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CN108452848B - Catalyst - Google Patents

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CN108452848B
CN108452848B CN201810236234.4A CN201810236234A CN108452848B CN 108452848 B CN108452848 B CN 108452848B CN 201810236234 A CN201810236234 A CN 201810236234A CN 108452848 B CN108452848 B CN 108452848B
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catalyst
propionitrile
reaction
primary amine
cinchona alkaloid
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CN108452848A (en
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刘可
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Shanghai lanli 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
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Catalysts (AREA)

Abstract

The invention relates to a catalyst for the preparation of
Figure DDA0001604029790000011
Is subjected to addition reaction with propionitrile to generate
Figure DDA0001604029790000012
It is C-9 primary amine cinchona alkaloid
Figure DDA0001604029790000013
And copperylenes
Figure DDA0001604029790000014
The molar ratio of the C-9 primary amine cinchona alkaloid to copper tryptophorine is 1: 1. realizes the asymmetric addition of propionitrile and breaks through the existing defects.

Description

Catalyst
The invention relates to a divisional application of an invention patent with the application date of 2016, 24 and 02 and the application number of 201610099742.3 and the name of 'a preparation method of isavuconazole'.
Technical Field
The invention belongs to the field of drug synthesis, relates to a catalyst for drug synthesis, and particularly relates to a catalyst for propionitrile addition in an isavuconazole synthesis process.
Background
In recent 20 years, the prevalence of invasive fungal infections has increased dramatically due to the widespread use of hematopoietic stem cell transplantation, solid organ transplantation, tumor chemotherapy, broad-spectrum antibiotics, glucocorticoids, and immunosuppressive agents. Invasive fungal infections are mainly caused by candida and aspergillus, and susceptible people are hypoimmunity patients, and are frequently generated in the fields of blood, ICU, transplantation, respiration and infection, wherein the proportion of hematology patients, such as bone marrow transplantation, leukemia and lymphoma patients accounts for about 61%, the proportion of infection and respiration patients accounts for about 17%, and the patients mainly focus on aids, respiratory failure and hypoimmunity. The domestic clinical research shows that the incidence of invasive fungal infection in hematopoietic stem cell transplantation patients is 7-14%; invasive fungal infections in the ICU field account for 8% -15% of hospital acquired infections; ICU and transplant patients account for about 15% of the total weight, and are mostly patients with solid organ transplantation, major surgery and parenteral nutrition.
Figure BDA0001604029770000012
(isaconazole sulphate) is a water-soluble prodrug of triazole isaconazole for use in the treatment of invasive aspergillosis and invasive mucor infections in patients over 18 years of age. The isavuconazole sulfate is a prodrug of isavuconazole which is a triazole antifungal drug, and the isavuconazole inhibits synthesis of important components ergosterol of a fungal cell membrane by inhibiting 14-alpha-maltosterol demethylase in a cytochrome P450 enzyme system, so that chemical composition of the fungal cell membrane is changed, membrane function is disordered, permeability is increased, intracellular fluid overflows, and the effects of bacteriostasis and sterilization are achieved. In the existing preparation method of isavuconazole sulfate, the process steps are multiple, which means that the yield is reduced and the cost is obviously increased. If the synthesis steps can be reduced, the reaction time can be greatly reduced, thereby improving the production efficiency; and the yield can be improved, and the yield can be reduced, so that the production enterprises can be in an advantage position in market competition.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a catalyst for propionitrile addition in an isavuconazole synthesis process.
In order to achieve the purpose, the invention adopts the technical scheme that: a catalyst for use in making
Figure BDA0001604029770000011
Is subjected to addition reaction with propionitrile to generate
Figure BDA0001604029770000021
It is C-9 primary amine cinchona alkaloid
Figure BDA0001604029770000022
And copperylenes
Figure BDA0001604029770000023
The molar ratio of the C-9 primary amine cinchona alkaloid to copper tryptophineThe ratio is 1: 1.
optimally, the use method comprises the following steps: adding propionitrile, catalyst and organic solvent into a reaction container, cooling to-20-5 deg.C, and adding dropwise a solution containing propionitrile
Figure BDA0001604029770000024
And (3) carrying out reaction purification on the N, N-dimethylacetamide.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the catalyst of the invention adopts the C-9 primary amine cinchona alkaloid and the copper tryptophine to be mixed, realizes the asymmetric addition of propionitrile, and breaks through the existing defects.
Drawings
Figure 1 is a process flow diagram of the preparation method of isavuconazole of the present invention.
Detailed Description
The invention will be further explained with reference to the embodiments of the drawings.
Example 1
The invention provides a preparation method of isavuconazole, which comprises the following steps as shown in figure 1:
(a) sequentially adding 1mol of difluorophenylacetyl chloride, 1.2mol of triazole, 0.15mol of CuI, 1.5mol of potassium carbonate and 0.8L of DMF (N, N-dimethylformamide) into a reaction kettle, heating to 80 ℃, stirring for reaction for 10 hours, and detecting by TLC (thin layer chromatography) after the reaction is completed; filtering to obtain filtrate, concentrating under reduced pressure to recover DMF, and recrystallizing the residue with ethyl acetate to obtain off-white solid, namely a first product, with the yield of 73%;
(b) 4mol of propionitrile and 0.1mol of catalyst (containing 0.05mol of C-9 primary amine cinchona alkaloid with the chemical formula of
Figure BDA0001604029770000031
