CN110105253A - Application of the serialization micro passage reaction in pharmaceutical synthesis - Google Patents
Application of the serialization micro passage reaction in pharmaceutical synthesis Download PDFInfo
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- CN110105253A CN110105253A CN201810100499.1A CN201810100499A CN110105253A CN 110105253 A CN110105253 A CN 110105253A CN 201810100499 A CN201810100499 A CN 201810100499A CN 110105253 A CN110105253 A CN 110105253A
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- serialization
- reaction
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- microchannel plate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides application of the serialization micro passage reaction in pharmaceutical synthesis, more particularly to more reaction serializations of serialization micro passage reaction.The serialization more reacted has the characteristics of continuous output of the multistep reaction continuous feed of more significant ground, successive reaction and product, has the advantage of safe and environment-friendly and suitable industrialization.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to application of the serialization micro passage reaction in pharmaceutical synthesis,
The characteristics of can be realized the continuous output of multistep reaction continuous feed, successive reaction and product has safe and environment-friendly and is suitble to produce
The advantage of industry.
Background technique
Micro passage reaction is in periodical literature the 5th phase chemical industry progress of volume 23 " microreactor research and prospect " in 2004
In, the superiority for having big reactor incomparable in chemistry and chemical field by report microreactor shows temperature control,
Reactor volume, conversion ratio and yield guarantee safety, be easy to amplify etc..
Also, in periodical literature chemical progress 2008 the 1st phases " micro passage reaction answering in synthetic reaction of volume 20
With " page 67 common gas-liquid-solid multinomial catalysis is defined as to the hydrogenation of organic compound and is reacted.In urging for cyclohexene
Change the cross channel microreactor intersected in hydrogenation reaction using long and short two channel.It is catalysed and reduced into aniline in nitrobenzene
Gas-liquid-solid reaction is carried out using 64 parallel channels.But by further studying, think in the periodical literature,
Proper mode is that catalyst is fixed on to channel surface, has bigger contact area between such reactant, more
It is suitble to the phase reaction in microchannel to ketone, alkene, diene, alkynes etc..
Summarize in addition, the periodical literature has carried out experimental result to hydrogenation,
In Chinese granted patent CN103694169B, 2,2,4- trimethyl -1,2- dihydros are prepared using micro passage reaction
Quinoline and its polymer, Chinese patent application CN105566120A prepare isooctyl ester nitrate using micro passage reaction, and China is specially
Aniline diazotising is prepared phenylhydrazine using micro passage reaction by benefit application CN106316879A.
However, above-mentioned react the relatively conventional one-step reaction that is related to using micro passage reaction, current research and development are existing
Shape is also confined in the microchannel level of one-step reaction, thus, from angle prepared by final pharmaceutical synthesis and industrialized production
Degree sets out, it is necessary to which developing one whole should prepare final raw material from starting material or in which mesosome multistep serialization microchannel plate
One precursor reactant of serialization of medicine finally successfully realizes the theory and most of application of the serialization micro passage reaction in pharmaceutical synthesis
The good target for reaching industrialized production with this special kind of skill.
Summary of the invention
The present invention provides a kind of application of serialization micro passage reaction in pharmaceutical synthesis, can be realized multistep reaction
The characteristics of continuous output of continuous feed, successive reaction and product, has the advantage of safe and environment-friendly and suitable industrialization.
To achieve the above object, technical solution provided by the invention are as follows:
Firstly, preparing this intermediate of azido compound by serialization micro passage reaction, the azido compound can
Think it is well known in the art have general formula structure be RN3Compound, preferably can be nitrine sulfoacid compound.
First aspect present invention provides the method that serialization microchannel plate should prepare nitrine sulfoacid compound, by hydrazine sulphur
The aqueous solution of acyl compound and sodium nitrite is prepared in micro passage reaction.
Wherein, R is substituent group commonly used in the art, such as alkyl, alkoxy, aryl etc..It is more preferably methyl, methylbenzene
Base, to dodecylphenyl or p-methoxyphenyl.
The two step serialization microchannel plates that second aspect of the present invention can be realized nitrine sulfoacid compound are answered, by hydrazine chemical combination
After object reacts in first micro passage reaction with sulfonyl chloride compound, continue micro- at second with the aqueous solution of sodium nitrite
In channel reactor reaction can serialization be prepared,
Wherein, R is substituent group commonly used in the art, such as alkyl, alkoxy, aryl etc..It is more preferably methyl, methylbenzene
Base, to dodecylphenyl or p-methoxyphenyl.
The above-mentioned azido compound being prepared through two step serializations of the present invention can be further through third microchannel plate
Device preparation is answered to train southern intermediate.Specifically, third aspect present invention provides under the action of nitrine sulfoacid compound, formula III
The further serialization microchannel plate that compound prepares the southern intermediate formula IV compound of training in micro passage reaction is answered,
Wherein, R1It is preferably TBS or TBDMS for hydroxyl protection base.
