CN103159747A - Synthetic method of lapatinib - Google Patents
Synthetic method of lapatinib Download PDFInfo
- Publication number
- CN103159747A CN103159747A CN201310059666XA CN201310059666A CN103159747A CN 103159747 A CN103159747 A CN 103159747A CN 201310059666X A CN201310059666X A CN 201310059666XA CN 201310059666 A CN201310059666 A CN 201310059666A CN 103159747 A CN103159747 A CN 103159747A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- chloro
- iodo
- fluorophenyl
- methoxyl group
- 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
- 0 *C1*C(NO)=CC1 Chemical compound *C1*C(NO)=CC1 0.000 description 1
Abstract
The invention relates to a synthetic method of lapatinib. 2-furaldehyde diethyl acetal, N-[3-Cl-4-[(3- fluorobenzoic) methoxy] phenyl]-6-I-4-quinazoline amine and the like serve as raw material, are subjected to three steps of reaction to obtain the lapatinib. The method implements one-pot reaction and is easy to operate, the reaction conversion rate reaches up to 70%, and the purity reaches 98%. Involved solvents are small in toxicity, high in recycling rate and few in three wastes. The involved intermediates are good in crude product purity, can be directly used for latter reaction without the need for aftertreatment and purification, and are suitable for industrial magnification production.
Description
Technical field
The present invention relates to the synthetic method of lapatinibditosylate.
Background technology
two tosic acid lapatinibditosylates (Iapatinib), formal name used at school is N-(3-chloro-4-((3-fluorophenyl) methoxyl group) phenyl)-6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl)-2-furyl)-4-quinazoline amine two tosilate, it is the medicine of the target HER2 of new class, in March, 2007 U.S.'s approval listing, be used for the treatment of the advanced breast cancer patient that those HER2 cross expression, the singularity of lapatinibditosylate is that the sufferer of accepting other chemotherapeutics treatments can't produce cross-resistance to it, and the progression of disease that can effectively slow down breast cancer.Also have at present many other clinical experiments carrying out studying lapatinibditosylate for the result for the treatment of of other cancers.The lapatinibditosylate molecular structural formula is as follows:
Lapatinibditosylate is as the medicine of a new target HER2, can have effect in the patient after Trastuzumab is treated unsuccessfully for HER2, and some data presentation are arranged also, it has certain therapeutic action for the patient that brain shifts, because traditional medicine often is difficult to see through hemato encephalic barrier and enters nervus centralis, so be called as the another important breakthrough of mammary cancer molecular targeted field target HER2 due to new mechanism of action lapatinibditosylate.Lapatinibditosylate for HER2 and HER1, is the medicine of target spot more than, lapatinibditosylate be oral, be micromolecular compound, may be more easily barrier by the blood brain, so the treatment field from now on may be wider, be particularly useful for the patient of long-term treatment.
At present, the synthetic method of lapatinibditosylate mainly contains following three kinds of methods:
W09935146(Ge Lansu company, the applying date is on January 8th, 1999) proposed a kind of take 2-chloro-4-nitrophenols as starting raw material, prepare the method for lapatinibditosylate through reactions such as addition, catalytic hydrogenation, replacement, Suzuki coupling, reduction aminations, its synthetic route is as follows:
The method protected aldehyde radical before this, went protection to carry out reductive amination process after linked reaction is completed again, and made reactions steps long; Owing to having used expensive and organic heteroaryl stannane reagent 5-(1 of severe toxicity having been arranged, 3-dioxolane-2-yl)-2-(tributyl stannyl)-furans, safety in production and the environmental protection of medicine and intermediate there is greater risk; In addition, synthetic pilot process need to carry out column chromatographic isolation and purification, aftertreatment more complicated.
W02005120504A2(Ge Lansu company, application on June 1st, 2005) another kind of method has been proposed: take 4-chloro-6-iodine quinazoline as starting raw material, replace having the stannane base furan compound of severe toxicity to prepare lapatinibditosylate with 5-formylfuran-2-boric acid.Its synthetic route is as follows:
But the aldehyde radical in the reaction intermediate of the method is at high temperature unstable, very easily changes in reaction process, is not easy to control reaction conditions, and side reaction and impurity are more; And per step reactions steps all must be carried out purification process, and not only aftertreatment is complicated, and will use a large amount of organic solvents, causes industrialized production difficulty and environmental protection cost significantly to increase.
