CN1814597A - New method for preparing voriconazole - Google Patents

New method for preparing voriconazole Download PDF

Info

Publication number
CN1814597A
CN1814597A CN 200510127699 CN200510127699A CN1814597A CN 1814597 A CN1814597 A CN 1814597A CN 200510127699 CN200510127699 CN 200510127699 CN 200510127699 A CN200510127699 A CN 200510127699A CN 1814597 A CN1814597 A CN 1814597A
Authority
CN
China
Prior art keywords
formula
acid
compound
reaction
salt
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
Application number
CN 200510127699
Other languages
Chinese (zh)
Inventor
黄维宣
崔东冬
郭金华
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.)
FENGDE MEDICINE SCIENCE-TECHNOLOGY Co Ltd BEIJING
Original Assignee
FENGDE MEDICINE SCIENCE-TECHNOLOGY Co Ltd BEIJING
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 FENGDE MEDICINE SCIENCE-TECHNOLOGY Co Ltd BEIJING filed Critical FENGDE MEDICINE SCIENCE-TECHNOLOGY Co Ltd BEIJING
Priority to CN 200510127699 priority Critical patent/CN1814597A/en
Publication of CN1814597A publication Critical patent/CN1814597A/en
Pending legal-status Critical Current

Links

Abstract

The invention relates to preparation formula I compound and its salt accepted in pharmacology.

