CN105777740A - Preparation method of isavuconazole and isavuconazole prepared through method - Google Patents

Preparation method of isavuconazole and isavuconazole prepared through method Download PDF

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CN105777740A
CN105777740A CN201610099742.3A CN201610099742A CN105777740A CN 105777740 A CN105777740 A CN 105777740A CN 201610099742 A CN201610099742 A CN 201610099742A CN 105777740 A CN105777740 A CN 105777740A
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saperconazole
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CN105777740B (en
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刘可
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Suzhou Genespots Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J35/00—Catalysts, in general, characterised by their form or physical properties
    • B01J35/19—Catalysts containing parts with different compositions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention relates to a preparation method of isavuconazole and isavuconazole prepared through the method.The preparation method comprises the following steps that 1, diflurophenyl acetylchloride, triazole, CuI, potassium carbonate and first organic solvent are sequentially added into a reaction kettle, reacting under stirring is performed at the temperature of 80 DEG C-100 DEG C, and then purifying is performed to obtain a first product; 2, propionitrile, a catalyst and second organic solvent are added into a reaction container, the temperature is lowered to minus 20 DEG C-minus 5 DEG C, the second organic solvent containing the first product is dropwise added, reacting and purifying are performed to obtain a second product, and a mixture composed of C-9 primary amine quinine and copper pigment alkali is adopted as the catalyst; 3, the second product is added into another reaction container, diethylphosphorodithioate, water and mixed isopropanol solvent are added into the reaction container, heating is performed until the temperature is increased to 80 DEG C-90 DEG C, reacting under stirring and purifying are sequentially performed, and a third product is obtained; 4, the third product, 2-bromo-4'-acetylbenzonitrile and third organic solvent are mixed, react under stirring at the temperature of 60 DEG C-70 DEG C and then purified, and the isavuconazole is obtained.Accordingly, a novel synthetic route is redesigned, and the reaction steps are reduced.

Description

The preparation method of a kind of Saperconazole that ends and the Chinese mugwort Saperconazole prepared by it
Technical field
The invention belongs to drug world, relate to a kind of Chinese mugwort Saperconazole, be specifically related to a kind of Saperconazole that ends preparation method and The Chinese mugwort Saperconazole prepared by it.
Background technology
Over nearly 20 years, due to hematopoietic stem cell transplantation, solid organ transplantation, chemotherapy of tumors, broad ectrum antibiotic and sugar cortex Hormone, the extensive application of immunosuppressant, the prevalence of invasive infections with fungi is notable ascendant trend.Invasive infections with fungi Main by caused by Candida and Eurotium, its Susceptible population is immunocompromised patients, mostly occurs in blood, ICU, transplanting And breathe and infect field, wherein hematology patient, the proportion such as bone marrow transplantation, leukemia and Lymphoma accounts for 61%, infect and respiratory diseases accounts for 17%, be mainly grouped as the patient of acquired immune deficiency syndrome (AIDS), respiratory failure and immunologic hypofunction. Domestic clinical research shows, in patients with hematopoietic stem cells transplantation, the sickness rate of invasive infections with fungi is 7%-14%；ICU leads Territory invasive infections with fungi accounts for the 8%-15% of hospital acquired infections；The proportion of ICU and transplant patient accounts for 15%, mostly is real The patient of body organ transplantation, major surgery and parenteral alimentation.
(Chinese mugwort Saperconazole sulfuric ester) was the water-soluble prodrug of triazole Chinese mugwort Saperconazole, for treatment 18 weeks Year the aggressive aspergillin infection of above patient and aggressive Mucor infection.Chinese mugwort Saperconazole sulfuric ester is triazole antifungal The prodrug of medicine Chinese mugwort Saperconazole, Chinese mugwort Saperconazole is by the 14-α-Mai Mao sterol demethylation in suppression cytochrome P 450 Enzyme system Enzyme thus suppress the synthesis of fungal cell membrane important composition composition ergosterol so that fungal cell membrane chemical composition change, film Dysfunction, permeability increases, and intracellular fluid is excessive, and then reaches the antibacterial and effect of sterilization.Existing Chinese mugwort Saperconazole sulphuric acid In the preparation method of ester, processing step is various, it is meant that productivity reduces, and cost significantly rises.If able to reduce its synthesis step Suddenly, it is possible to greatly reduce its response time, thus improve production efficiency；And productivity can be improved, drop high yield, then can Manufacturing enterprise is had the advantage status in the market competition.