CN102295638A(Qilu Pharmaceutical Co., Ltd.; application on June 24th, 2010) a kind of method for preparing lapatinibditosylate has been proposed; with 5-formylfuran-2-boric acid, N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine, 2-methylsulfonyl-ethamine and catalyzer add in solvent; first generate the transition intermediate; obtain target product with reductive agent such as sodium triacetoxy borohydride reduction again, its synthetic route is as follows:
The reaction process of transition intermediate is wayward in the method, and the suitability for industrialized production difficulty is larger, and iodo thing intermediate poor stability wherein, and is not only expensive, and cancellation easily occurs iodine.
Summary of the invention
The present invention is based on above problem a kind of simple preparation lapatinibditosylate and the synthetic method of intermediate thereof are provided.Compare with existing method, catalyzer is cheap, be simple and easy to, reactions steps is few, and reaction conditions is gentle, and yield is higher, and side reaction is few, the easy separating-purifying of product.
The method according to this invention can illustrate by following reaction equation:
Concrete technical scheme of the present invention is as follows:
A kind of synthetic method of two tosic acid lapatinibditosylates, it comprises the steps:
under step 1. nitrogen protection, 2-furfural diethyl acetal (IV) and dry ten times of amount glycol dimethyl ethers or tetrahydrofuran solvent are cooled to-40 ℃, the tetrahydrofuran solution of n-Butyl Lithium is dropped in reaction system, keep-40 ~-50 ℃ and stir 2.5 ~ 3h, drip the triisopropyl boric acid ester, then after-60 ℃ of stirring 1h, allow system naturally be warming up to room temperature, slowly drip Glacial acetic acid, stir 30min, then drip suitable quantity of water, add wherein solvent methanol or ethanol and triethylamine, then add N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine (III) and 10% palladium carbon, reaction system is warming up to reflux temperature, reaction 14h, after being down to room temperature, reaction mixture temperature filters, filter cake spent glycol dme or tetrahydrofuran solvent washing, merging filtrate, concentrated, wherein: described 2-furfural diethyl acetal and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 2.0:1 ~ 4.0:1, described n-Butyl Lithium and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 2.0:1 ~ 3.0:1, described triisopropyl boric acid ester and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1, described triethylamine and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1, described 10% palladium carbon and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-mass ratio of 6-iodo-4-quinazoline amine is 0.1:1 ~ 0.2:1,
Step 2. adds triethylamine and 2-(methylsulfonyl) methyl alcohol or the ethanolic soln of ethamine (V), then stirring at room 1h, add again reductive agent, stirring at room 1.5h, described 2-(methylsulfonyl) ethamine and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1; Described reductive agent is sodium triacetoxy borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE;
step 3. is in the reaction mixture that step 2 obtains, under ice bath is cooling, drip the 5N aqueous sodium hydroxide solution, then stirring at room 15min, standing demix, tell organic phase, drip glycol dimethyl ether or the tetrahydrofuran solution of tosic acid in the organic phase, tosic acid and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 5.0:1 ~ 6.0:1, after stirring 40min, with solid filtering, spent glycol dme or tetrahydrofuran (THF) washing leaching cake, then recrystallization, vacuum-drying, obtain two tosic acid lapatinibditosylates (I).
The present invention compares with art methods, and its remarkable advantage is: the raw material that (1) the present invention selects is cheap and easy to get, and process for purification is easy, and operation is simple, and product yield and purity are all higher.(2) solvent is good to reaction substrate and product solvability, and reaction is thorough, Reaction time shorten, while solvent recoverable, good economy performance.(3) the present invention adopts one kettle way, and aftertreatment is simple, and intermediates need not made with extra care, and is fit to amplify produce.
