CN105713059A - Method for synthesizing zidovudine azide intermediate by using microchannel reactor - Google Patents
Method for synthesizing zidovudine azide intermediate by using microchannel reactor Download PDFInfo
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- CN105713059A CN105713059A CN201610001628.2A CN201610001628A CN105713059A CN 105713059 A CN105713059 A CN 105713059A CN 201610001628 A CN201610001628 A CN 201610001628A CN 105713059 A CN105713059 A CN 105713059A
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- zidovudine
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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Abstract
The invention discloses a method for synthesizing zidovudine azide intermediate by using a microchannel reactor, comprising: mixing and reacting zidovudine oxygen bridge and azide reagent as materials in a high-throughput microchannel reactor, acquiring outflow after reacting is over and a product flows out of an outlet of the reactor, cooling the outflow to 50-80 DEG C, dropwise adding water, adding an organic solvent for extracting and layering, and washing, concentrating and drying an organic layer to obtain the zidovudine azide intermediate. The microchannel reactor is used as a reaction device for continuous azide reaction, and the method has the advantages of high reacting speed, temperature control stability and process safety.
Description
Technical field
The present invention relates to the use of micro passage reaction and carry out azido reaction, specifically utilize the G1 glass high pass of Corning Incorporated
The method of amount micro passage reaction synthesis zidovudine azide intermediate.
Background technology
Zidovudine is anti-AIDS (AIDS) medicine of first FDA approval listing, azide intermediate (its structural formula such as formula
Shown in 1) it is a key intermediate in synthetic route.The synthesis of document introduction is all to carry out in tradition tank reactor
, response time length (see US5124442 and Synthesis, 1991 (3), 39-40), and the nitrine reagent tool used
There is explosive characteristic,
Formula 1
Wherein R is selected from alkyl, aryl alkyl, hydroxy alkyl or acyl group.
Healthy and free from worry high flux micro passage reaction is by special glass or special ceramic material manufacture, has outstanding resisting
Corrosive nature, high temperature resistant (200 DEG C) high pressure (18 kilograms of pressure), it is adaptable to multiple chemical reaction.The multiple structure of its uniqueness is whole
Body designs so that the mass-transfer performance of its total heat exchange efficiency and fluid mixing all exceeds a lot of times than traditional stirred tank reactor.
There is in multiple chemosynthesis is applied significant advantage: improve reaction yield and product purity, eliminate safe hidden trouble, shorten anti-
Answer the production cycle, reduce use and the generation of refuse of solvent.It is capable of from laboratory process to industrial amplification production
Slitless connection.
Micro passage reaction is utilized to synthesize in the middle of zidovudine nitrine to the azido reaction carrying out zidovudine oxygen bridge material
The method of body yet there are no document report.The present invention selects the high flux micro passage reaction of Corning Incorporated to carry out zidovudine oxygen
The azido reaction of bridge thing, synthesizes zidovudine azide intermediate, and product separation yield is more than 90%, and safety ratio passes
The autoclave mechanically stirred reactor of system wants height.