Description

A kind of novel method for preparing voriconazole
Technical field
The present invention relates to prepare the novel method of voriconazole.
Background technology
Since the eighties; the sickness rate of deep fungal infection is rising year by year; especially high-risk patient's such as immunosuppression increase; and resistance fungi and the more prevalent of fungi newly occur; significantly changed the popularity of deep fungal infection; infection as aspergillus tubigensis and other moulds constantly increases, and non-Candida albicans becomes the major cause of monilial infection.Make people press for the high deep fungal infection of a kind of more effective novel antifungal drug antagonism mortality ratio.
Voriconazole (Voriconazole) is the novel antifungal triazole new drug of center institute of Pfizer exploitation, is the analog of fluconazole.SARS wreaked havoc during the Chinese the earth in 2003, SARS patient's life in the deep fungal infection serious threat, Pfizer has offered Beijing and 600 voriconazoles of Shanghai City government (prestige is all), makes clinical expert be saved the life that how SARS merge the deep fungal infection patient! The curative effect of the brilliance that prestige is all and good security obtain the approval of clinical expert! Voriconazole success is at present gone on the market in China.
But the voriconazole specificity suppresses 14-α-sterol demethyl enzyme, and biosynthesizing has better restraining effect to ergosterol, and the anti-microbial activity of anti-aspergillus tubigensis and other pathomycetes obviously strengthens, and pharmacokinetics is more superior.The antimicrobial spectrum of voriconazole is obviously widened, and aspergillus tubigensis and other moulds are had very strong killing action; Anti-microbial activity strengthens, and external anti-candida activity is 10 ~ 100 times of fluconazole, and resistance candidiasis such as candida krusei are also had clearly anti-microbial effect.In a comparative research, treatment aggressive aspergillin infection aspergillin infection patient accepts voriconazole (n=144) or amphotericin B (n=133) treatment at random, looks back the council (DRC) assess patient by data and whether treats success.Result after 12 weeks shows that treating successful patient's ratio is 53% in the voriconazole group, and the amphotericin B group only is 32% (P<0.0001).Two groups of patients' survival rate is also significantly different, and voriconazole group patient's survival rate is 71%, and the amphotericin B group is 58%, and antipode is up to 13%.Because of aspergillin infection caused directly or associated death be 13% in the voriconazole group, the amphotericin B group is 19% (P<0.001).Treat emerging rare fungi infestation to rare deep fungal infection, as the especially most advanced and sophisticated sufficient actinomycetes of sufficient actinomycetes, the efficient of voriconazole reaches 59%, even to having the sickle mycete disease of the non-constant of antifungal drug curative effect now, the success ratio of voriconazole still can reach 40%.
In a word, voriconazole have that curative effect height, toxic side effect are little, better tolerance and the advantage that has no drug resistance.This will select for clinical treatment provides a kind of new better selection for serious deep fungal infection patient brings glad tidings.
The present invention relates to (2R, 3S)-new preparation process of 2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol (voriconazole).Patent of invention CN1040504C has reported with 4-chloro-6-ethyl-5-fluorine pyrimidine and 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone, in the presence of diisopropylamine lithium, in-70 ℃ react key intermediate 3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2, the 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-Ding-2-alcohol, then through the dechlorination of palladium carbon catalysis hydrogenolysis, after 1R-(-)-10-camphorsulfonic acid split voriconazole.Patent WO9706160 discloses with organic zinc reagent and has existed down with 4-chloro-6-(1-bromotrifluoromethane)-5-fluorine pyrimidine and 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone in suitable organic solvent such as tetrahydrofuran (THF), react (2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2, the 4-difluorophenyl)-1-(1H-1,2, the 4-triazol-1-yl)-Ding-2-alcohol, then salify purifying, after the dechlorination of palladium carbon catalysis hydrogenolysis, after 1R-(-)-10-camphorsulfonic acid split voriconazole.Patent CN147825A discloses with 4-chloro-6-(1-bromotrifluoromethane)-5-fluorine pyrimidine and 1-(2 under the lewis acid effect of zinc, the 4-difluorophenyl)-2-(halo-1H-1,2, the 4-triazol-1-yl) ethyl ketone reacts in suitable organic solvent such as tetrahydrofuran (THF), get (2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2, the 4-difluorophenyl)-1-(halo-1H-1,2, the 4-triazol-1-yl)-and Ding-2-alcohol, after the dechlorination of palladium carbon catalysis hydrogenolysis also gets voriconazole after 1R-(-)-10-camphorsulfonic acid splits.Last in sum method need be used cold condition (60 ℃ to-70 ℃) and hydrogenation hydrogenation, brings many inconvenience to suitability for industrialized production.Need explore the voriconazole novel synthesis, to reduce production costs for this reason.
Summary of the invention
The present invention relates to have the active triazole derivative of antifungal drug, promptly about (2R, 3S)-new preparation process of 3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-Ding-2-alcohol.Its chemical structural formula is suc as formula shown in (I):
Formula (I)
According to the 4-ethyl-5 fluorine pyrimidine or derivatives thereof azoles that we directly are selected from the market in the process of the method disclosed in the present preparation formula (I) compound is starting raw material, through many halos, again under lewis acid acid effect with 1-(2, the 4-difluorophenyl)-2-(1H-1,2,4-triazole-1 one base) condensation of ethyl ketone or derivatives thereof.Allow the people pleasantly surprised be that how halogenated halogen after the condensation does not exist and significantly improved yield, so not only solved the difficult problem of suitability for industrialized production and well avoided before patent CN1040504C, patent WO9706160 and all restrictions among the patent CN147825A.
The following route of said preparation formula (I) compound or its pharmaceutically useful salt:
Formula (II) formula (III)
Formula III formula (IV) formula V formula (I)
1. formula (III) is directly obtained through many halos by formula (II) compound, for example the amount used such as Chang Yong halo agent NBS, CBS, bromine and chlorine element 2 to 5 times of molar equivalents preferably.
2. formula (III) compound and formula (IV) compound, at zinc, iodine and/or Lewis acid, react in the proton-inert organic solvent the formula V compound.
X in the formula 1And X 2The group that can remove by reduction reaction for hydrogen, chlorine, bromine, iodine or other.
Y 1And Y 2Independently be selected from chlorine, bromine or iodine respectively, particularly preferred Y 1And Y 2Be bromine simultaneously.