And 0.05mol of copper tryptophorin, of the formula
Figure BDA0001604029770000032
) 0.1mol of benzoic acid and 0.5L N, N-Dimethylacetamide (DMA), cooling to-10 ℃, stirring and dropwise adding 1mol of benzoic acid and N-dimethylacetamide0.3L N, N-dimethylacetamide solution of the first product is reacted for 8 hours at-10 ℃, after TLC detection reaction is completed, 0.3L hydrochloric acid with concentration of 1mol/L is added to quench the reaction, 0.2L ethyl acetate is used for extraction three times, organic phases are combined, dried by anhydrous sodium sulfate, decompressed and concentrated, the obtained oily matter is recrystallized by N-heptane/dichloromethane (volume ratio 1: 1), and filtered and dried to obtain white-like solid, namely the second product, yield is 80%, dr. is 97: 3;
(c) adding a mixed solvent of 1mol of a second product, 4mol of diethyl dithiophosphate, 0.6L of water and 0.6L of isopropanol into a three-neck reaction bottle, heating to 80 ℃, stirring for reacting for 20 hours, cooling to 0 ℃ after TLC detection reaction is completed, dropwise adding 0.4L of sodium bicarbonate solution with the mass concentration of 5%, extracting three solutions by using 0.3L of ethyl acetate, combining organic phases, washing the organic phases once by using 0.1L of saturated sodium bicarbonate, 0.1L of water and 0.1L of saturated saline water in sequence, drying the organic phases by using anhydrous sodium sulfate, filtering, and concentrating; recrystallizing in 0.3L isopropanol, crystallizing at 0 deg.C, stirring for 1 hr, and vacuum filtering to obtain a third product with yield of 60%;
(d) adding 1mol of the third product, 1.05mol of 2-bromo-4' -cyanoacetophenone and 0.3L of 95% ethanol (namely 95 ethanol) into a three-neck reaction flask, stirring and reacting at 60 ℃ for 2 hours, and adding a solution prepared by adding a solvent with a volume ratio of 1: 1, heating to 55 ℃, adding triethylamine to adjust the pH value to 4, cooling to 50 ℃, stirring for 0.5 hour, then cooling to room temperature for about 2 hours, stirring for 10 hours at room temperature, filtering, and filtering to obtain a filter cake, wherein the volume ratio of the filter cake to the filter cake is 1: 1, washing with a mixed solvent of water and 95% ethanol, and drying in an oven, wherein the yield is 70%.
Example 2
This example provides a method for preparing isavuconazole, which is substantially the same as that in example 1, except that: in step (b), no benzoic acid was added, the final second product yield was 75%, dr. was 95: 5.
example 3
This example provides a method for preparing isavuconazole, which is substantially the same as that in example 1, except that: in the step (b), the molar ratio of the C-9 primary amine cinchona alkaloid to the copper tryptophorine in the catalyst is 5: 1, yield of the final second product 76%, dr. was 95: 5.
example 4
This example provides a method for preparing isavuconazole, which is substantially the same as that in example 1, except that: in the step (b), the molar ratio of C-9 primary amine cinchona alkaloid to copper tryptophorine in the catalyst is 1: 5, yield of the final second product was 73%, dr. was 95: 5.
example 5
The embodiment provides a preparation method of isavuconazole, which comprises the following steps:
(a) sequentially adding 1mol of difluorophenylacetyl chloride, 1.1mol of triazole, 0.1mol of CuI, 1.2mol of potassium carbonate and 0.8L of DMF (N, N-dimethylformamide) into a reaction kettle, heating to 100 ℃, stirring for reacting for 8 hours, and detecting by TLC (thin layer chromatography) after the reaction is completed; filtering to obtain filtrate, concentrating under reduced pressure to recover DMF, and recrystallizing the residue with ethyl acetate to obtain off-white solid, i.e. a first product, with a yield of 70%;
(b) in a three-necked reaction flask, 3mol of propionitrile and 0.2mol of catalyst (containing 0.1mol of C-9 primary amine cinchona alkaloid with the chemical formula of
Figure BDA0001604029770000041
And 0.1mol of copper tryptophorin, of the formula
Figure BDA0001604029770000042
) 0.2mol of benzoic acid and 0.5 mol of LN, N-Dimethylacetamide (DMA), cooling to-10 ℃, stirring and dropwise adding a 0.3L N, N-dimethylacetamide solution containing 1mol of the first product, reacting at-5 ℃ for 8 hours, after the TLC detection reaction is completed, adding 0.3L of hydrochloric acid with the concentration of 1mol/L to quench the reaction, extracting three times with 0.2L of ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and mixing the obtained oily substance with N-heptane/dichloromethane (volume ratio 1: 1) recrystallization, filtration and drying to obtain an off-white solid, i.e. a second product, with a yield of 70%, dr. of 95: 5;
(c) adding a mixed solvent of 1mol of a second product, 5mol of diethyl dithiophosphate, 0.6L of water and 0.6L of isopropanol into a three-neck reaction bottle, heating to 80 ℃, stirring for reacting for 20 hours, cooling to 0 ℃ after TLC detection reaction is completed, dropwise adding 0.4L of sodium bicarbonate solution with the mass concentration of 5%, extracting three solutions by using 0.3L of ethyl acetate, combining organic phases, washing the organic phases once by using 0.1L of saturated sodium bicarbonate, 0.1L of water and 0.1L of saturated saline water in sequence, drying the organic phases by using anhydrous sodium sulfate, filtering, and concentrating; recrystallizing in 0.3L isopropanol, crystallizing at 0 deg.C, stirring for 1 hr, and vacuum filtering to obtain a third product with yield of 60%;
(d) adding 1mol of the third product, 1.1mol of 2-bromo-4' -cyanoacetophenone and 0.3L of 95% ethanol (namely 95 ethanol) into a three-neck reaction flask, stirring and reacting at 60 ℃ for 2 hours, and adding a solution prepared by adding a solvent with a volume ratio of 1: 1, heating to 70 ℃, adding triethylamine to adjust the pH value to 4, cooling to 50 ℃, stirring for 0.5 hour, then cooling to room temperature for about 2 hours, stirring for 10 hours at room temperature, filtering, and filtering to obtain a filter cake, wherein the volume ratio of the filter cake to the filter cake is 1: 1, washing with a mixed solvent of water and 95% ethanol, and drying in an oven, wherein the yield is 70%.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.