Summary of the invention
It is an object of the invention to provide one utilizes micro passage reaction to flow zidovudine oxygen bridge material nitrine continuously
Changing the method that zidovudine azide intermediate is synthesized, the method does not use conventional mechanical stirring-type reactor, utilizes fluid
The kinetic energy of itself completes sufficiently to mix, and reaction effect is good.And the heat-transfer effect of micro passage reaction own is good, can significantly carry
The conversion ratio of high raw material, course of reaction highly effective and safe, without amplifying risk.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, its feature includes following
Step:
1) preparation of reaction solution: under conditions of 60 80 DEG C, is slowly added to Azide reagent in organic solvent, prepares folded
Diazotizing reagent solution;Equally under conditions of 60 80 DEG C, zidovudine oxygen bridge material is slowly added in organic solvent, prepares
Zidovudine oxygen bridge material solution;
Wherein the structural formula of zidovudine oxygen bridge material is as follows:
Wherein the structural formula of zidovudine azide intermediate is as follows:
Wherein the Tr in zidovudine oxygen bridge material and zidovudine azide intermediate is trityl group;
2) solution feed of above two reactant to micro passage reaction will carry out hybrid reaction, reacted afterproduct from
The outlet of reactor is flowed out, and obtains effluent;
3) by step 2) effluent that obtains is cooled to 50-80 DEG C, and it is added dropwise in water, adds organic solvent and carry out extraction point
Layer, organic layer is scrubbed, concentrate, be dried and i.e. can get product zidovudine azide intermediate.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that nitrine
The mol ratio changing reagent and zidovudine oxygen bridge material is 1:1-6:1, preferably 2:1-3:1.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that micro-logical
The reaction time of road reactor is the 5-90 second;Reaction temperature is 80-150 DEG C;Reaction pressure is 0.3-1.5MPa.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that micro-logical
The reaction time of road reactor is the 15-50 second;Reaction temperature is 100-130 DEG C;Reaction pressure is 0.7-0.9 MPa.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that micro-logical
Road reactor is at least one, and micro passage reaction is heart-shaped structure G1 glass high channel micro passage reaction.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that nitrine
Changing the mass ratio of Azide reagent and organic solvent in reagent solution is 1:6-1:19, preferably 1:11 1:13.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that Qi Duo
It is 1:2-1:10 that husband determines the mass ratio of zidovudine oxygen bridge material and organic solvent in oxygen bridge material solution, preferably 1:3 1:
5。
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that nitrine
Changing reagent is Hydrazoic acid,sodium salt or Lithium Azide.
A kind of described method utilizing micro passage reaction synthesis zidovudine azide intermediate, it is characterised in that organic
Solvent is DMF or DMSO.
By using above-mentioned technology, compared with prior art, beneficial effects of the present invention following "
1) present invention carries out zidovudine oxygen bridge material synthesis zidovudine azide intermediate, this reactor by micro passage reaction
The heat transfer property of superelevation can be provided, it is possible to be greatly improved the conversion ratio of raw material, improve the selectivity of product, it can be ensured that be dangerous
The safe handling of Hydrazoic acid,sodium salt, it is easy to carry out industrialized production;
2) by the present invention in that with micro passage reaction without enlarge-effect, it is easy to upgrading is amplified, it is possible to achieve from research and development to production
Seamless scale-up;
3) micro passage reaction that the present invention uses is continuous flow reactor, can shorten the response time, improves production efficiency and product
Can, and it is easy and simple to handle, reaction condition is gentle, is suitable to industrial application.
Accompanying drawing explanation
Fig. 1 is the flow chart of the micro passage reaction of the present invention.
Detailed description of the invention
Be used for illustrating the present invention below in conjunction with embodiment, those skilled in the art invention is done simple replace or
Improve within falling within the technical scheme that the present invention is protected.
Micro passage reaction used by the present invention is the heart-shaped structure G1 glass high channel microchannel that Corning Incorporated produces
Reactor.
Embodiment 1:
The present invention at the flow chart of micro passage reaction as it is shown in figure 1, A and B is respectively sodium azide solution and zidovudine oxygen
Two feeding-passages of bridge thing, are connected with feed pump respectively, and two feeding-passages of A and B are briefly referred to as pump A and pump B.
Under conditions of 70 DEG C, Hydrazoic acid,sodium salt 83.6 g is slowly added in 1003.2 g DMSO, prepares Hydrazoic acid,sodium salt molten
Liquid;Equally under conditions of 70 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1500 g DMSO, prepares zidovudine
Oxygen bridge material solution.Pump A is used for into sodium azide solution, and arranging flow velocity is 25.4 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.036
Mol/min, pump B are used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 38.0 mL/min, are equivalent to zidovudine oxygen bridge
Thing 0.018 mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 2:1, Hydrazoic acid,sodium salt and zidovudine
Oxygen bridge material reacts in micro passage reaction, and reaction temperature is 120 DEG C, when the reaction in each micro passage reaction stops
Between be 30 s, system pressure is 0.7 Mpa.Product, after outlet out, is added to the water, and through extracting, wash, concentrating, is dried
I.e. can get product zidovudine azide intermediate, yield 90.8%.