Z 1And Z 2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by the reduction reaction selectivity respectively, particularly preferred Z 1And Z 2Be hydrogen or chlorine.
Preferred formula (II) compound is 4-ethyl-5 a fluorine pyrimidine.
Preferred formula (III) compound is 4-(1,1-two bromotrifluoromethanes)-5-fluorine pyrimidine.
Preferred formula (IV) compound is 1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) ethyl ketone.
Preferred formula V compound be (2R, 3S/2S, 3R)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol.
Formula V
X in the formula 1, X 2, R 1And R 2Definition respectively as mentioned above.
3. also use lead, copper or other heavy metal in the formula V process, wherein preferred heavy metal is plumbous, and its usage quantity is about 5% equivalent, need use Lewis acid such as zinc chloride, zinc bromide or zinc iodide in addition, and preferred Lewis acid is a zinc bromide.Employed proton-inert organic solvent is tetrahydrofuran (THF), glycol dimethyl ether, 1, and 4-dioxane, methylene dichloride, toluene or other non-proton inert organic solvents need with drying treatment such as sodium silks as these organic solvents uses are last.
4. the formula V compound is changed into its acid salt purification process.Its method is known by the worker of this area.Prepared acid salt is spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, R-(-)-10-camphorsulfonic acid, (+)-3-bromo-10-camphorsulfonic acid, (-)-3-bromo-10-camphorsulfonic acid, phosphoric acid, to methylsulfonic acid or benzene sulfonate, preferably hydrogen chlorate.
5. the acid salt of formula V compound or formula V compound gets formula (I) compound by reduction reaction, and described reduction reaction is catalytic hydrogenolysis or transfer catalysis hydrogenolysis.The also available transfer catalysis hydrogenolysis preparation of formula V compound is for example used palladium carbon catalyst, ammonium formate to reflux and can be obtained formula (I) compound.In the present invention, preparation formula (I) compound does not need hydrogenation by preferred compound, and through type (III) compound and the coupling of formula (IV) compound obtain, and have avoided bottleneck and unsafe factor in this industrial production of hydrogenation.
6. formula (I) compound and optical activity acid-respons are got diastereoisomeric salt, split the enantiomorph that promptly gets formula (I) compound through fractional crystallization, wherein preferred optical activity acid is 1S-(+) or 1R-(-)-10-camphorsulfonic acid.
The formula that described preparation method makes (I) compound or pharmaceutically acceptable salt thereof for (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol.
Embodiment
The preparation of embodiment 1.4-(1,1-two bromotrifluoromethanes)-5-fluorine pyrimidine
In the three neck round-bottomed flasks of 3000ml, add 300g 4-ethyl-5-fluorine pyrimidine, the 5g benzoyl peroxide, the 1500ml methylene dichloride adds 1000g N-bromo-succinimide at twice, and slowly reflux is 15 hours.Be cooled to 10 ℃ at ice bath then, filter.With 500ml washed with dichloromethane solid, merging filtrate, add the 1000ml saturated aqueous solution of sodium bicarbonate and stirred 30 minutes, tell dichloromethane layer more once, 500ml washing, anhydrous magnesium sulfate drying with the washing of 500ml sodium bicarbonate aqueous solution.Filter, concentrated evaporate to dryness gets 564g reddish-brown oily matter, yield 83.4%.Mass spectrum (FAB) 285 (M+1).
Embodiment 2. (2R, 3S/2S, 3R)-preparation of 3-(5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol hydrochloride
In the 2000ml round-bottomed flask, add the 100g zinc powder, the 5g lead powder, the 100ml tetrahydrofuran (THF) refluxed 2 hours, under the ice bath cooling, dripped 90g iodine and 100ml tetrahydrofuran solution, control adding speed, temperature is no more than 40 ℃ in making.Be cooled to below-10 ℃, drip the mixing solutions of the 200ml tetrahydrofuran (THF) of 80g 1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) ethyl ketone and 130g 4-chloro-6-(1,1-two bromotrifluoromethanes)-5-fluorine pyrimidine, controlled temperature is below-5 ℃.Finish, 0 ℃ was stirred 2 hours.Add the 60ml Glacial acetic acid, add 1000ml water then, stir half an hour after, transfer pH8 with yellow soda ash again, filter, filtrate decompression concentrates evaporate to dryness, adds the 2000ml acetic acid ethyl dissolution, the 500ml washing, the 5ml EDTA disodium salt aqueous solution with 5% is washed 2 times, washes anhydrous sodium sulfate drying 1 time.Filter, the Virahol saturated solution 20ml that filtrate adds hydrogenchloride separates out white solid, filters, and gets condensation product 136g, productive rate 95.5%.m.p.130-132℃。Ultimate analysis C 16H 14F 3N 5O calculated value: C55.01%, H4.01%, N20.06%, F16.33%; Measured value: C55.23%, H4.15%, N19.94%, F16.17%.Mass spectrum (FAB) 350 (M+1).Hydrogen nuclear magnetic resonance spectrum (DMSO-d 6) δ 9.038 (d, J=2.7, Hz, 1H), 8.847 (d, J=1.8Hz, 1H), 8.227 (s, 1H), 7.609 (s, 1H), 7.261 (m, 1H), 7.177 (m, 1H), 6.916 (m, 1H), 5.973 (s, 1H), 4.797 (d, J=14.5Hz, 1H), 4.336 (d, J=14.5Hz, 1H), 3.925 (q, J=7.1Hz, 1H), 1.109 (d, J=7.1Hz, 1H).
Embodiment 3. (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-preparation of 2-alcohol R-(-)-10-camsilate half methyl alcohol compound
In the round-bottomed flask of 3000ml, add 100g (2R, 3S/2S, 3R)-2-(2, the 4-difluorophenyl)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol, 2100ml acetone, 700m methyl alcohol, solid have dissolved the back and have added the 50.0g l-camphor sulfonic acid, there is a large amount of white solids to separate out, stirs after 2 hours suction filtration, with acetone/methanol (3: 1) solution washing, dry white crystals 62.5g, the productive rate 36.5% of getting, m.p.182-184 ℃, [a] D 25-54 ° (2mg/ml methyl alcohol).Ultimate analysis C 26H 30F 3N5O 5S1/2CH 3OH calculated value: C53.27%H5.36% N11.73% S5.36% F9.55%; Measured value: C53.38% H5.25% N11.81% S5.44%F9.71%.Mass spectrum (FAB) 350 (M+1).
Embodiment 4. (2R, 3S)-preparation of 2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol (voriconazole)
In the three neck round-bottomed flasks of 1000ml, and adding 60g (2R, 3S)-2-(2, the 4-difluorophenyl)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate half methyl alcohol compound, 180ml water, the 180ml methylene dichloride is after being stirred to solid and dissolving fully, add the 4N sodium hydroxide solution and transfer pH9, continue to stir 1 hour, take out then and tell organic layer, water layer is used dichloromethane extraction 1 time again, merge organic layer, wash anhydrous sodium sulfate drying 3 times.Filter, concentrate, the Virahol recrystallization gets the 37.5g white crystals, productive rate 92%, m.p.131-132 ℃.[a] D 25-62 ° (1mg/ml methyl alcohol).Ultimate analysis C 16H 14F 3N 5O calculated value: C55.01% H4.01% N20.05% F16.32%; Measured value: C55.02% H3.88% N20.23% F16.25%.Mass spectrum (EI) 350.1243 (M+1), 349.1143,268.0789,224.0647,182.0537,141.0135,125.0566,83.0502.Hydrogen nuclear magnetic resonance spectrum (DMSO-d 6) δ 9.0554 (d, J=2.7Hz, 1H), 8.862 (d, J=2.0Hz, 1H), 8.242 (s, 1H), 7.624 (s, 1H), 7.283 (m, 1H), 7.192 (m, 1H), 6.927 (m, 1H), 6.00 (s, 1H), 4.817 (d, J=14.3Hz, 1H), 4.352 (d, J=14.3Hz, 1H), 3.941 (q, J=7.1Hz, 1H), 1.123 (d, J=7.1Hz, 1H).

