CN109053505A - A kind of synthetic method of Fei Luokao former times important intermediate - Google Patents
A kind of synthetic method of Fei Luokao former times important intermediate Download PDFInfo
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- CN109053505A CN109053505A CN201810876892.XA CN201810876892A CN109053505A CN 109053505 A CN109053505 A CN 109053505A CN 201810876892 A CN201810876892 A CN 201810876892A CN 109053505 A CN109053505 A CN 109053505A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
Abstract
The present invention relates to a kind of synthetic methods of the intermediate of Fei Luokao former times, using to mesyl isobutyrophenone as starting material, using one kettle way, in NBS(N- bromosuccinimide) brominated intermediates are first generated under system, hydrolyze to obtain target compound [2- hydroxyl -1-(4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone] again, used material is without to the disagreeableness material of environment, it will not generate to the disagreeableness by-product of environment, such as thio-ether type compounds, it is easy to operate, without security risk, reaction condition is mild, it is suitble to industrialized production, by-product is few, and for the preferred recrystallisation solvent of target compound, it can obtain all very high product of yield and purity, it is used directly for subsequent preparation Fei Luokao former times, obtain the finished product Fei Luokao former times of high-purity.
Description
Technical field
The present invention relates to pharmaceutical chemical synthesis fields, in particular to a kind of conjunction of Fei Luokao former times important intermediate
At method.
Background technique
Fei Luokao former times is a kind of important non-steroidal anti-inflammatory veterinary drug, and effect mainly passes through selective depression epoxy
Change the synthesis for the prostaglandin that enzyme -2 (COX-2) is mediated, to block arachidonic acid to be converted into prostaglandin, and then generates solution
Heat, analgesia and anti-inflammatory effect.Compared with other non-steroidal anti-inflammatory veterinary drugs, Fei Luokao former times efficiently can selectively press down
COX-2 processed, and can be absorbed by organisms rapidly, there is significant curative effect to relief from osteoarthritis pain.
Compound 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone, structural formula are as follows:It is
Synthesize the important intermediate of veterinary drug Fei Luokao former times.
There is following several method about the synthesis report of the intermediate at present:
Method one is patent document US5981576, and the Fei Luokao former times of US6020343A, CN1203066C report synthesizes road
Line.Using thioanisole as starting material, Friedel-Crafts reaction occurs with isobutyryl chloride and generates compound A, compound A hydroxylating generationization
Object B is closed, compound B is crystallized under ether and Hexane system after oxidant such as (OXONE ammonium persulfate-sodium bisulfate) oxidation,
Target compound C is obtained, reaction equation is as follows:
The major defect of the synthesis technology has: 1, starting material is done using the thioanisole with bad smell, in environmental protection
Aspect has very big pressure.2, hydroxylating has used carbon tetrachloride, and carbon tetrachloride is a kind of solvent, be it is known can so that
Cancer, to the solvent that human and environment is all unfavorable.3, the ether and hexane that its recrystallisation solvent is used all are extremely inflammable and explosive solvents, no
It is suitble to industrialized production.
Method two is the Fei Luokao former times synthetic route of patent document CN104803956A report.Equally it is with thioanisole
Beginning raw material occurs Friedel-Crafts reaction with isobutyryl chloride and generates compound A；Compound A is reacted with bromine again generates brominated intermediates, so
Alkali is done in sodium hydroxide afterwards, tetrabutylammonium bromide obtains compound B to hydrolyze under conditions of phase transfer catalyst；Compound B is most
After oxidant such as (OXONE ammonium persulfate-sodium bisulfate) oxidation, liquid separation is extracted, dry concentration directly obtains targeted
Close object C.Reaction equation is as follows:
The shortcomings that synthesis technology, has: 1, still starting material is done using the thioanisole with bad smell, in environmental protection
Aspect has very big pressure.2, the bromine that bromination reaction uses has extremely strong strong toxic and corrosivity, and pole is unfavorable for environment and duty
Industry health, it should avoid as far as possible using.3, the synthesis technology is that directly extractant is concentrated under reduced pressure dry to obtain target chemical combination
Object C cannot be guaranteed without the purity of suitable crystallization processes, therefore compound C.And compound C is as veterinary drug Fei Luokao
The important intermediate of former times, purity will have a direct impact on the purity of finished product Fei Luokao former times.
