies, anhydrous sodium sulfate is dried, and filters, removes unnecessary organic solvent under reduced pressure, and ethyl acetate, petroleum ether recrystallization obtain product
(E)-3-(4-amino-3,5-3,5-dimethylphenyl) propyl group-2-acrylamide III crude product 4.8g, productivity 51%.
The product III above-mentioned reaction generated adds in round-bottomed flask, adds 10mL phosphorus oxychloride 40 DEG C reaction 1h.Reaction
Crude product (E)-3-(4-amino-3,5-dimethyl benzene is filtered to obtain after reactant liquor is poured slowly into after end in 50g trash ice stirring 1h
Base) propyl group-2-alkene eyeball IV.Gained crude product is dissolved in dehydrated alcohol, stirs half an hour after adding ethanol solution hydrochloride, filter
(E)-3-(4-amino-3,5-3,5-dimethylphenyl) propyl group-2-alkene cyanogen hydrochlorate 1,5.0g, productivity 95%.
Intermediate compound IV: white feather shape crystal, fusing point: 78-80 DEG C.
1H NMR(400MHz,CDCl3) δ 7.22 (d, J=16.5Hz, 1H, CH=), 7.05 (s, 2H, PhH), 5.59 (d, J
=16.5Hz, 1H ,=CH), 3.95 (s, 2H, NH), 2.18 (s, 6H, CH3).13C NMR(100MHz,CDCl3)δ150.94,
146.21,129.86,128.02,123.28,121.50,119.60,90.28,77.38,77.06,76.74,17.50.
(2) synthesis of compound VII
2-methyl mercapto-4-pyrimidone V (70mmol, 10g) is placed in circle with p-aminophenyl formonitrile HCN VI (77mmol, 9.14g)
End flask, the lower oil bath of nitrogen protection is heated to 160 DEG C of reaction 2h, then rises high-temperature and continue reaction 2h to 180 DEG C.Reaction terminates
Being cooled to room temperature, add appropriate DMF, ultrasonic smashing after half an hour is stirred in dissolving is filtered, filter cake acetonitrile
After washing with dichloromethane, being vacuum dried to obtain compound VII crude product 10.3g, white solid, productivity is 70%.
(3) synthesis of intermediate 2
Above-mentioned gained crude product is added in round-bottomed flask, add 20mL phosphorus oxychloride, be heated to reflux stirring 1h.Reaction terminates
After be cooled to room temperature, reactant liquor is poured slowly in 100g trash ice, stir half an hour.Filtering, gained filter cake is dissolved in 50mL water, carbon
Acid potassium regulation pH to 7-8, filters.Filter cake acetonitrile washs, and is vacuum dried to obtain intermediate 9.9g, white solid, productivity 89%.
(4) synthesis of rilpivirine 3
Intermediate 1 (1g, 5mmol) and intermediate 2 (1.2g, 5mmol) are joined in microwave reaction pipe, to microwave reaction
Put in microwave reactor after pipe adds 10mL acetonitrile, reaction temperature 140 DEG C, react 90min under high-speed stirred.Reaction knot
The solution of potassium carbonate regulation pH dripping 10% in Shu Houxiang microwave reaction pipe is 8-9.Filter, after the washing of filter cake acetonitrile, obtain profit
Wei Lin 1.28g, white solid, productivity is 71%, and fusing point is 138-140 DEG C.The total recovery of this synthetic route is 51% ×
95% × 70% × 89% × 71%=21.4%.
1H NMR (400MHz, DMSO) δ 9.62 (s, 1H, NH), 8.95 (s, 1H, NH), 7.98 (t, J=27.2Hz, 2H,
PhH), 7.69 (m, 3H ,=CH, PhH), 7.49 (s, 2H, PhH), 6.46 (d, J=16.7Hz, 1H ,=CH), 2.18 (s, 6H,
CH3)。
Claims (8)
1. a preparation method for rilpivirine shown in formula 3,
Compound of formula I and Formula II compound occur Heck to react under the effect of catalyst, part and alkali, are then dehydrated, become salt
Hydrochlorate obtains key intermediate 1；
Formula V compound and Formula IV compound are substituted, after chlorination key intermediate 2；
Intermediate 1 and intermediate 2 finally utilize microwave reaction generation replacement to obtain rilpivirine 3.
