CN108452848A - A kind of catalyst - Google Patents

A kind of catalyst Download PDF

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Publication number
CN108452848A
CN108452848A CN201810236234.4A CN201810236234A CN108452848A CN 108452848 A CN108452848 A CN 108452848A CN 201810236234 A CN201810236234 A CN 201810236234A CN 108452848 A CN108452848 A CN 108452848A
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Prior art keywords
catalyst
reaction
added
primary amine
cupereine
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CN201810236234.4A
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Chinese (zh)
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CN108452848B (en
Inventor
刘可
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Shanghai lanli Biotechnology Co., Ltd
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Suzhou Jindian 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
    • B01J35/19—
    • 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
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The present invention relates to a kind of catalyst, for makingAddition reaction generation is carried out with propionitrileIt is 9 primary amine quinines of CAnd cupereineThe molar ratio of the mixture of composition, 9 primary amine quinines of the C and cupereine is 1：1.The asymmetric addition for realizing propionitrile breaches existing defect.

Description

A kind of catalyst
It is on February 24th, 2016 that the present invention, which is the applying date, entitled " a kind of application No. is 201610099742.3 The divisional application of the patent of invention of the preparation method of Chinese mugwort Saperconazole ".
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of pharmaceutical synthesis catalyst, and in particular to a kind of Chinese mugwort Saperconazole The catalyst of propionitrile addition is used in building-up process.
Background technology
In the past 20 years, due to hematopoietic stem cell transplantation, solid organ transplantation, chemotherapy of tumors, broad-spectrum antibiotic and sugared cortex The illness rate of the extensive use of hormone, immunosuppressor, invasive infections with fungi is in notable ascendant trend.Invasive infections with fungi Mainly caused by Mycotoruloides and Eurotium, Susceptible population is immunocompromised patients, is mostly occurred in blood, ICU, transplanting And breathe and infect field, wherein hematology patient, as the proportion of bone-marrow transplantation, leukaemia and Lymphoma accounts for about 61%, infection and respiratory diseases account for about 17%, main to concentrate as the patient of AIDS, respiratory failure and immunologic hypofunction. Domestic clinical research shows in patients with hematopoietic stem cells transplantation that the incidence of invasive infections with fungi is 7%-14%；ICU is led Domain invasive infections with fungi accounts for the 8%-15% of hospital acquired infections；The proportion of ICU and transplant patient accounts for about 15%, mostly in fact Body organ transplant, major surgery and parenteral alimentation patient.
(Chinese mugwort Saperconazole sulfuric ester) is the water-soluble prodrug of triazole Chinese mugwort Saperconazole, for treating 18 The aggressive aspergillin infection of one full year of life above patient and aggressive Mucor infection.Chinese mugwort Saperconazole sulfuric ester is that triazole is anti-true The prodrug of bacterium drug Chinese mugwort Saperconazole, Chinese mugwort Saperconazole pass through the 14- α-Mai Mao sterol piptonychias inhibited in cytochrome P 450 Enzyme system Base enzyme is to inhibit the synthesis of fungal cell membrane important composition ingredient ergosterol, so that fungal cell membrane chemical composition changes, Film dysfunction, permeability increase, and intracellular fluid is excessive, and then have the function that antibacterial and sterilization.Existing Chinese mugwort Saperconazole sulphur In the preparation method of acid esters, processing step is various, it is meant that yield reduces, and cost significantly rises.If its synthesis can be reduced Step can greatly reduce its reaction time, to improve production efficiency；And yield can be improved, drop in high yield, then can Enough status so that manufacturing enterprise has the advantage in market competition.
Invention content
It is provided the invention aims to overcome the deficiencies in the prior art and is used for third in a kind of Chinese mugwort Saperconazole building-up process The catalyst of nitrile addition.