Summary of the invention
The invention aims to overcome the deficiencies in the prior art to provide the preparation method of a kind of Saperconazole that ends.
For reaching above-mentioned purpose, the technical solution used in the present invention is: the preparation method of a kind of Saperconazole that ends, it include with Lower step:
A () is sequentially added into difluorophenyl chloroacetic chloride, triazole, CuI, potassium carbonate and the first organic solvent in reactor, The first product is purified to obtain after 80～100 DEG C of stirring reactions；
B () adds propionitrile, catalyst, the second organic solvent in reaction vessel, be cooled to-20～-5 DEG C, and dropping contains Second organic solvent of the first product, reaction purifies to obtain the second product；Described catalyst is C-9 primary amine quinine and coppery element The mixture of alkali composition；
C second product is added in another reaction vessel by (), add phosphordithiic acid diethylester, water and isopropanol mixing molten Agent, is heated to 80～90 DEG C, purifies to obtain third product after stirring reaction；
D bromo-with 2-for third product 4 '-cyano-acetophenone, the 3rd organic solvent are mixed by () after, anti-60～70 DEG C of stirrings Purify after should.
Optimally, the mixing that described catalyst is C-9 primary amine quinine and coppery element alkali is 1: 1 composition in molar ratio Thing.
Further, in step (a), the mol ratio of described difluorophenyl chloroacetic chloride, triazole, CuI and potassium carbonate is 1: 1 ～1.2: 0.1～0.15: 1.1～1.5.
Further, in described step (a), after 80～100 DEG C of stirring reactions 8～10 hours, cross leaching filtrate, decompression Reclaim the first organic solvent and obtain residue, obtain the first product by re-crystallizing in ethyl acetate.
Further, in described step (b), before being cooled to-20～-5 DEG C, it is additionally added benzoic acid, the first product, third Nitrile, catalyst and benzoic mol ratio are 1: 3～5: 0.1～0.2: 0.1～0.2.
Further, in described step (b), after dropping is containing the second organic solvent of the first product, add hydrochloric acid Reaction, is extracted with ethyl acetate repeatedly, merges organic facies, is dried with anhydrous sodium sulfate, and after filtration, rotary evaporation removes acetic acid second Ester, with the normal heptane that volume ratio is 1: 1 and dichloromethane recrystallization, is dried to obtain the second product after filtration.
Further, in described step (c), the second product and the phosphordithiic acid diethylester that mol ratio is 1: 4～5 is added Enter in another reaction vessel, add water and isopropyl alcohol mixed solvent that volume ratio is 1: 1, little 80～90 DEG C of reactions 15～20 Time；Being cooled to 0～5 DEG C again, dropping mass concentration is the sodium bicarbonate solution cancellation reaction of 5～10%, is extracted with ethyl acetate Repeatedly, wash with saturated sodium bicarbonate solution, water and saturated aqueous common salt respectively after merging organic facies, take organic facies anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes ethyl acetate, with recrystallisation from isopropanol, is dried to obtain third product after filtration.
Further, in described step (d), by third product and the bromo-4 '-cyano group of 2-that mol ratio is 1: 1.05～1.1 After 1-Phenylethanone. adds in the 3rd organic solvent, 60～70 DEG C of stirring reactions 2～5 hours；And with triethylamine regulation pH to 3.5～ 4, it is cooled to room temperature at 1～2 hour after being cooled to 50～58 DEG C of stirrings 0.5 hour, and is stirred at room temperature 5～10 hours, mistake After filter, filter cake volume ratio is ethanol and the water mixed solvent washing of 1: 1, is dried.
A further object of the present invention is to provide a kind of Chinese mugwort Saperconazole, and it is prepared by any of the above-described method.