Claims (13)

1. the method for preparation formula (I) compound and formula (I) compound pharmacy acceptable salt.
The following route of said preparation formula (I) compound or its pharmaceutically useful salt:
X in the formula 1And X 2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by reduction or other correlated responses respectively;
Y 1And Y 2Independently be selected from chlorine, bromine, iodine or alkyl sulfonic ester respectively;
Z 1And Z 2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by reduction or other correlated responses respectively;
(a) formula (III) compound is prepared through halogenating reaction by corresponding pyrimidine derivatives;
(b) make the reaction of formula (III) compound and formula (IV) compound, in zinc, iodine and/or Lewis acid and non-proton inert organic solvents, react, obtain the formula V compound;
(c) transforming the formula V compound is its acid salt;
(d) reduction formula V compound or its acid salt obtain formula (I) compound;
(e) conversion type (I) compound is its acid salt.
2. method according to claim 1 wherein can be selected identical or different halo agent or sulfonylation agent, preferentially selects bromine, NBS, chlorine element or CBS.
3. method according to claim 1 is wherein used lead, copper or other heavy metal in the reaction process (b).
4. according to the described method of claim 1, wherein use iodine in the reaction process (b).
5. according to the described method of claim 1, wherein the Lewis acid that uses in the reaction process (b) is zinc chloride, zinc bromide or zinc iodide.
6. according to the described method of claim 1, wherein the non-proton inert organic solvents that uses in the reaction process (b) is tetrahydrofuran (THF), glycol dimethyl ether, 1,4-dioxane, methylene dichloride, toluene or other non-proton inert organic solvents.
7. according to the described method of claim 1, wherein prepared acid salt is spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, R-(-)-10-camphorsulfonic acid, (+)-3-bromo-10-camphorsulfonic acid, (-)-3-bromo-10-camphorsulfonic acid, phosphoric acid or alkylsulfonate in the reaction process (c), and preferred salt is the hydrogen chlorate.
8. according to the described method of claim 1, wherein the reduction reaction described in the reaction process (d) is catalytic hydrogenolysis or transfer catalysis hydrogenolysis.
9. described according to Claim 8 method, wherein said catalytic hydrogenolysis is used palladium carbon catalyst, carries out described reduction reaction by the hydrogenolysis method.
10. described according to Claim 8 method, wherein said transfer catalysis hydrogenolysis is used palladium carbon catalyst, and formate carries out described reduction reaction.
11. according to the described method of claim 9, wherein also have acid absorber, particularly preferably be sodium acetate.
12. according to the described method of claim 1, wherein the acid salt that makes in the reaction process (d) is S-(+)-or R-(-)-10-camsilate.
13. according to the described method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof that makes of compounds process for production thereof for (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol or its salt.
CN 200510127699 2005-12-09 2005-12-09 New method for preparing voriconazole Pending CN1814597A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200510127699 CN1814597A (en) 2005-12-09 2005-12-09 New method for preparing voriconazole