In order to achieve the above objectives, the technical solution adopted by the present invention is：A kind of catalyst, for making Addition reaction generation is carried out with propionitrileIt is C-9 primary amine quininesAnd copper Color tree alkaliThe molar ratio of the mixture of composition, the C-9 primary amine quinine and cupereine is 1：1.
Optimally, its application method is：Propionitrile, catalyst, organic solvent are added into reaction vessel, is cooled to -20 ~-5 DEG C, dropwise addition containsDMAC N,N' dimethyl acetamide carry out reaction purification.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：Catalyst of the present invention leads to It crosses and is mixed using C-9 primary amine quinine and cupereine, realize the asymmetric addition of propionitrile, breach existing defect.
Description of the drawings
Attached drawing 1 is the process flow chart of the preparation method of present invention Chinese mugwort Saperconazole.
Specific implementation mode
Below in conjunction with attached drawing embodiment, invention is further explained.
Embodiment 1
The present invention provides a kind of preparation method of Chinese mugwort Saperconazole, as shown in Figure 1, it includes the following steps：
(a) sequentially added into reaction kettle 1mol difluorophenyls chloroacetic chloride, 1.2mol triazoles, 0.15molCuI, 1.5mol potassium carbonate and 0.8L DMF (n,N-Dimethylformamide) are warming up to 80 DEG C and are stirred to react 10 hours, TLC (thin layer colors Spectrometry) detection is after the reaction was complete；Filtrate is filtered to take, carries out that recycling DMF is concentrated under reduced pressure, residue is then obtained with re-crystallizing in ethyl acetate Off-white powder, i.e. the first product, yield 73%；
(b) in three neck reaction bulbs, 4mol propionitrile is added, 0.1mol catalyst (includes 0.05mol C-9 primary amine quinines Alkali, chemical formula areWith 0.05mol cupereines, chemical formula is ), 0.1mol benzoic acid and 0.5L n,N-dimethylacetamide (DMA), be cooled to -10 DEG C, agitation and dropping contains the productions of 1mol first The 0.3L n,N-dimethylacetamide solution of object reacts 8 hours at -10 DEG C, and TLC detections are added a concentration of after the reaction was complete Reaction is quenched in the hydrochloric acid 0.3L of 1mol/L, three times with the extraction of 0.2L ethyl acetate, merges organic phase, is dried with anhydrous sodium sulfate, It is concentrated under reduced pressure, gained grease normal heptane/dichloromethane (volume ratio 1：1) it recrystallizes, filtration drying obtains off-white powder, i.e., Second product, yield 80%, dr. 97：3；
(c) it is different that the second products of 1mol, 4mol phosphordithiic acid diethylester, 0.6L water and 0.6L are added in three neck reaction bulbs Propanol solvent mixture is heated to 80 DEG C, is stirred to react 20 hours, and TLC is detected after the reaction was complete and is cooled to 0 DEG C, and it is dense that quality is added dropwise The sodium bicarbonate solution 0.4L that degree is 5%, then three are extracted with 0.3L ethyl acetate, merge organic phase, with 0.1L unsaturated carbonates Hydrogen sodium, 0.1L water, 0.1L saturated salt solutions washed once successively, and organic phase is dried with anhydrous sodium sulfate, filter, concentrate； 0.3L recrystallisation from isopropanol stirs 1 hour in 0 DEG C of crystallization, and suction filtration can obtain third product, yield 60%；
(d) 1mol third products, the bromo- 4 '-cyano-acetophenones of 1.05mol 2- and 0.3L are added in three neck reaction bulbs 95% ethyl alcohol (i.e. 95 ethyl alcohol), is stirred to react 2 hours at 60 DEG C, and it is 1 that TLC, which is detected and volume ratio is added after the reaction was complete,：1 water With the mixed solvent of 95 ethyl alcohol, it is heated to 55 DEG C, it is 4 that triethylamine, which is added, and adjusts pH, is cooled to 50 DEG C and stirs 0.5 hour, subsequent 2 Or so hour is down to room temperature, is stirred at room temperature 10 hours, and filter cake volume ratio is 1 after filtering：The mixing of 1 water and 95 ethyl alcohol Solvent washs, and is placed in baking oven dry, yield 70%.
Embodiment 2
The present embodiment provides it is a kind of Chinese mugwort Saperconazole preparation method, preparation process with it is almost the same in embodiment 1, no Be：In step (b), benzoic acid is not added, the yield of final second product is 75%, dr. 95：5.
Embodiment 3
The present embodiment provides it is a kind of Chinese mugwort Saperconazole preparation method, preparation process with it is almost the same in embodiment 1, no Be：In step (b), the molar ratio of C-9 primary amine quinine and cupereine is 5 in catalyst：1, final second product Yield be 76%, dr. 95：5.
Embodiment 4