2. preparation method as claimed in claim 1, it is characterised in that used in the described synthesis preparing intermediate 1
Catalyst, part and alkali are palladium, three (o-methyl-phenyl-) phosphine and sodium acetates respectively.
3. preparation method as claimed in claim 1, it is characterised in that described prepares substitution reaction during intermediate 2
Selection frit reaction is carried out；The chlorination reagent of chlorination reaction is phosphorus oxychloride.
4. preparation method as claimed in claim 1, it is characterised in that comprise the steps:
(1) initiation material compound of formula I and Formula II compound dissolution are in non-protonic solvent, at catalyst acetic acid palladium, part
Heck reaction occurs under the effect of three (o-methyl-phenyl-) phosphines and alkali sodium acetate, and then in ethanol solution hydrochloride, hydrochloric acid salt is raw
Become intermediate 1；Wherein, compound of formula I: Formula II compound: palladium: three (o-methyl-phenyl-) phosphine: the mol ratio of sodium acetate is
1.0:1.0-1.1:0.1-0.3:0.1-0.3:1.5, reaction dissolvent is Isosorbide-5-Nitrae-dioxane, N-Methyl pyrrolidone, N, N-bis-
Methylformamide or N,N-dimethylacetamide, reaction temperature is 80-130 DEG C；
(2) intermediate V and cyano-aniline VI is occurred under melting condition the nucleophilic substitution of first sulfydryl of intermediate V, so
After under conditions of phosphorus oxychloride is as chlorination reagent chlorination generate intermediate 2；Wherein, compound V: cyano-aniline VI is rubbed
That ratio is 1.0:1.0-1.1, and reaction temperature is 150-180 DEG C；
(3) joining in polar reaction solvent by intermediate 1 and intermediate 2, reaction obtains rilpivirine；Wherein, intermediate 1 He
The molar ratio of intermediate 2 is 1.0:1.0-1.1；Reaction dissolvent is N-Methyl pyrrolidone, dioxane or acetonitrile, reaction
Temperature 100-150 DEG C, the response time is 5-120min.
5. preparation method as claimed in claim 1, it is characterised in that the compound of formula I described in step (1): Formula II chemical combination
Thing: palladium: three (o-methyl-phenyl-) phosphine: the mol ratio of sodium acetate is 1.0:1.0:0.3:0.3:1.5；Reaction temperature is 130
℃；Reaction dissolvent is DMAC N,N' dimethyl acetamide.
6. preparation method as claimed in claim 1, it is characterised in that in step (2), compound V: cyano-aniline VI is rubbed
Your ratio is 1.0:1.0, and reaction temperature is 160-180 DEG C, 160 DEG C of reaction 2h, then rises high-temperature and reacts 2h to 180 DEG C.
7. preparation method as claimed in claim 1, it is characterised in that in step (3), intermediate 1 and the mol ratio of intermediate 2
Example is 1.0:1.0.
8. preparation method as claimed in claim 1, it is characterised in that in step (3), intermediate 1 is joined with intermediate 2
Microwave reactor carries out microwave reaction；The reaction dissolvent of wherein said microwave reaction is acetonitrile；Temperature is 140-150 DEG C；
Response time is 90-120min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610352775.4A CN106008366A (en) | 2016-05-25 | 2016-05-25 | Preparation method of rilpivirine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610352775.4A CN106008366A (en) | 2016-05-25 | 2016-05-25 | Preparation method of rilpivirine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106008366A true CN106008366A (en) | 2016-10-12 |
Family
ID=57093641
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610352775.4A Pending CN106008366A (en) | 2016-05-25 | 2016-05-25 | Preparation method of rilpivirine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106008366A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112010810A (en) * | 2020-09-09 | 2020-12-01 | 瑞阳制药股份有限公司 | Method for preparing high-purity rilpivirine intermediate by one-pot method |
| CN112778214A (en) * | 2021-01-13 | 2021-05-11 | 安徽贝克联合制药有限公司 | Intermediate for synthesizing rilpivirine, synthesis method thereof and rilpivirine synthesis method |
| CN113788837A (en) * | 2021-08-02 | 2021-12-14 | 深圳湾实验室坪山生物医药研发转化中心 | Trilaciclib synthesis method |
