CN107459500A - A kind of pipeline synthesis technique for arranging net class medicine - Google Patents
A kind of pipeline synthesis technique for arranging net class medicine Download PDFInfo
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- CN107459500A CN107459500A CN201710872304.0A CN201710872304A CN107459500A CN 107459500 A CN107459500 A CN 107459500A CN 201710872304 A CN201710872304 A CN 201710872304A CN 107459500 A CN107459500 A CN 107459500A
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- pipeline
- synthesis technique
- net class
- class medicine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- 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
- B01J14/00—Chemical processes in general for reacting liquids with liquids; Apparatus specially adapted therefor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to the pipeline synthesis technique for arranging net class medicine, the synthesis technique is based on pipeline reactor, and the pipeline reactor includes the first segment pipe for preheating and the second segment pipe for reaction, and synthesis step is as follows：Raw material is dissolved separately in organic solvent, is pumped into pipeline reactor respectively, is introduced into the first segment pipe and is preheated；The second segment pipe is respectively enterd after the preheating some time and is pumped into inorganic base aqueous solution via second segment pipe joint, is discharged after retaining some time, post processing is carried out and respectively obtains the net class bulk drug of row.Compared with prior art, the beneficial effects of the present invention are：The device miniaturization and serialization for arranging net class production of raw medicine are realized using pipe reaction technique, material mass-and heat-transfer is stable, has higher synthesis yield than gap reaction.
Description
Technical field
The invention belongs to chemical drugs synthesis technical field, and in particular to arrange the pipeline synthesis technique of net class medicine.
Background technology
Net class medicine is arranged, such as Dapagliflozin, Ai Gelie is net, canagliflozin and ipragliflozin etc., is a kind of glucopyranose
The benzene derivative of base substitution, sodium-glucose available for type ii diabetes treatment operate albumen (SGLT2) inhibitor in the same direction, all
In commercially available extensive use.The production technology of such bulk drug is all gap production technology at present, and it is big reaction vessel to be present,
The problems such as yield is unstable, the serious large-scale production for limiting bulk drug.
The content of the invention
The purpose of the present invention is exactly to improve the reaction efficiency for arranging net class medicine final step hydrolysis, so as to realize reaction
Device miniaturization and serialization, improve production capacity.
The technical solution adopted by the present invention is as follows：
A kind of pipeline synthesis technique for arranging net class medicine, the synthesis technique are based on pipeline reactor, the pipe reaction
Device includes the first segment pipe for preheating and the second segment pipe for reaction, and synthesis step is as follows：Such as raw material point in formula (I)
It is not dissolved in organic solvent, is pumped into pipeline reactor respectively, is introduced into the first segment pipe and is preheated；After preheating some time
Respectively enter the second segment pipe and be pumped into inorganic base aqueous solution via second segment pipe joint, discharge, enter after retaining some time
Row post processing respectively obtains the net class bulk drug of row as shown in formula (II)；
Preferably, the pipeline reactor is 0.5 millimeter -500 millimeters of interior diameter, the tetrafluoroethene that 1 meter -500 meters of length
Pipe or stainless steel tube or titanium alloy tube.
More there is choosing, preferably interior diameter is 10 millimeters, the tetrafluoroethene pipe of 100 meters of length.
Preferably, it is that flow velocity used in 1mL/min-5L/min is 1mL/min-5L/min that raw material, which is pumped into flow velocity,；It is preferred that 50mL/
min。
Preferably, inorganic base used be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate,
Cesium carbonate, lithium carbonate, sodium acid carbonate, saleratus, ammonium hydrogen carbonate, sodium phosphate, potassium phosphate, phosphoric acid caesium, lithium phosphate；It is preferred that hydrogen-oxygen
Change lithium.
Preferably, organic solvent used is：Tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane, ethyl acetate,
Butyl acetate, dimethyl carbonate, diethyl carbonate, diethylene glycol dimethyl ether, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether(MTBE),
Cyclopentyl methyl ether, benzene, toluene, fluorobenzene, chlorobenzene, C4~C8 alkane in one or two kinds of any of the above ratio mixing it is molten
Agent；Preferably described solvent is 2- methyltetrahydrofurans.
Preferably, the ratio of raw materials used (I) and organic solvent is 1: 2~1: 1000 (kg: L), preferably 1: 5.