Embodiment 2:
Device: healthy and free from worry G1 heart-shaped structure high flux micro passage reaction.
Under conditions of 75 DEG C, Hydrazoic acid,sodium salt 104.5 g is slowly added in 1358.5 g DMF, prepares Hydrazoic acid,sodium salt molten
Liquid;Equally under conditions of 75 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1050 g DMF, prepares zidovudine
Oxygen bridge material solution.Pump A is used for into sodium azide solution, and arranging flow velocity is 42.7 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.047
Mol/min, pump B are used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 33.0 mL/min, are equivalent to zidovudine oxygen bridge
Thing 0.019 mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 2.5:1, Hydrazoic acid,sodium salt and Qi Duofu
Determining oxygen bridge material to react in micro passage reaction, reaction temperature is 110 DEG C, and the reaction in each micro passage reaction stops
Time is 25 s, and system pressure is 0.8 Mpa.Product, after outlet out, is added to the water, and through extracting, wash, concentrating, does
Dry i.e. can get product zidovudine azide intermediate, yield 90.2%.
Embodiment 3:
Under conditions of 68 DEG C, Hydrazoic acid,sodium salt 125.4 g is slowly added in 1504.8 g DMSO, prepares sodium azide solution;
Equally under conditions of 68 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1140 g DMSO, prepares zidovudine oxygen
Bridge thing solution.Pump A is used for into sodium azide solution, and arranging flow velocity is 39.6 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.056 mol/
Min, pump B are used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 30.0 mL/min, is equivalent to zidovudine oxygen bridge material
0.019 mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 3:1, Hydrazoic acid,sodium salt and zidovudine oxygen
Bridge thing reacts in micro passage reaction, and reaction temperature is 120 DEG C, the reaction time in each micro passage reaction
Being 20 s, system pressure is 0.8 Mpa.Product, after outlet out, is added to the water, and through extracting, wash, concentrating, is dried i.e.
Available product zidovudine azide intermediate, yield 91.0%.
Embodiment 4:
Under conditions of 75 DEG C, Lithium Azide 63 g is slowly added in 756 g DMSO, prepares Lithium Azide solution;Exist equally
Under conditions of 75 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1140 g DMSO, prepares zidovudine oxygen bridge material molten
Liquid.Pump A is used for into Lithium Azide solution, and arranging flow velocity is 35.1 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.066 mol/min, pump
B is used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 53.0 mL/min, is equivalent to zidovudine oxygen bridge material 0.033
mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 2:1, and Hydrazoic acid,sodium salt and zidovudine oxygen bridge material exist
Reacting in micro passage reaction, reaction temperature is 125 DEG C, and the reaction time in each micro passage reaction is 23
S, system pressure is 0.8 Mpa.Product, after outlet out, is added to the water, through extract, wash, concentrating, dry the most available
Product zidovudine azide intermediate, yield 91.3%.
Embodiment 5:
Under conditions of 70 DEG C, Lithium Azide 72.4 g is slowly added in 905 g DMSO, prepares Lithium Azide solution;Equally
Under conditions of 70 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1170 g DMSO, prepares zidovudine oxygen bridge material
Solution.Pump A is used for into Lithium Azide solution, and arranging flow velocity is 33.3 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.060 mol/min,
Pump B is used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 43.0 mL/min, is equivalent to zidovudine oxygen bridge material 0.026
mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 2.3:1, Hydrazoic acid,sodium salt and zidovudine oxygen bridge material
Reacting in micro passage reaction, reaction temperature is 120 DEG C, and the reaction time in each micro passage reaction is 27
S, system pressure is 0.7 Mpa.Product, after outlet out, is added to the water, through extract, wash, concentrating, dry the most available
Product zidovudine azide intermediate, yield 90.6%.
