CN103588662A - Method for synthesis of betamipron in continuous-flow microreactor - Google Patents
Method for synthesis of betamipron in continuous-flow microreactor Download PDFInfo
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Abstract
The invention discloses a method for synthesis of betamipron in a continuous-flow microreactor. The method comprises the following steps: 1) injecting an aqueous solution containing 0.5-1 M of a mixture of beta-alanine, sodium hydroxide and sodium bicarbonate into a micro mixer through a connecting pipe at a flow rate of 4-48 [mu]l/min, at the same time, injecting benzoyl chloride into the micro mixer through a same-diameter connecting pipe at a flow rate of 0.35-4.14 [mu]l/min, mixing, then allowing the mixed solution to go into the micro-tube reactor for reaction, and thus obtaining a betamipron sodium salt solution, wherein the water bath temperature of the microreactor is -5 DEG C to 5 DEG C, the micro-tube diameter of the micro-tube reactor is 0.3-1.5 mm, and the tube length is 1-3 m; 2) acidizing the betamipron sodium salt solution by concentrated hydrochloric acid until the pH is 2, precipitating out a betamipron solid, filtering, washing, and drying to obtain the betamipron. The betamipron is synthesized in the continuous-flow microreactor; through precise control of mixing of the raw materials and strengthening condensation reaction conditions, the main reaction speed is accelerated, and generation of a benzoyl chloride hydrolysis side reaction is reduced, so that the content of benzoic acid in the crude product is reduced, the purification operation is simplified, and the betamipron yield is improved.
Description
Technical field
The present invention relates to the method for synthetic Betamipron, relate in particular to the method for synthetic Betamipron in a kind of continuous current micro-reactor.
Background technology
Betamipron (Betamipron) also referred to as "
n-benzoyl-Beta-alanine ", be a kind of normal and compound that microbiotic panipenem share with the ratio of 1:1.Panipenem-Betamipron belongs to carbapenem antibiotic medicine, the features such as, toxicity strong with has a broad antifungal spectrum, anti-microbial activity and resistance are low have caused to be paid close attention to widely, become that in the microbiotic market, effective antibacterials ， world of the infection of severe infections, multi-drug resistant bacteria, polyinfection in treatment institute, oneself occupies critical role [1].Betamipron energy competitive inhibition panipenem is to tubular secretion, thereby reduction panipenem is in renocortical concentration, weakens the renal toxicity of panipenem.
The synthetic method of bibliographical information is that to take β-alanine and excessive Benzoyl chloride (1.5-2 times of equivalent) be raw material, and in popular response device, after condensation, Betamipron [2] is prepared in acidifying.The phenylformic acid that in reaction process, Benzoyl chloride hydrolysis produces is Main By product, with benzene washing, remove most phenylformic acid, more just can obtain highly purified Betamipron through recrystallization repeatedly, in purge process, use the benzene of high poison as solvent, complicated operation, and purification yield is low.
Use serialization micro passage reaction (microreactor, Microreactor/Microfluidic reactor) carry out chemical reaction (micro-fluidic reaction or the reaction of micro-Continuous Flow, Microfluidic reaction/ Microcontinuous flow reaction) become an emerging reaction technology and be successfully used to synthetic multiple organic compound [3,4].Continuous Flow micro-reaction device is by Micropump, micro-reservoir, connect microtubule, micro mixer, microreactor forms, its principal character is that the resulting structure of containing fluid (comprises passage, reaction chamber and other functional component) in a dimension, be at least micron order yardstick, compare with conventional chemical reactor, enlarged markedly the area-volume ratio of fluid environment, cause producing in microfluidic system a series of relevant with body surface, determine the peculiar effect of its property, as laminar flow effect, surface tension and capillary effect, Rapid Thermal conduction effect and diffusional effect etc.Therefore, utilize microflow control technique can reinforcing mass transfer and heat transfer effect etc. affect the factor of organic synthesis, and can change by designed channel flow pattern and the combination process of substrate, direction and degree that regulation and control reaction is carried out, improve selectivity, speed and the processing safety of reaction.Therefore, we have developed the novel method of synthetic Betamipron in continuous current micro-reactor.