Method three is the Fei Luokao former times synthetic route of patent document CN107686471A report.To be starting to brom-acetophenone
Raw material occurs methylation reaction with iodomethane, produces compound a；Then with methyl sulfinic acid sodium sulfonylation occurs for compound a again
Reaction generates compound b；For solvent, NBS (i.e. N- bromo succinyl is added with DMSO (i.e. dimethyl sulfoxide) in final compound b
Imines) in 80~100 DEG C of 10~14h of reaction.Then through extraction liquid separation, dry concentration, then it is mixed in methyl tertiary butyl ether(MTBE)/normal heptane
It is crystallized under bonding solvent system, obtains target compound C.Reaction equation is as follows:
According to document " Org.lett., 2015,17,876-879 " it is found that in the synthesis technology third step compound C shape
It is as follows at mechanism:
Wherein dimethyl sulfoxide serves not only as solvent during the reaction, and also offer hydroxylating obtains oxygen source, with bromination
Intermediate state reaction generates by-product dimethyl sulphide.Dimethyl sulphide is similar with thioanisole, there is bad smell, very not friendly to environment
It is good.And dimethyl sulphide flash-point is -38 DEG C, easily combustion explosion at high heat.And the step process needs to react 10 at 80~100 DEG C
~14h, there are security risks.
Dimethyl sulphide is also the very strong reagent of nucleophilicity simultaneously, can be with bromination intermediate state under the step-length time pyroreaction
Side reaction occurs, influences the purity of compound C.The recrystallisation solvent of the technique is methyl tertiary butyl ether(MTBE)/n-heptane system, and chemical combination
Solubility of the object C in two kinds of solvents is all very poor, especially normal heptane, almost insoluble.Therefore with the mixed solvent crystallization, it is difficult
Improve the purity of compound C.
Therefore, this field is safe and environment-friendly there is still a need for one kind and can be to the synthesis side that target compound C is purified
Method, to guarantee the purity of Fei Luokao former times important intermediate, the high-purity for Fei Luokao former times provides support.
Summary of the invention
The purpose of the present invention is to provide a kind of easy to operate, production cost is low, and safe and environment-friendly, and has to non-sieve
It examines former times important intermediate to be purified, is suitble to the synthetic method of industrialized production.
The present invention provides a kind of Fei Luokao former times important intermediate, 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -
The synthetic method of propyl- 1- ketone, comprising the following steps:
(1) mesyl isobutyrophenone, N-bromosuccinimide, catalyst and reaction dissolvent will be mixed, will be warming up to
60-80 DEG C of reaction, after completion of the reaction, is down to room temperature, obtains mixed liquor；
(2) aqueous alkali is added into above-mentioned mixed liquor, reacts at room temperature, after completion of the reaction, organic solvent and water is added,
Extraction, dry, filtering are concentrated under reduced pressure to get 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.
Reaction equation is as follows:
Using one pot reaction, the mixed liquor containing compound II that step (1) obtains is directly used in and is reacted in next step,
It is easy to operate without isolating and purifying intermediate II, high income.And the raw material used is simple and easy to get, environmentally friendly, reaction is not given birth to
The thioether class by-product influential on environment at the smell is awful.
Further, in step (1) reaction dissolvent be selected from acetonitrile, ethyl acetate or isopropyl acetate, preferably acetonitrile or
Ethyl acetate.
Further, it is 1 to the mass volume ratio (g/mL) of mesyl isobutyrophenone and reaction dissolvent in step (1):
3-6。
Further, catalyst is selected from thiocarbamide, ammonium acetate or p-methyl benzenesulfonic acid, preferably thiocarbamide or acetic acid in step (1)
Ammonium.
It further, is 1:0.1-0.5 to the molar ratio of mesyl isobutyrophenone and catalyst in step (1).
Further, to the molar ratio of mesyl isobutyrophenone and N-bromosuccinimide in step (1) are as follows: 1:
1.2-2.0。
Further, it is water-soluble to be selected from wet chemical, aqueous sodium carbonate, sodium hydroxide for the aqueous alkali of step (2)
Liquid or potassium hydroxide aqueous solution.
Further, which further includes re-crystallization step, and recrystallization solvent is selected from methyl tertiary butyl ether(MTBE), isopropyl
Alcohol, isopropyl acetate, ethyl acetate/methyl tertiary butyl ether(MTBE) mixed solvent or isopropyl acetate/methyl tertiary butyl ether(MTBE) mixed solvent.
The screening of recrystallization solvent substantially increases 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone purity.