Owing to technique scheme is used, the present invention compared with prior art has the advantage that the present invention ends Saperconazole Preparation method, on the one hand redesigned new synthetic route, decreased reactions steps, advantageously reduce cost and improve product The yield of product；On the other hand C-9 primary amine quinine and the catalyst of coppery element alkali composition are used, it is achieved that propionitrile asymmetric Synthesis, breaches existing defect.
Accompanying drawing explanation
Accompanying drawing 1 ends for the present invention process chart of preparation method of Saperconazole.
Detailed description of the invention
Below in conjunction with accompanying drawing embodiment, the present invention is further described.
Embodiment 1
The present invention provides the preparation method of a kind of Saperconazole that ends, as it is shown in figure 1, it comprises the following steps:
(a) be sequentially added in reactor 1mol difluorophenyl chloroacetic chloride, 1.2mol triazole, 0.15molCuI, 1.5mol potassium carbonate and 0.8L DMF (DMF), be warming up to 80 DEG C of stirring reactions 10 hours, TLC (thin layer color Spectrometry) after detection reaction completely；Crossing leaching filtrate, carry out concentrating under reduced pressure and reclaim DMF, residue then obtains by re-crystallizing in ethyl acetate Off-white color solid, the i.e. first product, productivity 73%；
B (), in three neck reaction bulbs, addition 4mol propionitrile, 0.1mol catalyst (comprise 0.05mol C-9 primary amine quinine Alkali, chemical formula isWith 0.05mol coppery element alkali, chemical formula is)、 0.1mol benzoic acid and 0.5LN, N-dimethyl acetylamide (DMA), it is cooled to-10 DEG C, agitation and dropping contains 1mol the first product 0.3L N,N-dimethylacetamide solution, react 8 hours at-10 DEG C, after TLC detection reaction completely, adding concentration is The hydrochloric acid 0.3L cancellation reaction of 1mol/L, extracts three times by 0.2L ethyl acetate, merges organic facies, be dried with anhydrous sodium sulfate, Concentrating under reduced pressure, gained grease normal heptane/dichloromethane (volume ratio 1: 1) recrystallization, filtration drying obtains off-white color solid, i.e. Second product, yield 80%, dr. is 97: 3；
C () adds 1mol the second product, 4mol phosphordithiic acid diethylester, 0.6L water and 0.6L in three neck reaction bulbs different Propanol solvent mixture, is heated to 80 DEG C, stirring reaction 20 hours, is cooled to 0 DEG C after TLC detection reaction completely, and dropping quality is dense Degree is the sodium bicarbonate solution 0.4L of 5%, then extracts three by 0.3L ethyl acetate, merges organic facies, uses 0.1L unsaturated carbonate Hydrogen sodium, 0.1L water, 0.1L saturated aqueous common salt washed once successively, and organic facies anhydrous sodium sulfate is dried, sucking filtration, concentration；? 0.3L recrystallisation from isopropanol, stirs 1 hour at 0 DEG C of crystallize, sucking filtration third product, yield 60%；
D () adds 1mol third product, the bromo-4 '-cyano-acetophenone of 1.05mol 2-and 0.3L in three neck reaction bulbs The ethanol (i.e. 95 ethanol) of 95%, adding volume ratio after 60 DEG C of stirring reactions 2 hours, TLC detection reaction completely is the water of 1: 1 With the mixed solvent of 95 ethanol, being heated to 55 DEG C, adding triethylamine regulation pH is 4, is cooled to 50 DEG C and stirs 0.5 hour, subsequently 2 Being down to room temperature about hour, be stirred at room temperature 10 hours, after filtration, filter cake volume ratio is water and the mixing of 95 ethanol of 1: 1 Solvent washs, and is placed in baking oven and is dried, yield 70%.
Embodiment 2
The present embodiment provides the preparation method of a kind of Saperconazole that ends, basically identical, no with embodiment 1 of its preparation process With: in step (b), not adding benzoic acid, the yield of final second product is 75%, and dr. is 95: 5.