Reference:
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Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, the method for synthetic Betamipron in a kind of continuous current micro-reactor is provided.
In continuous current micro-reactor, the step of the method for synthetic Betamipron is as follows:
1) aqueous solution of the Beta-alanine of 0.5 ~ 1M, sodium hydroxide and sodium bicarbonate mixture injects micro mixer by pipe connecting with flow velocity 4-48ul/min, simultaneously, Benzoyl chloride injects after micro mixer mixing with flow velocity 0.35-4.14 ul/min by same diameter pipe connecting, enter microtubule reactor reaction, obtain the solution of Betamipron sodium salt, the bath temperature of microreactor is-5
oc ~ 5
oc;
2) solution of Betamipron sodium salt is acidified to pH=2 through concentrated hydrochloric acid, separates out Betamipron solid, and after filtration, washing, dry obtain Betamipron, the molecular structural formula of Betamipron is:
The microtubule diameter of described microtubule reactor is 0.3 ~ 1.5mm, and pipe range is 1 ~ 3m.
The present invention is synthetic Betamipron in continuous current micro-reactor, by accurate control raw material, mix and strengthening condensation reaction condition, accelerate main reaction speed, reduce the generation of Benzoyl chloride hydrolytic side reactions, thereby benzoic content in reduction crude product, simplify purification process, improve the yield of Betamipron.
Accompanying drawing explanation
Fig. 1 is the method flow schematic diagram of synthetic Betamipron in continuous current micro-reactor.
Embodiment
In continuous current micro-reactor, the step of the method for synthetic Betamipron is as follows:
1) aqueous solution of the Beta-alanine of 0.5 ~ 1M, sodium hydroxide and sodium bicarbonate mixture injects micro mixer by pipe connecting with flow velocity 4-48ul/min, simultaneously, Benzoyl chloride injects after micro mixer mixing with flow velocity 0.35-4.14 ul/min by same diameter pipe connecting, enter microtubule reactor reaction, obtain the solution of Betamipron sodium salt, the bath temperature of microreactor is-5
oc ~ 5
oc;
2) solution of Betamipron sodium salt is acidified to pH=2 through concentrated hydrochloric acid, separates out Betamipron solid, and after filtration, washing, dry obtain Betamipron, the molecular structural formula of Betamipron is:
The microtubule diameter of described microtubule reactor is 0.3 ~ 1.5mm, and pipe range is 1 ~ 3m.
Following examples will contribute to understand the present invention, but be not limited to content of the present invention:
Micro-fluidic the synthesizing of embodiment 1 Betamipron (I)
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=24 ul/min and V
b=2.06 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 1 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.82 g, and HPLC purity is 95%, yield is that 90%(is in L-Ala).
1H?NMR?(CD
3OD,?ppm):?
δ2.65?(t,?
J?=?6.9?Hz,?2H),?3.62?(t,?
J?=?6.9?Hz,?2H),?7.40-7.50?(3H),?7.79?(m,?2H).?
13C?NMR?(CD
3OD,?ppm):?
δ34.65,?37.09,?128.30,?129.58,?132.72,?135.59,?170.35,?175.46.?HRMS?
m/
z?calcd?for?C10H11NO3?(M+),?193.0739;?found,?193.0736.
Embodiment 2
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=4 ul/min and V
b=0.35 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 1 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.66 g, and HPLC purity is 86%, yield is that 74%(is in L-Ala).
Embodiment 3
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=28ul/min and V
b=2.41ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 1 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.78 g, and HPLC purity is 92%, yield is that 85%(is in L-Ala).