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200510127699 CN1814597A (en) 2005-12-09 2005-12-09 New method for preparing voriconazole

Publications (1)

Publication Number Publication Date
CN1814597A true CN1814597A (en) 2006-08-09

Family

ID=36906976

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200510127699 Pending CN1814597A (en) 2005-12-09 2005-12-09 New method for preparing voriconazole

Country Status (1)

Country Link
CN (1) CN1814597A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020323A3 (en) * 2007-08-06 2009-04-09 Hanmi Pharm Ind Co Ltd Process for preparing voriconazole
WO2011110198A1 (en) 2010-03-10 2011-09-15 Synthron B.V. A process for making voriconazole
CN106117186A (en) * 2016-06-12 2016-11-16 重庆莱美隆宇药业有限公司 A kind of voriconazole and the preparation method of intermediate thereof
CN110305113A (en) * 2019-07-05 2019-10-08 镇江市第四人民医院(镇江市妇幼保健院) A kind of synthetic method of voriconazole impurity B

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020323A3 (en) * 2007-08-06 2009-04-09 Hanmi Pharm Ind Co Ltd Process for preparing voriconazole
US8263769B2 (en) 2007-08-06 2012-09-11 Hanmi Science Process for preparing voriconazole
WO2011110198A1 (en) 2010-03-10 2011-09-15 Synthron B.V. A process for making voriconazole
CN106117186A (en) * 2016-06-12 2016-11-16 重庆莱美隆宇药业有限公司 A kind of voriconazole and the preparation method of intermediate thereof
CN106117186B (en) * 2016-06-12 2018-08-24 重庆莱美隆宇药业有限公司 A kind of preparation method of voriconazole and its intermediate
CN110305113A (en) * 2019-07-05 2019-10-08 镇江市第四人民医院(镇江市妇幼保健院) A kind of synthetic method of voriconazole impurity B

Similar Documents

Publication Publication Date Title
EP3601268B1 (en) Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
WO2008018822A1 (en) Chemical process for preparation of aromatic cyclopropane esters and amides
CN1473825A (en) Process for preparing voriconazole
EP1871750A1 (en) Improved process for the preparation of letrozole
EP2609099A2 (en) Sitagliptin, salts and polymorphs thereof
CN1814597A (en) New method for preparing voriconazole
CN104640864A (en) Ticagrelor adducts with divalent metal salts
CN100579977C (en) Method for producing antifungal drug in triazole class
CN105985329B (en) Novel preparation method of posaconazole compound
CN1488630A (en) Method for preparing triazole antifungal agent
CN103254191B (en) Substituted aroma four lopps antifungal compound and preparation method thereof and application
EP2703409B1 (en) Intermediate for synthesizing caspofungin and preparation method therefor
EP3159343B1 (en) Improved process for the preparation of triazole and salt thereof
CN103265559A (en) Substituted tricyclo-quinone compounds, and preparation method and application thereof
JP3407088B2 (en) Method for producing triazole derivative and intermediate thereof
EP3424927B1 (en) Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid
AU2005284330B2 (en) Method for manufacturing enantiomeric imidazole compounds
CN107353256B (en) Method for synthesizing 4-acetyl-1, 2, 3-triazole compound by one-pot method
CN111423380A (en) Preparation method of clotrimazole
WO2006128688B1 (en) Process for the preparation of pramipexole
CN103265525A (en) Substituted thieno-quinone compounds, and preparation method and application thereof
CN112480172A (en) Use of borane-pyridine complexes for the preparation of pharmaceutical compounds
CN111499519A (en) N-benzyl aniline derivative and preparation method and application thereof
EP1124826A1 (en) Process for the preparation of 2-(r)-(1- (r)-(3,5-bis (trifluoromethyl) phenyl)ethoxy) -4-((5-dimethylaminomethyl) -1,2,3-triazol -4-yl)methyl) -3-(s)-(4- fluorophenyl) morpholine
CN101328167B (en) Preparation of losartan

Legal Events

Date Code Title Description
PB01 Publication
C06 Publication
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
DD01 Delivery of document by public notice

Addressee: Wen Ying

Document name: Deemed as a notice of withdrawal (Trial)

C57 Notification of unclear or unknown address
WD01 Invention patent application deemed withdrawn after publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)