The present invention also provides above-mentioned preparation methods to prepare the purposes in Fei Luokao former times.
The application method applies also for compoundSynthesis, wherein R1 be Ar group, R2 be straight chain or branch
The Cn alkane group of chain, R3 are the Cn alkane group of hydrogen or linear chain or branched chain, specific such as compounds Ⅳ, V.
The Fei Luokao former times important intermediate of preparation of the embodiment of the present invention has the advantage that
(1) present invention using to mesyl isobutyrophenone as starting material, using one kettle way, in NBS (N- bromo succinyl
Imines) brominated intermediates are first generated under system, then hydrolyze to obtain target compound [2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -
2- methyl -propyl- 1- ketone], used material without to the disagreeableness material of environment, will not be generated to the disagreeableness pair of environment
Product, such as thio-ether type compounds.
(2) operation of the present invention is simple, and no security risk, reaction condition is mild, is suitble to industrialized production.
(3) by-product of the present invention is few, and for the preferred recrystallisation solvent of target compound, can obtain yield and purity
All very high product is used directly for subsequent preparation Fei Luokao former times, obtains the finished product Fei Luokao former times of high-purity.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.
The structure of compound is nuclear magnetic resonance (1H NMR) or MS to determine.
Nuclear Magnetic Resonance (1H NMR) is Bruker AVANCE-400, and nuclear magnetic resonance (1H NMR) is displaced (δ) with million points
One of the unit of (ppm) provide, measurement solvent is DMSO-d6, is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6
(ppm) it is provided as unit.
Term " room temperature " of the invention refers to that temperature is between 10-25 DEG C.
Combined with specific embodiments below, the present invention is further detailed:
The preparation of 1 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (10.0g, 1.0eq) and 50mL acetonitrile will be mixed, it is sub- to add N- bromo succinyl
Amine (11.8g, 1.5eq), thiocarbamide (1.0g, 0.3eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction, have reacted under stirring
Entirely.It is cooled to room temperature, is then slowly added into the solution of prepared sodium hydroxide (5.0g) and water (25.0g), continues room temperature and stirs
10~12h is mixed, hydrolysis is complete.Ethyl acetate and water is added, extracts liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate
Solvent is evaporated off in filtrate decompression afterwards, and 20mL isopropanol is then added, is warming up to 70 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification, filters, dry
Obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(9.18g, light tan solid, yield 85.7%,
98.1%) HPLC purity is.
The characterization result of Fei Luokao former times important intermediate provided in this embodiment is as follows:
1HNMR (CDCl3) δ 1.61 (6H, s), δ 3.09 (3H, s), δ 3.32 (1H, br), δ 8.02-8.00 (2H, m), δ
8.22-8.19 (2H, m)
LC-MS: the intermediate molecule amount is 242.29, and mass spectrum gives the peak [M+H] ﹢, and m/z 243.2 meets its molecule
Amount.
The preparation of 2 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (30.0g, 1.0eq) and 90mL acetonitrile will be mixed, it is sub- to add N- bromo succinyl
Amine (37.8g, 1.6eq), thiocarbamide (2.0g, 0.2eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction, have reacted under stirring
Entirely.It is cooled to room temperature, is then slowly added into the solution of prepared sodium hydroxide (15.0g) and water (75.0g), continues room temperature and stirs
10~12h is mixed, hydrolysis is complete.Ethyl acetate and water is added, extracts liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate
Solvent is evaporated off in filtrate decompression afterwards, and 45mL isopropyl acetate is then added, is warming up to 75 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification, filtering,
It is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(28.0g, light tan solid, yield
98.8%) 87.2%, HPLC purity are.
The preparation of 3 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (30.0g, 1.0eq) and 150mL acetonitrile will be mixed, it is sub- to add N- bromo succinyl
Amine (37.8g, 1.6eq), ammonium acetate (2.0g, 0.2eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction under stirring, reaction
Completely.It is cooled to room temperature, is then slowly added into the solution of prepared potassium hydroxide (21.0g) and water (105.0g), continues room
Temperature 10~12h of stirring, hydrolysis are complete.Ethyl acetate and water is added, extracts liquid separation, organic phase is dry with anhydrous sodium sulfate,
Solvent is evaporated off in filtrate decompression after filtering, and 45mL isopropyl acetate is then added, is warming up to 75 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification,
Filtering, is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(27.4g, light tan solid, yield
98.5%) 85.3%, HPLC purity are.