Embodiment
Embodiment 1
Under nitrogen protection; with 2-furfural diethyl acetal (31.6g; 2.5eq); be transferred in flask with the glycol dimethyl ether of 310mL drying; system is cooled to-40 ℃; tetrahydrofuran solution (106mL with n-Butyl Lithium; 2.2mol/L; 2.5eq) drop in reaction system, keep-40 ~-50 ℃ and stir 2.5 ~ 3h, then drip triisopropyl boric acid ester 51.2mL; then stir 1h relief system at-60 ℃ and naturally be warming up to room temperature; slowly drip the 12.8mL Glacial acetic acid, then stir 30min, then drip 15.5mL water.Add wherein 126mL methyl alcohol, then the 25.9mL triethylamine adds N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine (37.5g, 1eq), then 10% palladium carbon 4.5g is warming up to reflux temperature with reaction system, reaction 14h.After being down to room temperature, reaction mixture temperature filters the washing of filter cake spent glycol dme, merging filtrate.add the 8g triethylamine in filtrate, add again 13 gram 2-(methylsulfonyls) solution of ethamine and 15mL methyl alcohol, then stirring at room 1h, add again sodium triacetoxy borohydride (18g), stirring at room 1.5h, then ice bath cooling under, drip the aqueous sodium hydroxide solution 120mL of 5N, then stirring at room 15min, standing demix, tell organic phase, drip the solution of 80g tosic acid/120mL glycol dimethyl ether in the organic phase, after stirring 40min, with solid filtering, spent glycol dme washing leaching cake, then recrystallizing methanol, vacuum-drying, finally obtain sterling two tosic acid lapatinibditosylate 40.2g.Productive rate 72%, HPLC:98.3%.HNMR(DMSO)2.27(s,6H),3.11(s,3H),3.50(t,2H),3.60(t,2H),4.47(s,2H),5.32(s,2H),6.90(s,1H),7.1(d,J=7.8Hz,4H),7.19(t,1H),7.20(t,1H),7.22(d,J=3.2Hz,1H),7.23-7.25(m,3H),7.56(d,J=8.0Hz,4H),7.62(dd,J1=8.7Hz,J2=8.0Hz,1H),7.87(s,1H),7.91(d,J=8.9Hz,1H),8.42(d,J=8.7Hz,1H),8.93(s,1H),9.03(s,1H),9.32?(s,1H),11.34(s,1H)。
Embodiment 2
Under nitrogen protection; with 2-furfural diethyl acetal 474g, and the tetrahydrofuran (THF) of 4500mL drying is transferred in flask, system is cooled to-40 ℃; tetrahydrofuran solution (1590mL with n-Butyl Lithium; 2.2mol/L) drop in reaction system, keep-40 ~-50 ℃ and stir 2.5 ~ 3h, then drip triisopropyl boric acid ester 768mL; then stir 1h relief system at-60 ℃ and naturally be warming up to room temperature; slowly drip the 192mL Glacial acetic acid, then stir 30min, then drip 78mL water.Add wherein 1890mL ethanol, then the 388mL triethylamine adds N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine 562g, then 10% palladium carbon 68g is warming up to reaction system back flow reaction 14h.Filter after reaction mixture temperature is down to room temperature, filter cake washs with tetrahydrofuran (THF), merging filtrate.add the 120g triethylamine in filtrate, add again the 2-(methylsulfonyl) solution of ethamine 195g and 225mL methyl alcohol, then stirring at room 1h, add again sodium borohydride 48.4g, stirring at room 1.5h, then ice bath cooling under, drip the aqueous sodium hydroxide solution 1800mL of 5N, stirring at room 15min, standing demix, tell organic phase, drip the solution of 1200g tosic acid/1800mL tetrahydrofuran (THF) in the organic phase, after stirring 40min, with solid filtering, use the tetrahydrofuran (THF) washing leaching cake, then recrystallizing methanol, vacuum-drying, finally obtain sterling two tosic acid lapatinibditosylate 590g.productive rate 70.5%, purity 98%.HNMR (DMSO) 2.27(s, 6H), 3.11(s, 3H), 3.50(t, 2H), 3.60(t, 2H), 4.47 (s, 2H), 5.32(s, 2H), 6.90(s, 1H), 7.1(d, J=7.8Hz, 4H), 7.19(t, 1H), 7.20(t, 1H), 7.22(d, J=3.2Hz, 1H), 7.23-7.25(m, 3H), 7.56(d, J=8.0Hz, 4H), 7.62(dd, J1=8.7Hz, J2=8.0Hz, 1H), 7.87(s, 1H), 7.91(d, J=8.9Hz, 1H), 8.42(d, J=8.7Hz, 1H), 8.93(s, 1H), 9.03(s, 1H), 9.32(s, 1H), 11.34(s, 1H).