The present embodiment provides it is a kind of Chinese mugwort Saperconazole preparation method, preparation process with it is almost the same in embodiment 1, no Be：In step (b), the molar ratio of C-9 primary amine quinine and cupereine is 1 in catalyst：5, final second product Yield be 73%, dr. 95：5.
Embodiment 5
The present embodiment provides a kind of preparation methods of Chinese mugwort Saperconazole, it includes the following steps：
(a) 1mol difluorophenyls chloroacetic chloride, 1.1mol triazoles, 0.1molCuI, 1.2mol are sequentially added into reaction kettle Potassium carbonate and 0.8L DMF (n,N-Dimethylformamide) are warming up to 100 DEG C and are stirred to react 8 hours, TLC (thin-layered chromatography) inspections It surveys after the reaction was complete；Filtrate is filtered to take, carries out that recycling DMF is concentrated under reduced pressure, residue then obtains off-white color with re-crystallizing in ethyl acetate Solid, i.e. the first product, yield 70%；
(b) in three neck reaction bulbs, 3mol propionitrile is added, 0.2mol catalyst (includes 0.1mol C-9 primary amine quinines Alkali, chemical formula areWith 0.1mol cupereines, chemical formula is)、 0.2mol benzoic acid and 0.5LN, N- dimethylacetylamides (DMA) are cooled to -10 DEG C, and agitation and dropping contains the first products of 1mol 0.3L n,N-dimethylacetamide solution, reacted 8 hours at -5 DEG C, a concentration of 1mol/ is added after the reaction was complete in TLC detections Reaction is quenched in the hydrochloric acid 0.3L of L, three times with the extraction of 0.2L ethyl acetate, merges organic phase, is dried with anhydrous sodium sulfate, decompression is dense Contracting, gained grease normal heptane/dichloromethane (volume ratio 1：1) it recrystallizes, filtration drying obtains off-white powder, i.e., the second production Object, yield 70%, dr. 95：5；
(c) it is different that the second products of 1mol, 5mol phosphordithiic acid diethylester, 0.6L water and 0.6L are added in three neck reaction bulbs Propanol solvent mixture is heated to 80 DEG C, is stirred to react 20 hours, and TLC is detected after the reaction was complete and is cooled to 0 DEG C, and it is dense that quality is added dropwise The sodium bicarbonate solution 0.4L that degree is 5%, then three are extracted with 0.3L ethyl acetate, merge organic phase, with 0.1L unsaturated carbonates Hydrogen sodium, 0.1L water, 0.1L saturated salt solutions washed once successively, and organic phase is dried with anhydrous sodium sulfate, filter, concentrate； 0.3L recrystallisation from isopropanol stirs 1 hour in 0 DEG C of crystallization, and suction filtration can obtain third product, yield 60%；
(d) 1mol third products, the bromo- 4 '-cyano-acetophenones of 1.1mol 2- and 0.3L are added in three neck reaction bulbs 95% ethyl alcohol (i.e. 95 ethyl alcohol), is stirred to react 2 hours at 60 DEG C, and it is 1 that TLC, which is detected and volume ratio is added after the reaction was complete,：1 water With the mixed solvent of 95 ethyl alcohol, it is heated to 70 DEG C, it is 4 that triethylamine, which is added, and adjusts pH, is cooled to 50 DEG C and stirs 0.5 hour, subsequent 2 Or so hour is down to room temperature, is stirred at room temperature 10 hours, and filter cake volume ratio is 1 after filtering：The mixing of 1 water and 95 ethyl alcohol Solvent washs, and is placed in baking oven dry, yield 70%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, all according to the present invention Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.

Claims (2)

1. a kind of catalyst, for makingAddition reaction generation is carried out with propionitrile It is characterized in that：It is C-9 primary amine quininesAnd cupereine The molar ratio of the mixture of composition, the C-9 primary amine quinine and cupereine is 1：1.
2. catalyst according to claim 1, which is characterized in that its application method is：Third is added into reaction vessel Nitrile, catalyst, organic solvent are cooled to -20~-5 DEG C, and dropwise addition containsN, N- dimethylacetamides Amine carries out reaction purification.
CN201810236234.4A 2016-02-24 2016-02-24 Catalyst Active CN108452848B (en)

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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
US11634394B2 (en) 2018-03-06 2023-04-25 Upl Ltd Process for preparation of fungicidally active triazole compounds
CN110551064B (en) * 2018-06-01 2021-01-01 重庆世森医药科技有限公司 Preparation method of isavuconazole sulfate and intermediate thereof
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
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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CN108452848B (en) 2020-12-11
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