CN108689917A - A kind of Etoricoxib intermediate continuous flow production technology - Google Patents
A kind of Etoricoxib intermediate continuous flow production technology Download PDFInfo
- Publication number
- CN108689917A CN108689917A CN201710226227.1A CN201710226227A CN108689917A CN 108689917 A CN108689917 A CN 108689917A CN 201710226227 A CN201710226227 A CN 201710226227A CN 108689917 A CN108689917 A CN 108689917A
- Authority
- CN
- China
- Prior art keywords
- reaction
- continuous flow
- reactor
- production technology
- etoricoxib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a kind of Etoricoxib intermediate continuous flow production technologies, it is related to applied technical field of the Technology of Fine Chemical Industry in production of raw medicine;Its method is:Step 1:Using non-nucleophilic organic alkali as reagent, the synthesis of intermediate is carried out in continuous current micro-reactor;Step 2:Oxidation technology is carried out in continuous current micro-reactor under transition-metal catalyst effect using cheap inorganic oxidizer;Specifically include following reaction step:Using 4- (methyl mercapto) phenylacetic acids and 6- methyl-acidum nicotinicum methyl esters as starting material; by using continuous flow type microreactor, two-step reaction occurs and generates 1- (6- picoline -3- bases) -2- (4- methanesulfonylphenYls) ethyl ketone;The present invention is using the equipment of novel reagent, catalyst and novelty, and more than 70%, reaction heat and gas generate to obtain good control yield, has the characteristics that catalyst is novel, reaction condition is relatively mild.
Description
Technical field:
The present invention relates to a kind of Etoricoxib intermediate continuous flow production technologies, belong to Technology of Fine Chemical Industry and are given birth in bulk pharmaceutical chemicals
Applied technical field in production.
Background technology:
Etoricoxib is the anti-arthritic drugs developed by drugmaker of the U.S., trade name Ankang letter, wherein 1-
(6- picoline -3- bases) -2- (4- methanesulfonylphenYls) ethyl ketone is the intermediate of this drug most critical.
At present there are mainly two types of the synthetic routes of this intermediate:
The first process route be first sulfone by sulfide oxidation, then be condensed.Since second step condensation is needed carboxyl
It is converted into carbanion, and the methyl at sulfone functional group ortho position equally has stronger acidity, side reaction is more, and yield is low.
Second of process route is first to be condensed, and is then reoxidized.This route has higher selectivity.
However, the Article 2 process route of reported in literature has certain defect.Such as:
The first step using highly basic such as lithium hexamethyldisilazide, lithium diisopropylamines costly, it is of high cost and
It is more dangerous, and because using the higher reagent of activity, reaction heat is very high, and process safety is difficult to ensure.
For second step using oxidising agents such as potassium bichromate, metachloroperbenzoic acids, Atom economy is low, and material is more high
It is expensive.And equally having reaction heat very high, process safety is difficult to the defect ensured.
In conclusion the technique of the synthesis Etoricoxib intermediate of document report, there is that material is of high cost, process safety
The disadvantages such as property is low.
In traditional batch production technology, some processes can by conduct heat, mass transfer and reaction time are influenced.Such as part
The prodigious reaction of reaction heat, needs extremely slow charging rate with Heat Transfer Control;Partial selective is not easy to control, intermediate product can be with
Raw material continues the reaction of effect, needs to design special feed way;Portion temperature sensitivity response, due to the reaction of batch technique
Time is difficult to control, and needs to reduce reaction temperature.
Invention content:
In view of the above-mentioned problems, the technical problem to be solved in the present invention is to provide a kind of productions of Etoricoxib intermediate continuous flow
Technique.
A kind of Etoricoxib intermediate continuous flow production technology of the present invention, its method are:Step 1:Using non-nucleophilic
Property organic alkali as reagent, the synthesis of intermediate is carried out in continuous current micro-reactor;
Step 2:Using cheap inorganic oxidizer, under transition-metal catalyst effect, in continuous current micro-reactor
Carry out oxidation technology;
Specifically include following reaction step:It is starting with 4- (methyl mercapto) phenylacetic acids and 6- methyl-acidum nicotinicum methyl esters
Raw material occurs two-step reaction and generates 1- (6- picoline -3- bases) -2- (4- methylsulfonyls by using continuous flow type microreactor
Base phenyl) ethyl ketone;Reaction equation is as follows:
Preferably, non-nucleophilic organic base described in the step 1, including lithium hexamethyldisilazide, diisopropyl
Base lithium amide, tertiary butyl magnesium chloride.