Embodiment 3
Under nitrogen protection; with 2-furfural diethyl acetal 950g, and the tetrahydrofuran (THF) of 9000mL drying is transferred in flask, system is cooled to-40 ℃; tetrahydrofuran solution (3180mL with n-Butyl Lithium; 2.2mol/L) drop in reaction system, keep-40 ~-50 ℃ and stir 2.5 ~ 3h, then drip triisopropyl boric acid ester 1536mL; then stir 1h relief system at-60 ℃ and naturally be warming up to room temperature; slowly drip the 384mL Glacial acetic acid, then stir 30min, then drip 156mL water.Add wherein 3780mL ethanol, then the 776mL triethylamine adds N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine 1124g, then 10% palladium carbon 134g is warming up to reflux temperature with reaction system, reaction 14h.Filter after reaction mixture temperature is down to room temperature, filter cake washs with tetrahydrofuran (THF), merging filtrate.add the 240g triethylamine in filtrate, add again the 2-(methylsulfonyl) solution of ethamine 390g and 450mL methyl alcohol, then stirring at room 1h, add again POTASSIUM BOROHYDRIDE 137.9g, stirring at room 1.5h, then ice bath cooling under, drip the aqueous sodium hydroxide solution 3600mL of 5N, stirring at room 15min, standing demix, tell organic phase, drip the solution of 2400g tosic acid/3600mL tetrahydrofuran (THF) in the organic phase, after stirring 40min, with solid filtering, use the tetrahydrofuran (THF) washing leaching cake, then recrystallizing methanol, vacuum-drying, finally obtain sterling two tosic acid lapatinibditosylate 1185g.Productive rate 70.8%, purity 98.1%.HNMR(DMSO)2.27(s,6H),3.11(s,3H),3.50(t,2H),3.60(t,2H),4.47(s,2H),5.32(s,2H),6.90(s,1H),7.1(d,J=7.8Hz,4H),7.19(t,1H),7.20(t,1H),7.22(d,J=3.2Hz,1H),7.23-7.25(m,3H),7.56(d,J=8.0Hz,4H),7.62(dd,J1=8.7Hz,J2=8.0Hz,1H),7.87(s,1H),7.91(d,J=8.9Hz,1H),8.42(d,J=8.7Hz,1H),8.93(s,1H),9.03(s,1H),9.32(s,1H),11.34(s,1H)。
Claims (1)
1. the synthetic method of a tosic acid lapatinibditosylate, is characterized in that it comprises the steps:
under step 1. nitrogen protection, 2-furfural diethyl acetal and dry ten times of amount glycol dimethyl ethers or tetrahydrofuran solvent are cooled to-40 ℃, the tetrahydrofuran solution of n-Butyl Lithium is dropped in reaction system, keep-40 ~-50 ℃ and stir 2.5 ~ 3h, drip the triisopropyl boric acid ester, then after-60 ℃ of stirring 1h, allow system naturally be warming up to room temperature, slowly drip Glacial acetic acid, stir 30min, then drip suitable quantity of water, add wherein solvent methanol or ethanol and triethylamine, then add N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-iodo-4-quinazoline amine and 10% palladium carbon, reaction system is warming up to reflux temperature, reaction 14h, after being down to room temperature, reaction mixture temperature filters, filter cake spent glycol dme or tetrahydrofuran solvent washing, merging filtrate, concentrated, wherein: described 2-second furfural and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 2.0:1 ~ 4.0:1, described n-Butyl Lithium and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 2.0:1 ~ 3.0:1, described triisopropyl boric acid ester and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1, described triethylamine and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1, described 10% palladium carbon and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-mass ratio of 6-iodo-4-quinazoline amine is 0.1:1 ~ 0.2:1,
Step 2. adds triethylamine and 2-(methylsulfonyl) methyl alcohol or the ethanolic soln of ethamine, then stirring at room 1h, add again reductive agent, stirring at room 1.5h, described 2-(methylsulfonyl) ethamine and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 1.0:1 ~ 2.0:1; Described reductive agent is sodium triacetoxy borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE;
step 3. is in the reaction mixture that step 2 obtains, under ice bath is cooling, drip the 5N aqueous sodium hydroxide solution, then stirring at room 15min, standing demix, tell organic phase, drip glycol dimethyl ether or the tetrahydrofuran solution of tosic acid in the organic phase, tosic acid and N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-molar ratio of 6-iodo-4-quinazoline amine is 5.0:1 ~ 6.0:1, after stirring 40min, with solid filtering, spent glycol dme or tetrahydrofuran (THF) washing leaching cake, then recrystallization, vacuum-drying, obtain two tosic acid lapatinibditosylates.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310059666XA CN103159747A (en) | 2013-02-26 | 2013-02-26 | Synthetic method of lapatinib |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310059666XA CN103159747A (en) | 2013-02-26 | 2013-02-26 | Synthetic method of lapatinib |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103159747A true CN103159747A (en) | 2013-06-19 |