Preferably, range of reaction temperature is 0 degree Celsius~100 degrees Celsius, preferably 20 degrees Celsius -40 degrees Celsius.
Preferably, the ratio of inorganic base and water used is 1: 2~1: 1000 (kg: L), preferably 1: 20.
Preferably, post-processing approach is：Reaction solution enters storage tank, carries out static layering, organic layer pickling, activated carbon decolorizing
After filter, filtrate is concentrated into a large amount of solids and separated out.
Compared with prior art, the beneficial effects of the present invention are：Realized using pipe reaction technique and arrange net class bulk drug
The device miniaturization and serialization of production, material mass-and heat-transfer is stable, has higher synthesis yield than gap reaction.
Embodiment：
Technical scheme, but protection scope of the present invention not limited to this are illustrated with specific embodiment below：
The preparation of the Dapagliflozin of embodiment 1
The tetrahydrofuran solution (concentration 0.3kg/L, 50L) of Dapagliflozin intermediate is pumped into interior with 20mL/min speed
Directly through 5 millimeters, in long 10 meters of first paragraph stainless steel reaction pipe, temperature control to 20 degree, sodium hydrate aqueous solution (0.5kg/L) with
10mL/min speed is pumped into interior directly through 5 millimeters, and in long 90 meters of second segment stainless steel reaction pipe, temperature control is to 20 degree, reaction solution
It is static to flow into vertical fluid-storage tank, separates organic phase, organic layer is washed once with 5% aqueous potassium hydrogen sulfate, mistake after activated carbon decolorizing
Filter, filtrate are concentrated into a large amount of solids and separated out, and filter to obtain 8.77kg Dapagliflozin products, yield 81.0%.
The preparation net Ai Gelie of embodiment 2
The ethyl acetate solution (concentration 0.03kg/L, 500L) of the net intermediates of Ai Gelie is pumped into 40mL/min speed
Inside directly through 10 millimeters, in long 20 meters of first paragraph tetrafluoroethene tube reaction pipe, temperature control is to 30 degree, potassium hydroxide aqueous solution
(0.1kg/L) be pumped into 20mL/min speed it is interior directly through 10 millimeters, in long 150 meters of second segment tetrafluoroethene tube reaction pipe,
For temperature control to 30 degree, reaction solution inflow vertical fluid-storage tank is static, separates organic phase, organic layer washes one with 5% aqueous potassium hydrogen sulfate
It is secondary, filtered after activated carbon decolorizing, filtrate is concentrated into a large amount of solids and separated out, and filters to obtain the net products of 8.27kg Ai Gelie, yield
73.5%.
The preparation of the canagliflozin of embodiment 3
The dimethyl carbonate solution (concentration 0.1kg/L, 100L) of canagliflozin intermediate is with 300mL/min speed pump
Enter interior directly through 20 millimeters, in long 20 meters of first paragraph titanium alloy reaction tube, temperature control is to 50 degree, lithium hydroxide aqueous solution (0.05kg/
L) be pumped into 100mL/min speed it is interior directly through 20 millimeters, in long 200 meters of second segment titanium alloy reaction tube, temperature control to 50 degree,
Reaction solution inflow vertical fluid-storage tank is static, separates organic phase, and organic layer is washed once with 5% aqueous potassium hydrogen sulfate, and activated carbon takes off
Filtered after color, filtrate is concentrated into a large amount of solids and separated out, and filters to obtain 6.26kg canagliflozin products, yield 84.6%.
The preparation of the ipragliflozin of embodiment 4
The toluene solution (concentration 0.15kg/L, 100L) of ipragliflozin intermediate is pumped into interior straight with 50mL/min speed
Through 100 millimeters, in long 20 meters of first paragraph stainless steel reaction pipe, temperature control to 10 degree, wet chemical (0.05kg/L) with
50mL/min speed is pumped into interior directly through 100 millimeters, and in long 100 meters of second segment stainless steel reaction pipe, temperature control reacts to 10 degree
It is static that liquid stream enters vertical fluid-storage tank, separates organic phase, organic layer is washed once with 5% aqueous potassium hydrogen sulfate, after activated carbon decolorizing
Filtering, filtrate are concentrated into a large amount of solids and separated out, and filter to obtain 8.47kg ipragliflozin products, yield 80.1%.