Preferably, oxidant described in the step 2 includes hydrogen peroxide, sodium hypochlorite, sodium chlorite.
Preferably, catalyst described in the step 2 includes manganous chloride, ferric trichloride, sodium tungstate, sodium molybdate.
Preferably, the dosage of the non-nucleophilic organic alkali in the step 1 is 2-5 equivalents, preferably 2.5-3 equivalents,
Reaction temperature is 50-100 DEG C.
Preferably, the reaction temperature of the continuous current micro-reactor in the step 2 is 20-80 DEG C.
Preferably, the continuous current micro-reactor is formed by nine glass response function block coupled in series, each glass is anti-
It answers function module all to use three-decker channel, is the flow channel layer of reacting fluid among it, is wrapped by two heat exchange layers
Folder, the reaction channel include feed inlet one, cold heat exchange fluid inlet and outlet one, feed inlet two, discharge port, cold heat exchange current
It is 8_mL that the reaction liquid of body 25 reaction channels of inlet and outlet, which holds fluid product, and heat exchange layers volume is 14_mL, unit reaction solution
Heat exchange area is up to 2500_m2/m3, a length of 2_m of each glass response function mould reaction channel in the block.
Preferably, the technological process of the continuous current micro-reactor is:It is micro- that reactant A, B squeeze into G1 with constant flow pump respectively
01, No. 02 pre- hot/cold of module of channel reactor, starts to mix, be reacted in No. 03 module, until No. 08 module reaction knot
Beam, reaction module number are 6, and every volume is 8.5mL, amounts to 51mL, micro- by the adjusting of high/low temperature control loop slot in experiment
Temperature in road reactor adjusts the flow and equivalent proportion of charging by constant flow pump, after each experiment condition setting, continuous operation
After 15min, it is considered as system run all right, sampling carries out gas chromatographic detection.
Compared with prior art, beneficial effects of the present invention are:Using setting for novel reagent, catalyst and novelty
Standby, yield is more than 70%, and reaction heat and gas generate to obtain good control, has catalyst novelty, reaction condition relatively warm
And the features such as.
Description of the drawings:
The present invention is described in detail by following specific implementations and attached drawing for ease of explanation,.
Fig. 1 is the schematic diagram of continuous current micro-reactor in the present invention;
Fig. 2 is the channel plane figure of continuous current micro-reactor in the present invention;
Fig. 3 is the sectional view of glass response function module in the present invention;
Fig. 4 be the present invention in continuous current micro-reactor flow chart,
Specific implementation mode:
In order to make the objectives, technical solutions and advantages of the present invention clearer, below by shown in the accompanying drawings specific
Embodiment describes the present invention.However, it should be understood that these descriptions are merely illustrative, and it is not intended to limit the model of the present invention
It encloses.In addition, in the following description, descriptions of well-known structures and technologies are omitted, to avoid unnecessarily obscuring the present invention's
Concept.
Present embodiment uses following technical scheme:Its method is:Step 1:Use non-nucleophilic organic alkali
As reagent, the synthesis of intermediate is carried out in continuous current micro-reactor;
Step 2:Using cheap inorganic oxidizer, under transition-metal catalyst effect, in continuous current micro-reactor
Carry out oxidation technology;
Specifically include following reaction step:It is starting with 4- (methyl mercapto) phenylacetic acids and 6- methyl-acidum nicotinicum methyl esters
Raw material occurs two-step reaction and generates 1- (6- picoline -3- bases) -2- (4- methylsulfonyls by using continuous flow type microreactor
Base phenyl) ethyl ketone;Reaction equation is as follows:
Further, non-nucleophilic organic base described in the step 1, including lithium hexamethyldisilazide, diisopropyl
Base lithium amide, tertiary butyl magnesium chloride, preferably tertiary butyl magnesium chloride.