Family
ID=48583314
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310059666XA Pending CN103159747A (en) | 2013-02-26 | 2013-02-26 | Synthetic method of lapatinib |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103159747A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105503839A (en) * | 2015-12-26 | 2016-04-20 | 神威药业集团有限公司 | Preparing method of lapatinib and preparing method of lapatinib ditosylate |
CN105527349A (en) * | 2014-09-29 | 2016-04-27 | 人福医药集团股份公司 | Analysis and detection method for impurity in lapatinib ditosylate bulk drug |
CN105738544A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for analyzing and detecting lapatinib ditosylate isomer impurities |
CN105738493A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for analyzing lapatinib ditosylate isomer impurities |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999035146A1 (en) * | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
WO2002002552A1 (en) * | 2000-06-30 | 2002-01-10 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
CN101575319A (en) * | 2009-06-18 | 2009-11-11 | 南京医科大学 | Process for preparing lapatinib synthetic intermediate |
WO2012017448A2 (en) * | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
-
2013
- 2013-02-26 CN CN201310059666XA patent/CN103159747A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999035146A1 (en) * | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
WO2002002552A1 (en) * | 2000-06-30 | 2002-01-10 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
CN101575319A (en) * | 2009-06-18 | 2009-11-11 | 南京医科大学 | Process for preparing lapatinib synthetic intermediate |
WO2012017448A2 (en) * | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
Non-Patent Citations (1)
Title |
---|
季兴,等: "拉帕替尼的合成", 《中国医药工业杂志》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105527349A (en) * | 2014-09-29 | 2016-04-27 | 人福医药集团股份公司 | Analysis and detection method for impurity in lapatinib ditosylate bulk drug |
CN105738544A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for analyzing and detecting lapatinib ditosylate isomer impurities |
CN105738493A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for analyzing lapatinib ditosylate isomer impurities |
CN105503839A (en) * | 2015-12-26 | 2016-04-20 | 神威药业集团有限公司 | Preparing method of lapatinib and preparing method of lapatinib ditosylate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103159747A (en) | Synthetic method of lapatinib | |
CN102746210A (en) | Synthesis method for key intermediate of silodosin | |
CN1443168A (en) | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis | |
CN105348257A (en) | Pomalidomide preparation method | |
CN105085395B (en) | Shellfish reaches the preparation method of quinoline | |
CN105085396B (en) | For preparing shellfish up to intermediate of quinoline and its preparation method and application | |
CN103012268B (en) | Novel preparation method for ivabradine | |
CN101928277B (en) | Preparation method of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid, related intermediate and application thereof | |
CN105399793A (en) | Cholanic acid preparation method | |
CN101519374B (en) | Method for synthesizing derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of same | |
CN103145692B (en) | Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone | |
CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
CN114349648A (en) | Preparation method of chiral amine compound | |
CN113980012A (en) | Purification method of emtricitabine | |
CN101875658A (en) | Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester | |
CN103450091A (en) | Imidazole derivatives, preparation method and applications thereof | |
CN107540646B (en) | Synthesis method of vilazodone intermediate | |
CN111892527B (en) | Indole derivatives and synthesis method thereof | |
CN102875499B (en) | The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof | |
CN105073739A (en) | Intermediates for use in the preparation of indazole derivatives and processes for the preparation thereof | |
CN103772282B (en) | A kind of preparation method of the 3-tertiary butyl-1H-pyrazoles-4-formaldehyde | |
CN104193745B (en) | A kind of imidazopyrimidine carboxylic acid compound and preparation method thereof | |
CN104327063B (en) | Acridine oxadiazole derivative, preparation method and uses thereof | |
CN102241649A (en) | Method for preparing tetrahydro-3-furanmethanol | |
CN108558878B (en) | Synthesis process of quinoline and derivatives thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130619 |