| CN114933567A (en) * | 2022-04-29 | 2022-08-23 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681774A (en) * | 2002-08-09 | 2005-10-12 | 詹森药业有限公司 | Processes for the preparation of 4- 4- 4-(2 -cyanoethenyl)-2,6-dimethylphenyl )amino) -2-pyrimidinyl)amino benzonitrile |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN103333117A (en) * | 2013-05-18 | 2013-10-02 | 嘉兴中科化学有限公司 | Preparation method of 4[(4-chloro-2-pyrmidyl)amino]cyanophenyl |
| CN105566162A (en) * | 2016-02-23 | 2016-05-11 | 苏州莱克施德药业有限公司 | Rilpivirine midbody preparing technology |
-
2016
- 2016-05-25 CN CN201610352775.4A patent/CN106008366A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681774A (en) * | 2002-08-09 | 2005-10-12 | 詹森药业有限公司 | Processes for the preparation of 4- 4- 4-(2 -cyanoethenyl)-2,6-dimethylphenyl )amino) -2-pyrimidinyl)amino benzonitrile |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN103333117A (en) * | 2013-05-18 | 2013-10-02 | 嘉兴中科化学有限公司 | Preparation method of 4[(4-chloro-2-pyrmidyl)amino]cyanophenyl |
| CN105566162A (en) * | 2016-02-23 | 2016-05-11 | 苏州莱克施德药业有限公司 | Rilpivirine midbody preparing technology |
Non-Patent Citations (1)
| Title |
|---|
| SHUANG-XI GU等: "Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112010810A (en) * | 2020-09-09 | 2020-12-01 | 瑞阳制药股份有限公司 | Method for preparing high-purity rilpivirine intermediate by one-pot method |
| CN112010810B (en) * | 2020-09-09 | 2024-01-30 | 瑞阳制药股份有限公司 | Method for preparing high-purity rilpivirine intermediate by one-pot method |
| CN112778214A (en) * | 2021-01-13 | 2021-05-11 | 安徽贝克联合制药有限公司 | Intermediate for synthesizing rilpivirine, synthesis method thereof and rilpivirine synthesis method |
| CN113788837A (en) * | 2021-08-02 | 2021-12-14 | 深圳湾实验室坪山生物医药研发转化中心 | Trilaciclib synthesis method |
| CN114933567A (en) * | 2022-04-29 | 2022-08-23 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidone |
| CN114933567B (en) * | 2022-04-29 | 2023-07-11 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidinone |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| KR101086678B1 (en) | Processes for the preparation of 4-[[4-[[4- (2-cyanoethenyl)-2, 6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile | |
| CN106008366A (en) | Preparation method of rilpivirine | |
| CN109020881B (en) | Preparation method of apatinib | |
| JPS63190857A (en) | 8-substituted 2-aminotetralines | |
| CN106187808A (en) | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate | |
| CN109369545B (en) | Synthesis process of 2-methyl-5-pyrazine formate | |
| CN104356092A (en) | Preparation method for vortioxetine | |
| CN106366022A (en) | Intermediate used for AZD9291 preparation, and preparation method and application thereof | |
| CN103483340B (en) | A kind of synthetic method of sitagliptin | |
| CN104341333A (en) | Preparation method of Pramiracetam sulfate | |
| CN104262264A (en) | New preparation technique of urapidil hydrochloride | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN101531634B (en) | High-purity blonanserin and preparation method thereof | |
| CN104974057A (en) | Preparation method and important intermediate of bromfenac sodium | |
| CN102911123A (en) | Preparation method of 2-chloro trifluoromethyl pyrimidine compound | |
| CN104693090A (en) | Silodosin and preparation methods for intermediates thereof | |
| CN104744512B (en) | New process for preparing tenofovir through one-pot method | |
| CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
| JP2014527032A (en) | Process for producing 2-amino-5-cyano-N, 3-dimethylbenzamide | |
| CN105294686A (en) | Preparation method of riociguat | |
| CN105646405B (en) | The preparation method of substituted adjacent amido benzonitrile compound, preparation method and Lapatinib | |
| CN104341359A (en) | Preparation method of tetramethyl-pyrazine | |
| CN105801559A (en) | Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate | |
| CN116768697B (en) | Method for preparing dipropylmalonic acid by using chloropropane as alkylating agent and application of dipropylmalonic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161012 |