Further, oxidant described in the step 2 includes hydrogen peroxide, sodium hypochlorite, sodium chlorite, preferably dioxygen
Water.
Further, catalyst described in the step 2 includes manganous chloride, ferric trichloride, sodium tungstate, sodium molybdate, excellent
Select sodium tungstate.
Further, the dosage of the non-nucleophilic organic alkali in the step 1 is 2-5 equivalents, preferred 2.5-3 equivalents,
Reaction temperature is 50-100 DEG C, preferably 60-70 DEG C.
Further, the reaction temperature of the continuous current micro-reactor in the step 2 is 20-80 DEG C, preferably 30-40 DEG C.
As shown in Figure 1, Figure 2, as indicated at 3, preferably, the continuous current micro-reactor is by nine glass response function module strings
Joining, each glass response function module uses three-decker channel, is the flow channel layer 12 of reacting fluid among it,
Sandwiched by two heat exchange layers 11,13, the reaction channel include feed inlet 1, cold heat exchange fluid inlet and outlet 1, into
Material mouth 23, discharge port 4, cold heat exchange fluid inlet and outlet 25;It is 8mL, heat exchange that the reaction liquid of reaction channel, which holds fluid product,
Layer volume is 14mL, and the heat exchange area that unit reaction solution is enjoyed is up to 2500m2/m3, it is the reaction of standard machinery jacket type stirring
1000 times of kettle, a length of 2m of each glass response function mould reaction channel in the block, concatenated heart-shaped structure unit, such as Fig. 2 institutes
Show so that reacting fluid is adequately disturbed and mixed in the flowing of module, while ensureing, without " back mixing " phenomenon, to ensure that
High mass transfer and heat transfer efficiency, reactor operating pressure reach as high as 1.8MPa, the pipelines of all and reaction mass contact and
Connector is all nonmetallic, to have excellent antiseptic property.
As shown in figure 4, further, the technological process of the continuous current micro-reactor is:Reactant A, B constant flow pumps point
01, No. 02 pre- hot/cold of module for not squeezing into G1 micro passage reactions, starts to mix, be reacted in No. 03 module, until No. 08
Module reaction terminates, and reaction module number is 6, and every volume is 8.5mL, amounts to 51mL, is followed by high/low temperature control in experiment
Annular groove adjusts the temperature in canaliculus reactor, and the flow and equivalent proportion of charging, each experiment condition setting are adjusted by constant flow pump
Afterwards, after continuous operation 15min, it is considered as system run all right, sampling carries out gas chromatographic detection, and entire experimental implementation is simple, fast
It is prompt, stable.
Embodiment 1:
1, the synthesis of 1- (6- picoline -3- bases) -2- (4- methyl mercaptos phenyl) ethyl ketone:
In a continuous flow type reactor, first material input inputs (the tetrahydrochysene furan of 4- (methyl mercapto) phenylacetic acid
It mutters solution (1mol/L concentration, 1mL/s flow velocitys), is heated to 60 degree through heat exchanger, second material input inputs tertiary butyl chloride
Change the tetrahydrofuran solution (2mol/L concentration, 1.5mL/s flow velocitys) of magnesium and mixed with solution shown in first entrance, and gas is installed
Body overflow device.It is then defeated from third material by 60 degree of heat exchanger in 60 minutes after the mixing of two kinds of solution
Entrance inputs the tetrahydrofuran solution (5mol/L concentration, 0.18mL/s flow velocitys) of 6- methvl-pyridinium -3- methyl formates, and 60
It by 60 degree of heat exchanger (must installation gas overflowing device) in minutes, and carries out concentration and collects tetrahydrofuran, concentrate
To material solution output speed about 1.0mL/s.
4th material input input toluene (1mL/s) then inputs 10% dilute hydrochloric acid in the 5th material input
(0.35mL/s), and must installation gas overflowing device.In continuous flow type dispenser, upper organic phase and output are collected.