The preparation of 4 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (10.0g, 1.0eq) and 50mL ethyl acetate will be mixed, and add N- bromo amber
Acid imide (9.4g, 1.2eq), thiocarbamide (1.7g, 0.5eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction under stirring, reaction
Completely.It is cooled to room temperature, is then slowly added into the solution of prepared sodium carbonate (10.0g) and water (50.0g), continues room temperature and stirs
10~12h is mixed, hydrolysis is complete.Ethyl acetate and water is added, extracts liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate
Solvent is evaporated off in filtrate decompression afterwards, and 10mL isopropyl acetate is then added, is warming up to 75 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification, filtering,
It is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(28.0g, light tan solid, yield
97.3%) 85.7%, HPLC purity are.
The preparation of 5 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (10.0g, 1.0eq) and 60mL acetonitrile will be mixed, it is sub- to add N- bromo succinyl
Amine (15.7g, 2.0eq), thiocarbamide (0.34g, 0.1eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction, have reacted under stirring
Entirely.It is cooled to room temperature, the solution of prepared potassium carbonate (10.0g) and water (50.0g) is then slowly added into, continues to be stirred at room temperature
10~12h, hydrolysis are complete.Ethyl acetate and water is added, liquid separation is extracted, after organic phase is dried, filtered with anhydrous sodium sulfate
Solvent is evaporated off in filtrate decompression, and 15mL isopropyl acetate is then added, is warming up to 75 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification, filters, and does
It is dry to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(9.1g, light tan solid, yield 85.0%,
97.2%) HPLC purity is.
The preparation of 6 Fei Luokao former times important intermediate of embodiment:
Mesyl isobutyrophenone (50.0g, 1.0eq) and 250mL acetonitrile will be mixed, it is sub- to add N- bromo succinyl
Amine (62.9g, 1.6eq), ammonium acetate (3.4g, 0.2eq) are warming up to 60~80 DEG C, and 1~2h of insulation reaction under stirring, reaction
Completely.It is cooled to room temperature, is then slowly added into the solution of prepared sodium hydroxide (20.0g) and water (100.0g), continues room
Temperature 10~12h of stirring, hydrolysis are complete.Ethyl acetate and water is added, extracts liquid separation, organic phase is dry with anhydrous sodium sulfate,
Filtrate is divided into five parts by quality after filtering, tests different recrystallisation solvents respectively:
Take first part of filtrate, then 10mL isopropyl acetate is added in evaporating solvent under reduced pressure, be warming up to 75 DEG C, even after dissolved clarification
Prompt drop temperature crystallization, filtering, is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(9.45g, shallow palm fibre
97.7%) color solid, yield 88.3%, HPLC purity are.
Second part of filtrate is taken, then evaporating solvent under reduced pressure is added 15mL methyl tertiary butyl ether(MTBE), is warming up to 55 DEG C, after dissolved clarification
At the uniform velocity cool down crystallization, and filtering is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone.(9.63g, shallowly
96.5%) brown solid, yield 89.9%, HPLC purity are.
Third part filtrate is taken, then 15mL methyl tertiary butyl ether(MTBE) and 5mL ethyl acetate, heating is added in evaporating solvent under reduced pressure
To 60 DEG C, at the uniform velocity cool down crystallization after dissolved clarification, filtering, be dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl-
1- ketone.(97.4%) 9.20g, light tan solid, yield 85.9%, HPLC purity are.
The 4th part of filtrate is taken, then 15mL methyl tertiary butyl ether(MTBE) and 5mL isopropyl acetate is added in evaporating solvent under reduced pressure, rise
Temperature is to 60 DEG C, and at the uniform velocity cool down crystallization after dissolved clarification, and filtering is dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -
Propyl- 1- ketone.(96.9%) 9.31g, light tan solid, yield 87.0%, HPLC purity are.
The 5th part of filtrate is taken, then evaporating solvent under reduced pressure is added 10mL ethyl acetate and is warming up to 70 DEG C, is at the uniform velocity added dropwise to
5mL normal heptane.Then at the uniform velocity cool down crystallization, filtering, be dried to obtain 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl-
1- ketone.(92.6%) 9.46g, light tan solid, yield 88.4%, HPLC purity are.
Comparative example 1 is prepared according to method disclosed in Chinese patent CN107686471A embodiment 10.