Embodiment 3
The present embodiment provides the preparation method of a kind of Saperconazole that ends, basically identical, no with embodiment 1 of its preparation process With: in step (b), in catalyst, C-9 primary amine quinine is 5: 1 with the mol ratio of coppery element alkali, final second product Yield be 76%, dr. is 95: 5.
Embodiment 4
The present embodiment provides the preparation method of a kind of Saperconazole that ends, basically identical, no with embodiment 1 of its preparation process With: in step (b), in catalyst, C-9 primary amine quinine is 1: 5 with the mol ratio of coppery element alkali, final second product Yield be 73%, dr. is 95: 5.
Embodiment 5
The present embodiment provides the preparation method of a kind of Saperconazole that ends, and it comprises the following steps:
A () is sequentially added into 1mol difluorophenyl chloroacetic chloride, 1.1mol triazole, 0.1molCuI, 1.2mol in reactor Potassium carbonate and 0.8L DMF (DMF), be warming up to 100 DEG C of stirring reactions 8 hours, and TLC (thin layer chromatography) examines After measured reaction is complete；Crossing leaching filtrate, carry out concentrating under reduced pressure and reclaim DMF, residue then obtains off-white color by re-crystallizing in ethyl acetate Solid, the i.e. first product, productivity 70%；
B (), in three neck reaction bulbs, addition 3mol propionitrile, 0.2mol catalyst (comprise 0.1mol C-9 primary amine quinine Alkali, chemical formula isWith 0.1mol coppery element alkali, chemical formula is)、 0.2mol benzoic acid and 0.5LN, N-dimethyl acetylamide (DMA), it is cooled to-10 DEG C, agitation and dropping contains 1mol the first product 0.3L N,N-dimethylacetamide solution, react 8 hours at-5 DEG C, after TLC detection reaction completely, addition concentration is 1mol/ The hydrochloric acid 0.3L cancellation reaction of L, extracts three times by 0.2L ethyl acetate, merges organic facies, be dried with anhydrous sodium sulfate, reduce pressure dense Contracting, gained grease normal heptane/dichloromethane (volume ratio 1: 1) recrystallization, filtration drying obtains off-white color solid, and i.e. second produces Thing, yield 70%, dr. is 95: 5；
C () adds 1mol the second product, 5mol phosphordithiic acid diethylester, 0.6L water and 0.6L in three neck reaction bulbs different Propanol solvent mixture, is heated to 80 DEG C, stirring reaction 20 hours, is cooled to 0 DEG C after TLC detection reaction completely, and dropping quality is dense Degree is the sodium bicarbonate solution 0.4L of 5%, then extracts three by 0.3L ethyl acetate, merges organic facies, uses 0.1L unsaturated carbonate Hydrogen sodium, 0.1L water, 0.1L saturated aqueous common salt washed once successively, and organic facies anhydrous sodium sulfate is dried, sucking filtration, concentration；? 0.3L recrystallisation from isopropanol, stirs 1 hour at 0 DEG C of crystallize, sucking filtration third product, yield 60%；
D () adds 1mol third product, the bromo-4 '-cyano-acetophenone of 1.1mol 2-and 0.3L in three neck reaction bulbs The ethanol (i.e. 95 ethanol) of 95%, adding volume ratio after 60 DEG C of stirring reactions 2 hours, TLC detection reaction completely is 1: 1 Water and the mixed solvent of 95 ethanol, be heated to 70 DEG C, and adding triethylamine regulation pH is 4, is cooled to 50 DEG C and stirs 0.5 hour, with Within latter about 2 hours, being down to room temperature, be stirred at room temperature 10 hours, after filtration, filter cake volume ratio is water and 95 ethanol of 1: 1 Mixed solvent washs, and is placed in baking oven and is dried, yield 70%.
Above-described embodiment, only for technology design and the feature of the explanation present invention, its object is to allow person skilled in the art Scholar will appreciate that present disclosure and implements according to this, can not limit the scope of the invention with this, all according to the present invention The equivalence that spirit is made changes or modifies, and all should contain within protection scope of the present invention.