Embodiment 4
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.025 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=32 ul/min and V
b=2.75 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.78 g, and HPLC purity is 90%, yield is that 83%(is in L-Ala).
Embodiment 5
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=36 ul/min and V
b=3.10 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 1 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.68 g, and HPLC purity is 85%, yield is that 74%(is in L-Ala).
Embodiment 6
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.025 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=48ul/min and V
b=4.14 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.83 g, and HPLC purity is 92%, yield is that 87%(is in L-Ala).
Embodiment 7
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16ml Benzoyl chloride in 13.5 ml water, respectively with flow velocity V
a=16ul/min and V
b=1.37 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 1 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.68 g, and HPLC purity is 87%, yield is that 76%(is in L-Ala).
Embodiment 8
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.028 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=24 ul/min and V
b=2.06 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 2 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.89 g, and HPLC purity is 90%, yield is that 88%(is in L-Ala).
Embodiment 9
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=32 ul/min and V
b=2.75 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.82 g, and HPLC purity is 92%, yield is that 87%(is in L-Ala).
Embodiment 10
0.01 mol L-Ala, 0.01 mol sodium hydroxide, 0.022 mol sodium bicarbonate are dissolved in gained solution A and 1.16 ml Benzoyl chlorides in 13.5 ml water, respectively with flow velocity V
a=36 ul/min and V
b=3.10 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.78 g, and HPLC purity is 86%, yield is that 79%(is in L-Ala).
Embodiment 11
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=6 ul/min and V
b=0.35 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.42 g, and HPLC purity is 85%, yield is that 83%(is in L-Ala).
Embodiment 12
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=24 ul/min and V
b=1.4 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.43 g, and HPLC purity is 86%, yield is that 85%(is in L-Ala).
Embodiment 13
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=36 ul/min and V
b=2.1 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.43 g, and HPLC purity is 91%, yield is that 90%(is in L-Ala).
Embodiment 14
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=48 ul/min and V
b=2.8 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.41 g, and HPLC purity is 85%, yield is that 83%(is in L-Ala).
Embodiment 15
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=6 ul/min and V
b=0.35 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.44 g, and HPLC purity is 86%, yield is that 86%(is in L-Ala).
Embodiment 16
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=48 ul/min and V
b=2.8 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.45 g, and HPLC purity is 86%, yield is that 86%(is in L-Ala).
Embodiment 17
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=6 ul/min and V
b=0.35 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.45 g, and HPLC purity is 88%, yield is that 88%(is in L-Ala).
Embodiment 18
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=48 ul/min and V
b=2.8 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.41 g, and HPLC purity is 85%, yield is that 83%(is in L-Ala).
Embodiment 19
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=6 ul/min and V
b=0.35 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 1 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.45 g, and HPLC purity is 86%, yield is that 86%(is in L-Ala).
Embodiment 20
0.0075 mol L-Ala, 0.0075 mol sodium hydroxide, 0.016 mol sodium bicarbonate are dissolved in gained solution A and 0.87 ml Benzoyl chloride in 15 ml water, respectively with flow velocity V
a=48 ul/min and V
b=2.8 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 1.40 g, and HPLC purity is 83%, yield is that 80%(is in L-Ala).
Embodiment 21
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=4 ul/min and V
b=0.46 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.60 g, and HPLC purity is 90%, yield is that 81%(is in L-Ala).
Embodiment 22
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=16 ul/min and V
b=1.86 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.66 g, and HPLC purity is 90%, yield is that 83%(is in L-Ala).
Embodiment 23
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=32 ul/min and V
b=3.71 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.74 g, and HPLC purity is 95%, yield is that 90%(is in L-Ala).
Embodiment 24
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=35.5 ul/min and V
b=4.12 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.65 g, and HPLC purity is 87%, yield is that 80%(is in L-Ala).
Embodiment 25
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=4 ul/min and V
b=0.46 ul/min enters in reactor and reacts after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.60 g, and HPLC purity is 87%, yield is that 78%(is in L-Ala).