The increase separation equipment of above-mentioned second microchannel and the third micro passage reaction property of can choose.
Specially feed pump 1 is sulfonyl chloride compound or the mixed liquor of its organic solvent；If methylsufonyl chloride is without being equipped with
At solution, and benzene sulfonyl chloride, paratoluensulfonyl chloride, to dodecyl benzene sulfonyl chloride or to Methoxybenzenesulfonyl chloride and organic solvent
Mixed liquor be feeding liquid etc.；
Feed pump 2 is hydrazine hydrate；
Feed pump 3 is sodium nitrite in aqueous solution；
Feed pump 4 is organic solvent；
Feed pump 5 is the mixed liquor of formula III compound and alkali；
Feed pump 6 is water.
Organic solvent described above can be the single molten of ethers, esters, arene, alkyl halide hydro carbons or alcohols solvent
Agent or mixed solvent.
The ether solvent is tetrahydrofuran or 2- methyltetrahydrofuran；The esters solvent is ethyl acetate, formic acid second
Ester or isopropyl acetate；The alcohols solvent is ethyl alcohol or isopropanol.
The aromatic hydrocarbon solvent is toluene；The halogenated alkanes solvents are methylene chloride.
The alkali is organic base, such as triethylamine, morpholine, N-methylmorpholine, DBU, potassium tert-butoxide, sodium tert-butoxide, diisopropyl
Base ethamine, pyridine, DMAP, triethylene diamine or tetramethylethylenediamine etc..
The temperature of the reaction is controlled at 0 DEG C~100 DEG C.
Above-mentioned multistep serialization microchannel plate should the property of can choose increase separation equipment.
Micro passage reaction used in the present invention can be single channel, multichannel, and the micro passage reaction can be
Multi-disc micro passage reaction is connected in series, and shape is U-shaped, T-type, Y type or cross type etc..
The microchannel plate that multistep continuous reaction of the present invention belongs to a wire type is answered, and has the advantage of safety and environmental protection.This hair
The microchannel plate that bright multistep continuous reaction belongs to a wire type is answered, and has the significant advantage in technical effect.Such as nitrine chemical combination
In the serialization preparation process of object, the prior art does not apply to the serialization of two steps, because of the substitution connection that the first step generates
Ammoniate is solid.However, the present invention continues to continue to react with the acid that first step microchannel plate should generate, will solve
The technical issues of certainly microchannel plate answers middle solid to make microchannel plate that should block, not can be carried out, so that second step microchannel plate should be able to
It is enough normally carried out, also, waste liquid is further reduced and more environmentally-friendly, energy conservation.
Figure of description
Fig. 1 is multistep serialization microchannel response diagram
Specific embodiment
For a further understanding of the present invention, exist below with reference to embodiment to serialization micro passage reaction provided by the invention
Application in pharmaceutical synthesis is described in detail.It is to be appreciated that the description of these embodiments is only further description
Feature of the invention, rather than the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1:
Feed pump 1: methylsufonyl chloride
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, and it is molten to obtain product
Liquid.White solid, yield 90%, purity 98% are obtained through processing.
Embodiment 2:
Feed pump 1: the mixed liquor of paratoluensulfonyl chloride and toluene
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, product solution processing
Obtain white solid, yield 89%, purity 98.5%.
Embodiment 3:
Feed pump 1: the mixed liquor of benzene sulfonyl chloride and dimethylbenzene
Feed pump 2: hydrazine hydrate
Feed pump 3: sodium nitrite in aqueous solution
Feed pump 4: methylene chloride
Feed pump 5: the mixed liquor of formula III compound and triethylamine
Feed pump 6: water
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, organic layer carries out subsequent reactions, and feed pump 5 starts the mixed liquor into formula III compound and alkali, mixed online
Reaction (2min~10min) is closed, temperature (20~80 DEG C) are arranged in reaction module, according to reaction dissolvent such as methylene chloride reaction module
Back pressure is needed to prevent temperature from increasing solvent evaporation, the reaction water inlet of node feed pump 6 carries out on-line cooling and is quenched, product solution processing
Obtain white solid, yield 88%, purity 97%.
Embodiment 4: methylsulphur acyl azide preparation
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, methylsulphur acyl azide dichloromethane solution, yield 80%.(due to the unstability of nitrine reagent, so using serialization
Reactor, while production while uses, avoid due to nitrine largely existing for risk)
Embodiment 5: p-toluene sulfonyt azide preparation
Feed pump 1 sets parameter with feed pump 2 while feeding, temperature (0 DEG C~100 needed for reaction module setting
DEG C), it carries out on-line mixing reaction (1min~10min), after feed pump 3 starts charging participation according to above-mentioned reaction time node
Continuous reaction, subsequent module temperature setting (10 DEG C~90 DEG C) carry out on-line mixing reaction (10s~120S), and reaction node carries out
On-line cooling to 20 DEG C, feed pump 4 start to carry out into Extraction solvent on-line mixing extract again by wire separation system water layer into
To waste, methylsulphur acyl azide dichloromethane solution, yield 75%.(due to the unstability of nitrine reagent, so using serialization
Reactor, while production while uses, avoid due to nitrine largely existing for risk).