Claims (9)

1. the preparation method of the Saperconazole that ends, it is characterised in that it comprises the following steps:
A () is sequentially added into difluorophenyl chloroacetic chloride, triazole, CuI, potassium carbonate and the first organic solvent in reactor, 80 ～purify to obtain the first product after 100 DEG C of stirring reactions；
B () adds propionitrile, catalyst, the second organic solvent in reaction vessel, be cooled to-20～-5 DEG C, and dropping is containing first Second organic solvent of product, reaction purifies to obtain the second product；Described catalyst is C-9 primary amine quinine and coppery element alkali group The mixture become；
C second product is added in another reaction vessel by (), add phosphordithiic acid diethylester, water and isopropyl alcohol mixed solvent, It is heated to 80～90 DEG C, after stirring reaction, purifies to obtain third product；
D bromo-with 2-for third product 4 '-cyano-acetophenone, the 3rd organic solvent are mixed by () after, after 60～70 DEG C of stirring reactions Purify.
The most according to claim 1, end the preparation method of Saperconazole, it is characterised in that: described catalyst is C-9 primary amine golden pheasant Receive alkali and coppery element alkali is the mixture of 1: 1 composition in molar ratio.
The most according to claim 2, end the preparation method of Saperconazole, it is characterised in that: in step (a), described difluorophenyl second The mol ratio of acyl chlorides, triazole, CuI and potassium carbonate is 1: 1～1.2: 0.1～0.15: 1.1～1.5.
The most according to claim 3, end the preparation method of Saperconazole, it is characterised in that: in described step (a), 80～100 DEG C stirring reaction 8～10 hours after, cross leaching filtrate, recovered under reduced pressure the first organic solvent obtains residue, heavily ties by ethyl acetate Brilliant the first product.
The most according to claim 4, end the preparation method of Saperconazole, it is characterised in that: in described step (b), being cooled to- 20～-5 DEG C before be additionally added benzoic acid, the first product, propionitrile, catalyst and benzoic mol ratio be 1: 3～5: 0.1～ 0.2: 0.1～0.2.
The most according to claim 5, end the preparation method of Saperconazole, it is characterised in that: in described step (b), dropping is containing the After second organic solvent of one product, add hydrochloric acid reaction, be extracted with ethyl acetate repeatedly, merge organic facies, with anhydrous Sodium sulfate is dried, and after filtration, rotary evaporation removes ethyl acetate, with the normal heptane that volume ratio is 1: 1 and dichloromethane recrystallization, The second product it is dried to obtain after filtration.
The most according to claim 6, end the preparation method of Saperconazole, it is characterised in that:, in described step (c), by mol ratio be Second product of 1: 4～5 and phosphordithiic acid diethylester add in another reaction vessel, and adding volume ratio is the water of 1: 1 and different Propanol solvent mixture, reacts 15～20 hours at 80～90 DEG C；Being cooled to 0～5 DEG C again, dropping mass concentration is 5～10% Sodium bicarbonate solution cancellation is reacted, and is extracted with ethyl acetate repeatedly, uses saturated sodium bicarbonate solution, water after merging organic facies respectively Washing with saturated aqueous common salt, take organic facies anhydrous sodium sulfate and be dried, after filtration, rotary evaporation removes ethyl acetate, uses isopropanol Recrystallization, is dried to obtain third product after filtration.
The most according to claim 7, end the preparation method of Saperconazole, it is characterised in that: in described step (d), by mol ratio Be 1: 1.05～1.1 third product and the bromo-4 '-cyano-acetophenone of 2-add in the 3rd organic solvent after, stir at 60～70 DEG C Mix reaction 2～5 hours；And with triethylamine regulate pH to 3.5～4, be cooled to 50～58 DEG C stirring 0.5 hour after at 1～2 hour Being cooled to room temperature, and be stirred at room temperature 5～10 hours, after filtration, filter cake volume ratio is ethanol and the water mixed solvent of 1: 1 Washing, is dried.