Claims (2)

1. A catalyst used in combination with a cocatalyst
Figure FDA0002536574800000011
Is subjected to addition reaction with propionitrile to generate
Figure FDA0002536574800000012
The method is characterized in that: it is C-9 primary amine cinchona alkaloid
Figure FDA0002536574800000013
And copperylenes
Figure FDA0002536574800000014
The molar ratio of the C-9 primary amine cinchona alkaloid to copper tryptophorine is 1: 1; the molar ratio of the catalyst to the propionitrile to the cocatalyst is 0.1: 4: 0.1, and the cocatalyst is benzoic acid.
2. The catalyst according to claim 1, characterized in that it is used by: adding propionitrile, catalyst and organic solvent into a reaction container, cooling to-20-5 deg.C, and adding dropwise a solution containing propionitrile
Figure FDA0002536574800000015
And (3) carrying out reaction purification on the N, N-dimethylacetamide.
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CN107778306B (en) * 2016-08-30 2020-10-16 江苏奥赛康药业有限公司 A kind of isavuconazole 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
MX2020009041A (en) 2018-03-06 2020-10-14 Upl Ltd A 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 isavuconazole intermediate

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WO2011042827A1 (en) * 2009-10-08 2011-04-14 CarboDesign LLC Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
CN104327047A (en) * 2014-10-17 2015-02-04 苏州明锐医药科技有限公司 Preparation method of efinaconazole
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

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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
SI2882723T1 (en) * 2012-08-07 2017-04-26 Basilea Pharmaceutica Ag 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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011042827A1 (en) * 2009-10-08 2011-04-14 CarboDesign LLC Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
CN104327047A (en) * 2014-10-17 2015-02-04 苏州明锐医药科技有限公司 Preparation method of efinaconazole
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

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