10% sodium bicarbonate solution (0.8mL/s) is inputted in the 6th material input, in continuous flow type dispenser,
Collect lower layer's water phase and output.
10% hydrochloric acid (1.2mL/s) is inputted in the 7th material input, in continuous flow type dispenser, collects lower layer
Water phase and output.
30% sodium hydroxide (0.5mL/s) is inputted in the 8th material input, is output to equipment for separating liquid from solid, is collected
Solid.
2, the synthesis of 1- (6- picoline -3- bases) -2- (4- methanesulfonylphenYls) ethyl ketone:
In a continuous flow type reactor, first material input inputs 1- (6- picoline -3- bases) -2- (4-
MethanesulfonylphenYl) ethyl ketone ethyl acetate solution (1mol/L concentration, 1mL/s flow velocitys), second input port inputs sodium tungstate
Aqueous solution (0.1mol/L concentration, 0.1mL/s flow velocitys), 30 degree are heated to through heat exchanger.Third material input inputs
10.5% hydrogenperoxide steam generator (1mL/s flow velocitys, 3 equivalents) is simultaneously mixed with solution shown in first entrance, after two kinds of solution mixing,
By the cooler of 20-30 degree in 60 minutes, then hypo solution is inputted from the 4th material input
(2mol/L concentration, 1mL/s flow velocitys) collects upper organic phase and output in continuous flow type dispenser.
Organic phase is collected into container, until when reaching 20 liters, the post-processing that is concentrated and crystallized.
The yield of two-step reaction is 72%, purity 98.5%.
Embodiment 2:
1, the synthesis of 1- (6- picoline -3- bases) -2- (4- methyl mercaptos phenyl) ethyl ketone:
In a continuous flow type reactor, first material input inputs (the 2- methyl of 4- (methyl mercapto) phenylacetic acid
Tetrahydrofuran solution (1mol/L concentration, 1mL/s flow velocitys) is heated to 70 degree through heat exchanger, and second material input inputs uncle
The 2- methyltetrahydrofurans solution (2mol/L concentration, 2mL/s flow velocitys) of butylmagnesium chloride is simultaneously mixed with solution shown in first entrance
It closes, and gas overflowing device is installed.After the mixing of two kinds of solution, by 70 degree of heat exchanger in 40 minutes, then from
Third material input input 6- methvl-pyridinium -3- methyl formates 2- methyltetrahydrofurans solution (5mol/L concentration,
0.18mL/s flow velocitys), and the heat exchanger (gas overflowing device must be installed) in 40 minutes by 70 degree.
4th material input inputs 10% dilute hydrochloric acid (0.35mL/s), and must installation gas overflowing device.Continuous
In streaming dispenser, upper organic phase and output are collected.
10% sodium bicarbonate solution (0.8mL/s) is inputted in the 5th material input, in continuous flow type dispenser,
Collect lower layer's water phase and output.
10% hydrochloric acid (1.2mL/s) is inputted in the 6th material input, in continuous flow type dispenser, collects lower layer
Water phase and output.
30% sodium hydroxide (0.5mL/s) is inputted in the 7th material input, is output to equipment for separating liquid from solid, is collected
Solid.
2, the synthesis of 1- (6- picoline -3- bases) -2- (4- methanesulfonylphenYls) ethyl ketone:
In a continuous flow type reactor, first material input inputs 1- (6- picoline -3- bases) -2- (4-
MethanesulfonylphenYl) ethyl ketone ethyl acetate solution (1mol/L concentration, 1mL/s flow velocitys), second input port inputs sodium tungstate
Aqueous solution (0.1mol/L concentration, 0.1mL/s flow velocitys), 30 degree are heated to through heat exchanger.Third material input input 25%
Liquor natrii hypochloritis's (1mL/s flow velocitys) simultaneously mixes with solution shown in first entrance, after two kinds of solution mixing, in 60 minutes
The interior cooler by 20-30 degree, then from the 4th material input input hypo solution (2mol/L concentration,
1mL/s flow velocitys), in continuous flow type dispenser, collect upper organic phase and output.
Organic phase is collected into container, until when reaching 20 liters, the post-processing that is concentrated and crystallized.