9. a Chinese mugwort Saperconazole, it is characterised in that: it is by the preparation method system of described Chinese mugwort Saperconazole arbitrary in claim 1 to 8 ?.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107778306A (en) * 2016-08-30 2018-03-09 江苏奥赛康药业股份有限公司 One kind Chinese mugwort Saperconazole compound and preparation method thereof
CN109206421A (en) * 2017-07-03 2019-01-15 上海医药集团股份有限公司 A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof
CN109535091A (en) * 2018-12-04 2019-03-29 淮安国瑞化工有限公司 Method for synthesizing cyproconazole by using 1- (4-chlorphenyl) -2- (1H-1, 2, 4-triazole-1-yl) ethanone
WO2019171160A1 (en) * 2018-03-06 2019-09-12 Upl Ltd A process for preparation of fungicidally active triazole compounds
CN110551064A (en) * 2018-06-01 2019-12-10 北京莱瑞森医药科技有限公司 Preparation method of isavuconazole sulfate and intermediate thereof
CN115611822A (en) * 2022-10-12 2023-01-17 四川澄华生物科技有限公司 Preparation method of isavuconazole intermediate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045008A1 (en) * 1998-03-06 1999-09-10 F. Hoffmann-La Roche Ag 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity
WO2011042827A1 (en) * 2009-10-08 2011-04-14 CarboDesign LLC Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
CN104507917A (en) * 2012-08-07 2015-04-08 巴斯利尔药物股份公司 Process for the manufacture of isavuconazole or ravuconazole
WO2015150947A1 (en) * 2014-03-29 2015-10-08 Wockhardt Limited A process for the preparation of isavuconazole and its intermediates

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327047B (en) * 2014-10-17 2016-04-06 苏州明锐医药科技有限公司 The preparation method of Ai Feikang azoles
CN104844652A (en) * 2015-02-10 2015-08-19 扬子江药业集团南京海陵药业有限公司 Isavuconazole phosphate ester, preparation method therefor and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045008A1 (en) * 1998-03-06 1999-09-10 F. Hoffmann-La Roche Ag 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity
WO2011042827A1 (en) * 2009-10-08 2011-04-14 CarboDesign LLC Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
CN104507917A (en) * 2012-08-07 2015-04-08 巴斯利尔药物股份公司 Process for the manufacture of isavuconazole or ravuconazole
WO2015150947A1 (en) * 2014-03-29 2015-10-08 Wockhardt Limited A process for the preparation of isavuconazole and its intermediates

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
宋婷婷等: "抗真菌药物艾沙康唑研究进展", 《中国新药杂志》 *
郭生金: "《有机合成新方法及其应用》", 30 June 2007, 北京中国石化出版社 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107778306A (en) * 2016-08-30 2018-03-09 江苏奥赛康药业股份有限公司 One kind Chinese mugwort Saperconazole compound and preparation method thereof
CN107778306B (en) * 2016-08-30 2020-10-16 江苏奥赛康药业有限公司 Isaconazole compound and preparation method thereof
CN109206421A (en) * 2017-07-03 2019-01-15 上海医药集团股份有限公司 A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof
WO2019171160A1 (en) * 2018-03-06 2019-09-12 Upl Ltd A process for preparation of fungicidally active triazole compounds
US11634394B2 (en) 2018-03-06 2023-04-25 Upl Ltd Process for preparation of fungicidally active triazole compounds
CN110551064A (en) * 2018-06-01 2019-12-10 北京莱瑞森医药科技有限公司 Preparation method of isavuconazole sulfate and intermediate thereof
CN109535091A (en) * 2018-12-04 2019-03-29 淮安国瑞化工有限公司 Method for synthesizing cyproconazole by using 1- (4-chlorphenyl) -2- (1H-1, 2, 4-triazole-1-yl) ethanone
CN109535091B (en) * 2018-12-04 2022-05-13 淮安国瑞化工有限公司 Method for synthesizing cyproconazole by using 1- (4-chlorphenyl) -2- (1H-1,2, 4-triazole-1-yl) ethanone
CN115611822A (en) * 2022-10-12 2023-01-17 四川澄华生物科技有限公司 Preparation method of isavuconazole intermediate
CN115611822B (en) * 2022-10-12 2023-09-19 四川澄华生物科技有限公司 Preparation method of isaconazole intermediate

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