B1 (40.0g, 1.0eq) is dissolved in 200mL dimethyl sulfoxide, add N-bromosuccinimide (6.3g,
0.2eq).It is warming up to 100 DEG C of reaction 12h.It is cooled to room temperature after fully reacting, ethyl acetate and water extraction is added, it is organic relevant
It is dry, with methyl tertiary butyl ether(MTBE)-normal heptane crystallization after evaporating solvent under reduced pressure, obtain compound C, it may be assumed that 2- hydroxy-2-methyl-(4- first
Base sulfonyl) phenyl -1- acetone, (35.4g, yield 82.7%, faint yellow solid, purity 92.1%).
By above-mentioned experiment it is found that 2- hydroxy-2-methyl-(4- methyl sulphonyl) phenyl-that 1-6 of the embodiment of the present invention is provided
The preparation method of 1- acetone, yield are slightly above comparative example 1, and purity is apparently higher than comparative example 1, and preparation of the invention
Method does not generate the thioether class by-product influential on environment that the smell is awful, and comparative example 1 generates the diformazan that the smell is awful
Thioether.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of Fei Luokao former times important intermediate, comprising the following steps:
(1) mesyl isobutyrophenone, N-bromosuccinimide, catalyst and reaction dissolvent will be mixed, and will be warming up to 60-80
DEG C reaction, after completion of the reaction, be down to room temperature, obtain mixed liquor；
(2) aqueous alkali is added into above-mentioned mixed liquor, reacts at room temperature, after completion of the reaction, organic solvent and water, extraction is added
It takes, dry, filtering is concentrated under reduced pressure to get 2- hydroxyl -1- (4- Metlianesulfonyl-phenyl) -2- methyl -propyl- 1- ketone；
Reaction equation is as follows:
2. the synthetic method of Fei Luokao former times important intermediate according to claim 1, which is characterized in that the reaction dissolvent
Selected from acetonitrile, ethyl acetate or isopropyl acetate.
3. the synthetic method of Fei Luokao former times important intermediate according to claim 2, which is characterized in that the reaction dissolvent
For acetonitrile or ethyl acetate.
4. the synthetic method of Fei Luokao former times important intermediate according to claim 2, which is characterized in that described to methylsulfonyl
The mass volume ratio (g/mL) of base isobutyrophenone and the reaction dissolvent is 1:3-6.
5. the synthetic method of Fei Luokao former times important intermediate according to claim 1-4, which is characterized in that described
Catalyst is selected from thiocarbamide, ammonium acetate or p-methyl benzenesulfonic acid, preferably thiocarbamide or ammonium acetate.
6. the synthetic method of Fei Luokao former times important intermediate according to claim 1, which is characterized in that described to methylsulfonyl
The molar ratio of base isobutyrophenone and catalyst is 1:0.1-0.5.
7. the synthetic method of Fei Luokao former times important intermediate according to claim 1, which is characterized in that described to methylsulfonyl
The molar ratio of base isobutyrophenone and N-bromosuccinimide are as follows: 1:1.2-2.0.
8. the synthetic method of Fei Luokao former times important intermediate according to claim 1, which is characterized in that the step (2)
Aqueous alkali be selected from wet chemical, aqueous sodium carbonate, sodium hydrate aqueous solution or potassium hydroxide aqueous solution.
9. the synthetic method of Fei Luokao former times important intermediate according to claim 1, which is characterized in that further include recrystallization
Step, it is molten that recrystallization solvent is selected from methyl tertiary butyl ether(MTBE), isopropanol, isopropyl acetate, ethyl acetate/methyl tertiary butyl ether(MTBE) mixing
Agent or isopropyl acetate/methyl tertiary butyl ether(MTBE) mixed solvent.
10. purposes of the preparation method described in any one of claim 1-9 in synthesis Fei Luokao former times.
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Cited By (4)
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| CN110452199A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN110452198A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN112500321A (en) * | 2020-09-25 | 2021-03-16 | 安徽省公众检验研究院有限公司 | Preparation method of feloxicib key intermediate |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110452199A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN110452198A (en) * | 2019-09-03 | 2019-11-15 | 山东鲁抗舍里乐药业有限公司 | A kind of preparation method of Fei Luokao former times |
| CN112500321A (en) * | 2020-09-25 | 2021-03-16 | 安徽省公众检验研究院有限公司 | Preparation method of feloxicib key intermediate |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
| CN112624943B (en) * | 2020-12-28 | 2022-07-01 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
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