Embodiment 6:
Under conditions of 72 DEG C, Lithium Azide 85 g is slowly added in 1062.5 g DMF, prepares Lithium Azide solution;Equally
Under conditions of 72 DEG C, zidovudine oxygen bridge material 300 g is slowly added in 1260 g DMF, prepares zidovudine oxygen bridge material molten
Liquid.Pump A is used for into Lithium Azide solution, and arranging flow velocity is 29.5 mL/min, is equivalent to Hydrazoic acid,sodium salt 0.045 mol/min, pump
B is used for into zidovudine oxygen bridge material solution, and arranging flow velocity is 35.0 mL/min, is equivalent to zidovudine oxygen bridge material 0.017
mol/min.Now the mol ratio of Hydrazoic acid,sodium salt and zidovudine oxygen bridge material is 2.7:1, Hydrazoic acid,sodium salt and zidovudine oxygen bridge material
Reacting in micro passage reaction, reaction temperature is 115 DEG C, and the reaction time in each micro passage reaction is 25
S, system pressure is 0.8 Mpa.Product, after outlet out, is added to the water, through extract, wash, concentrating, dry the most available
Product zidovudine azide intermediate, yield 90.9%.
Claims (9)
1. the method utilizing micro passage reaction synthesis zidovudine azide intermediate, its feature comprises the following steps:
1) preparation of reaction solution: under conditions of 60 80 DEG C, is slowly added to Azide reagent in organic solvent, prepares folded
Diazotizing reagent solution;Equally under conditions of 60 80 DEG C, zidovudine oxygen bridge material is slowly added in organic solvent, prepares
Zidovudine oxygen bridge material solution;
Wherein the structural formula of zidovudine oxygen bridge material is as follows:
Wherein the structural formula of zidovudine azide intermediate is as follows:
Wherein the Tr in zidovudine oxygen bridge material and zidovudine azide intermediate is trityl group;
2) solution feed of above two reactant to micro passage reaction will carry out hybrid reaction, reacted afterproduct from
The outlet of reactor is flowed out, and obtains effluent;
3) by step 2) effluent that obtains is cooled to 50-80 DEG C, and it is added dropwise in water, adds organic solvent and carry out extraction point
Layer, organic layer is scrubbed, concentrate, be dried and i.e. can get product zidovudine azide intermediate.
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
The mol ratio being characterised by Azide reagent and zidovudine oxygen bridge material is 1:1-6:1, preferably 2:1-3:1.
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
The reaction time being characterised by micro passage reaction is the 5-90 second;Reaction temperature is 80-150 DEG C;Reaction pressure is 0.3-
1.5MPa。
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
The reaction time being characterised by micro passage reaction is the 15-50 second;Reaction temperature is 100-130 DEG C;Reaction pressure is
0.7-0.9 MPa。
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
Being characterised by that micro passage reaction is at least one, micro passage reaction is the reaction of heart-shaped structure G1 glass high channel microchannel
Device.
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
It is characterised by Azide reagent solution that the mass ratio of Azide reagent and organic solvent is 1:6-1:19, preferably 1:11
– 1:13。
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
It is characterised by zidovudine oxygen bridge material solution that the mass ratio of zidovudine oxygen bridge material and organic solvent is 1:2-1:10, excellent
Elect 1:3 1:5 as.
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
It is characterised by that Azide reagent is Hydrazoic acid,sodium salt or Lithium Azide.
A kind of method utilizing micro passage reaction synthesis zidovudine azide intermediate the most according to claim 1, its
It is characterised by that organic solvent is DMF or DMSO.
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Cited By (1)
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