Claims (10)
1. a kind of method that serialization microchannel plate should prepare sulfonyl azide compound, which is characterized in that by hydrazine sulphonyl chemical combination
The aqueous solution of object and sodium nitrite is prepared in micro passage reaction,
Wherein, R is alkyl, alkoxy or aryl.
2. a kind of method that serialization microchannel plate should prepare sulfonyl azide compound, which is characterized in that by hydrazine compound with
After sulfonyl chloride compound reacts in first micro passage reaction, continue the aqueous solution with sodium nitrite second microchannel
In reactor reaction can serialization be prepared,
Wherein, R is alkyl, alkoxy or aryl.
3. preparation method according to claim 1 or 2, which is characterized in that the R is methyl, aminomethyl phenyl, to dodecane
Base phenyl or p-methoxyphenyl.
4. a kind of serialization microchannel plate should prepare the method for training southern intermediate, which is characterized in that prepared in claims 1 or 2
Under the action of obtained nitrine sulfoacid compound, the mixed liquor of formula III compound and alkali is answered through further serialization microchannel plate
Southern intermediate formula IV compound is trained in preparation,
Wherein, R1For hydroxyl protection base.
5. the preparation method according to claim 4, which is characterized in that R1For TBS or TBDMS.
6. a kind of serialization microchannel plate should prepare the method for training southern intermediate, which is characterized in that mesyl chloride is feeding liquid, water
Conjunction hydrazine is feeding liquid, and sodium nitrite in aqueous solution is feeding liquid, and the mixed liquor of formula III compound and alkali is feeding liquid, organic solvent
For feeding liquid, water is feeding liquid, should prepare the southern intermediate formula IV compound of training through multistep serialization microchannel plate,
7. the preparation method according to claim 4 or 6, which is characterized in that the alkali is organic base.
8. the preparation method according to claim 4 or 6, which is characterized in that the organic solvent is ethers, esters, fragrance
The single solvent or mixed solvent of hydro carbons, alkyl halide hydro carbons or alcohols solvent.
9. the preparation method according to claim 4 or 6, which is characterized in that the reaction temperature is 0 DEG C~100 DEG C.
10. the preparation method according to claim 4 or 6, which is characterized in that the multistep serialization microchannel plate Ying Zhongxuan
Selecting property increases separation equipment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810100499.1A CN110105253A (en) | 2018-02-01 | 2018-02-01 | Application of the serialization micro passage reaction in pharmaceutical synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201810100499.1A CN110105253A (en) | 2018-02-01 | 2018-02-01 | Application of the serialization micro passage reaction in pharmaceutical synthesis |
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| CN110105253A true CN110105253A (en) | 2019-08-09 |
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| CN201810100499.1A Pending CN110105253A (en) | 2018-02-01 | 2018-02-01 | Application of the serialization micro passage reaction in pharmaceutical synthesis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110467161A (en) * | 2019-09-25 | 2019-11-19 | 山东省化工研究院 | A kind of synthesis technology of sodium azide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105947999A (en) * | 2016-04-29 | 2016-09-21 | 南京远淑医药科技有限公司 | Method for synthesizing imidodisulfuryl fluoride lithium salt by utilizing hydrazine |
| CN107636161A (en) * | 2015-05-27 | 2018-01-26 | 豪夫迈·罗氏有限公司 | The mechanism of antimicrobial sensitiveness |
-
2018
- 2018-02-01 CN CN201810100499.1A patent/CN110105253A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107636161A (en) * | 2015-05-27 | 2018-01-26 | 豪夫迈·罗氏有限公司 | The mechanism of antimicrobial sensitiveness |
| CN105947999A (en) * | 2016-04-29 | 2016-09-21 | 南京远淑医药科技有限公司 | Method for synthesizing imidodisulfuryl fluoride lithium salt by utilizing hydrazine |
Non-Patent Citations (3)
| Title |
|---|
| DOUGLAS S. MASTERSON ET AL.，: "Free-Radical Azidation with γ-15N-Labeled Phenylsulfonyl Azide", 《SYNLETT》 * |
| VINICIUS R. CAMPOS ET AL.: "Synthesis, biological, and theoretical evaluations of new 1,2,3-triazoles against the hemolytic profile of the Lachesis muta snake venom", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 赵忠奎 等 编著: "《高效反应技术与绿色化学》", 31 July 2012, 中国石化出版 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110467161A (en) * | 2019-09-25 | 2019-11-19 | 山东省化工研究院 | A kind of synthesis technology of sodium azide |
| CN110467161B (en) * | 2019-09-25 | 2021-07-06 | 山东省化工研究院 | Synthesis process of sodium azide |
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