The yield of two-step reaction is 69%, purity 96.4%.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (8)
1. a kind of Etoricoxib intermediate continuous flow production technology, it is characterised in that:Its method is:
Step 1:Using non-nucleophilic organic alkali as reagent, the synthesis of intermediate is carried out in continuous current micro-reactor;
Step 2:It is carried out in continuous current micro-reactor under transition-metal catalyst effect using cheap inorganic oxidizer
Oxidation technology;
Specifically include following reaction step:Using 4- (methyl mercapto) phenylacetic acids and 6- methyl-acidum nicotinicum methyl esters as starting material,
By using continuous flow type microreactor, two-step reaction occurs and generates 1- (6- picoline -3- bases) -2- (4- mesyl benzene
Base) ethyl ketone;Reaction equation is as follows:
2. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:The step
Non-nucleophilic organic base described in one, including lithium hexamethyldisilazide, lithium diisopropylamine, tertiary butyl magnesium chloride.
3. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:The step
Oxidant described in two includes hydrogen peroxide, sodium hypochlorite, sodium chlorite.
4. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:The step
Catalyst described in two includes manganous chloride, ferric trichloride, sodium tungstate, sodium molybdate.
5. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:The step
The dosage of non-nucleophilic organic alkali in one is 2-5 equivalents, and reaction temperature is 50-100 DEG C.
6. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:The step
The reaction temperature of continuous current micro-reactor in two is 20-80 DEG C.
7. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1, it is characterised in that:It is described continuous
Fluid micro-reactor is formed by nine glass response function block coupled in series, and each glass response function module is logical using three-decker
Road is the flow channel layer of reacting fluid among it, is sandwiched by two heat exchange layers, and the reaction channel includes feed inlet
One, cold heat exchanges the reaction that fluid inlet and outlet one, feed inlet two, discharge port, cold heat exchange 25 reaction channel of fluid inlet and outlet
It is 8mL that liquid, which holds fluid product, and heat exchange layers volume is 14mL, and the heat exchange area of unit reaction solution is up to 2500m2/m3, each glass
The a length of 2m of glass response function mould reaction channel in the block.
8. a kind of Etoricoxib intermediate continuous flow production technology according to claim 1 or claim 7, it is characterised in that:It is described
The technological process of continuous current micro-reactor is:Reactant A, B squeeze into 01, No. 02 mould of G1 micro passage reactions with constant flow pump respectively
The pre- hot/cold of block starts to mix, be reacted in No. 03 module, until No. 08 module reaction terminates, reaction module number is 6, often
Piece volume is 8.5mL, amounts to 51mL, adjusts the temperature in canaliculus reactor by high/low temperature control loop slot in experiment, passes through
Constant flow pump adjusts the flow and equivalent proportion of charging and after continuous operation 15min, is considered as system operation after each experiment condition setting
Stablize, sampling carries out gas chromatographic detection.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710226227.1A CN108689917A (en) | 2017-04-08 | 2017-04-08 | A kind of Etoricoxib intermediate continuous flow production technology |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710226227.1A CN108689917A (en) | 2017-04-08 | 2017-04-08 | A kind of Etoricoxib intermediate continuous flow production technology |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108689917A true CN108689917A (en) | 2018-10-23 |
Family
ID=63842303
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710226227.1A Pending CN108689917A (en) | 2017-04-08 | 2017-04-08 | A kind of Etoricoxib intermediate continuous flow production technology |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108689917A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113185418A (en) * | 2021-05-13 | 2021-07-30 | 山东师范大学实验厂 | Continuous flow production process of haematochrome B |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1278795A (en) * | 1997-09-25 | 2001-01-03 | 麦克公司 | Process for making diaryl pyridines useful as cox-2 inhibitors |