The preparation of the Dapagliflozin of comparative example 1
In 500L reactor, add Dapagliflozin intermediate tetrahydrofuran solution (concentration 0.15kg/L,
100L), lithium hydroxide aqueous solution (concentration 0.15kg/L, 100L) temperature control is added to 20 degree stirring reactions 6 hours, it is static, divide
From organic phase, organic layer is washed once with 5% aqueous potassium hydrogen sulfate, is filtered after activated carbon decolorizing, and filtrate is concentrated into a large amount of solids
Separate out, filter to obtain 6.90kg Dapagliflozin products, yield 63.7%.
Claims (10)
1. a kind of pipeline synthesis technique for arranging net class medicine, it is characterised in that the synthesis technique is based on pipeline reactor, described
Pipeline reactor includes the first segment pipe for preheating and the second segment pipe for reaction, and synthesis step is as follows：Such as formula (I)
Middle raw material is dissolved separately in organic solvent, is pumped into pipeline reactor respectively, is introduced into the first segment pipe and is preheated；If preheating
The second segment pipe is respectively enterd after the dry time and is pumped into inorganic base aqueous solution via second segment pipe joint, after retaining some time
Discharging, carry out post processing and respectively obtain the net class bulk drug of row as shown in formula (II)；
2. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that the pipeline reactor is
0.5 millimeter -500 millimeters of interior diameter, the tetrafluoroethene pipe or stainless steel tube or titanium alloy tube of 1 meter -500 meters of length.
3. the pipeline synthesis technique of the net class medicine of row according to claim 2, it is characterised in that the pipeline reactor is
Interior diameter is 10 millimeters, the tetrafluoroethene pipe of 100 meters of length.
4. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that raw material is pumped into flow velocity and is
1mL/min-5L/min。
5. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that inorganic base used is hydrogen-oxygen
Change sodium, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acid carbonate, bicarbonate
Potassium, ammonium hydrogen carbonate, sodium phosphate, potassium phosphate, phosphoric acid caesium or lithium phosphate.
6. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that organic solvent used is：
Tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane, ethyl acetate, butyl acetate, dimethyl carbonate, diethyl carbonate,
Diethylene glycol dimethyl ether, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether(MTBE), cyclopentyl methyl ether, benzene, toluene, fluorobenzene, chlorobenzene, C4
The mixed solvent of one or two kinds of any of the above ratio in~C8 alkane.
7. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that raw material (I) quality kg with
The volume L ratios of organic solvent are 1: 2~1: 1000.
8. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that range of reaction temperature 0
Degree Celsius~100 degrees Celsius.
9. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that the quality of inorganic base used
The volume L ratios of kg and water are 1: 2~1: 1000.
10. the pipeline synthesis technique of the net class medicine of row according to claim 1, it is characterised in that in the step (1)
Post-processing approach is：Reaction solution enters storage tank, carries out static layering, organic layer pickling, is filtered after activated carbon decolorizing, filtrate concentration
Separated out to a large amount of solids.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710872304.0A CN107459500A (en) | 2017-09-25 | 2017-09-25 | A kind of pipeline synthesis technique for arranging net class medicine |
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| CN201710872304.0A CN107459500A (en) | 2017-09-25 | 2017-09-25 | A kind of pipeline synthesis technique for arranging net class medicine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396119A (en) * | 2018-04-24 | 2019-11-01 | 上海迪赛诺药业股份有限公司 | The preparation method of canagliflozin intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910609A (en) * | 2014-04-10 | 2014-07-09 | 安徽海华科技股份有限公司 | Method for synthesizing cresol |
-
2017
- 2017-09-25 CN CN201710872304.0A patent/CN107459500A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910609A (en) * | 2014-04-10 | 2014-07-09 | 安徽海华科技股份有限公司 | Method for synthesizing cresol |
Non-Patent Citations (3)
| Title |
|---|
| MENG ET AL.: "Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes", 《J. MED. CHEM.》 * |
| 张郢峰: "《化工单元操作技术 下》", 30 November 2012, 天津大学出版社 * |
| 李光霁: "《过程装备与控制工程生产实习指导》", 30 September 2012, 华东理工大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396119A (en) * | 2018-04-24 | 2019-11-01 | 上海迪赛诺药业股份有限公司 | The preparation method of canagliflozin intermediate |
| CN110396119B (en) * | 2018-04-24 | 2022-11-08 | 上海迪赛诺药业股份有限公司 | Preparation method of canagliflozin intermediate |
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