WO2001029004A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
WO2012066570A2 (en) * | 2010-11-15 | 2012-05-24 | Virdev Intermediates Pvt. Ltd. | A process for cyclooxygenase-2 selective inhibitor |
WO2013065064A1 (en) * | 2011-10-31 | 2013-05-10 | Sequent Scientific Limited | A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention |
CN104045596A (en) * | 2014-06-27 | 2014-09-17 | 成都克莱蒙医药科技有限公司 | Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one |
-
2017
- 2017-04-08 CN CN201710226227.1A patent/CN108689917A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1278795A (en) * | 1997-09-25 | 2001-01-03 | 麦克公司 | Process for making diaryl pyridines useful as cox-2 inhibitors |
WO2001029004A1 (en) * | 1999-10-15 | 2001-04-26 | Zambon Group S.P.A. | Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines |
US20020042375A1 (en) * | 2000-07-05 | 2002-04-11 | Heimbrook David C. | Method of treating cancer |
WO2012066570A2 (en) * | 2010-11-15 | 2012-05-24 | Virdev Intermediates Pvt. Ltd. | A process for cyclooxygenase-2 selective inhibitor |
WO2013065064A1 (en) * | 2011-10-31 | 2013-05-10 | Sequent Scientific Limited | A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention |
CN104045596A (en) * | 2014-06-27 | 2014-09-17 | 成都克莱蒙医药科技有限公司 | Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one |
Non-Patent Citations (3)
Title |
---|
何伟,等: "微反应器在合成化学中的应用", 《应用化学》 * |
穆金霞,等: "微通道反应器在合成反应中的应用", 《化学进展》 * |
郑亚锋,等: "微反应器研究及展望", 《化工进展》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113185418A (en) * | 2021-05-13 | 2021-07-30 | 山东师范大学实验厂 | Continuous flow production process of haematochrome B |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112979461B (en) | Full continuous flow preparation method of 3-chloro-4-oxoacetic acid amyl ester | |
CN105418343B (en) | The method that organic bromide is prepared using micro passage reaction | |
CN101489659B (en) | Mixing apparatus and process | |
CN105418548B (en) | For the microreactor and synthetic method of α-hydrogen atom chlorination of dicarbonyl compound α | |
CN105384617B (en) | The method that the chloracetyl cyclopropane of 1 chlorine 1 ' is prepared using microreactor device | |
CN108752161A (en) | The method of synthesis of alpha-single chloro ortho-xylene in continuous flow micro passage reaction | |
CN109134231A (en) | A kind of chloroacetic device and process of differential circulation continuous production | |
CN107501050A (en) | A kind of method that phenol is prepared using micro passage reaction | |
CN104649884B (en) | Method and production device of preparing glyoxylic acid through catalytic oxidization of glyoxal by air with nitrogen oxide under normal pressure | |
CN106608811A (en) | Method used for preparing chloropropene using microchannel reactors | |
CN108689917A (en) | A kind of Etoricoxib intermediate continuous flow production technology | |
Tan et al. | Coupling process of oxidation and extraction in a gas–liquid–liquid microdispersion system for H2O2 synthesis | |
CN108752175A (en) | A kind of continuous preparation method of benzil or derivatives thereof | |
Ahmed et al. | Role of operating conditions on cross contamination of products of the Bunsen reaction in iodine-sulfur process for production of hydrogen | |
CN107051366A (en) | A kind of continuous stream tubular reactor system and reaction control system | |
CN105013417B (en) | Continuous esterification micro-reaction apparatus and micro-reaction system composed of same | |
CN104478702A (en) | Method for synthesizing adipic acid by adopting microchannel reactor | |
CN201158590Y (en) | Chlorine dioxide generator | |
CN106334469A (en) | Static-state pipeline three-phase mixer and application thereof | |
CN109369498A (en) | A kind of method that microreactor continuously synthesizes the bromo- 2- rubigan -5- trifluoromethyl pyrpole -3- nitrile of 4- | |
CN100522897C (en) | Cyclohexane oxidation reactor | |
CN113845417B (en) | Method for synthesizing (+/-) -naproxen by using continuous flow micro-channel reactor oxidation | |
CN207365656U (en) | Pyrrolidones oxidation reaction apparatus | |
CN110105261A (en) | A method of continuous, rapid synthesis and purification epiphysin using microreactor | |
CN108003091A (en) | A kind of method that vismodegib is prepared using microchannel reaction unit |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181023 |