Embodiment 26
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=24 ul/min and V
b=2.78 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.69 g, and HPLC purity is 90%, yield is that 84%(is in L-Ala).
Embodiment 27
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=35.7 ul/min and V
b=4.14 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.68 g, and HPLC purity is 86%, yield is that 80%(is in L-Ala).
Embodiment 28
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=24 ul/min and V
b=2.78 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 1 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.72 g, and HPLC purity is 92%, yield is that 86%(is in L-Ala).
Embodiment 29
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=16 ul/min and V
b=1.86 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.7 mm, and pipe range is 3 m, and bath temperature is 0
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.66 g, and HPLC purity is 90%, yield is that 83%(is in L-Ala).
Embodiment 30
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=24 ul/min and V
b=2.78 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is-5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.72 g, and HPLC purity is 92%, yield is that 86%(is in L-Ala).
Embodiment 31
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=35.7 ul/min and V
b=4.14 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 0.3 mm, and pipe range is 1 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.70 g, and HPLC purity is 88%, yield is that 82%(is in L-Ala).
Embodiment 32
0.015 mol L-Ala, 0.015 mol sodium hydroxide, 0.03 mol sodium bicarbonate are dissolved in gained solution A and 1.74 ml Benzoyl chlorides in 15 ml water, respectively with flow velocity V
a=35.7 ul/min and V
b=4.14 ul/min enter in reactor and react after A pump and B pump advance injecting mixer simultaneously, and the diameter of reactor microtubule is 1.5 mm, and pipe range is 3 m, and bath temperature is 5
oc, the solution of the Betamipron sodium salt of collection is acidified to pH=2 with concentrated hydrochloric acid, filters and collects Betamipron solid, and washing is drained, and vacuum-drying, to constant weight, obtains 2.70 g, and HPLC purity is 86%, yield is that 80%(is in L-Ala).
Claims (2)
1. in continuous current micro-reactor, synthesize a method for Betamipron, it is characterized in that its step is as follows:
1) aqueous solution of the Beta-alanine of 0.5 ~ 1M, sodium hydroxide and sodium bicarbonate mixture injects micro mixer by pipe connecting with flow velocity 4-48ul/min, simultaneously, Benzoyl chloride injects after micro mixer mixing with flow velocity 0.35-4.14 ul/min by same diameter pipe connecting, enter microtubule reactor reaction, obtain the solution of Betamipron sodium salt, the bath temperature of microreactor is-5
oC~ 5
oC;
2) solution of Betamipron sodium salt is acidified to pH=2 through concentrated hydrochloric acid, separates out Betamipron solid, and after filtration, washing, dry obtain Betamipron, the molecular structural formula of Betamipron is:
。
2. method according to claim 1, the microtubule diameter that it is characterized in that microtubule reactor is 0.3 ~ 1.5mm, pipe range is 1 ~ 3m.
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| CN105541851A (en) * | 2015-12-16 | 2016-05-04 | 南京工业大学 | Synthetic method of 1,2,3, 4-tetrahydroquinoline derivative |
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | Method for preparing deuterated aniline compound by using microchannel reaction device |
| CN107445851A (en) * | 2017-06-21 | 2017-12-08 | 南京工业大学 | Method for continuously synthesizing quaternary ammonium salt by using micro-reaction device |
| CN109369722A (en) * | 2018-12-14 | 2019-02-22 | 中国海洋石油集团有限公司 | A kind of preparation method of bis-phosphite |
| CN111574494A (en) * | 2020-05-20 | 2020-08-25 | 黑龙江鑫创生物科技开发有限公司 | Method for synthesizing ticagrelor intermediate by using microchannel reactor |
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| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | Method for preparing deuterated aniline compound by using microchannel reaction device |
| CN106892790B (en) * | 2017-03-16 | 2020-04-07 | 南京工业大学 | Method for preparing deuterated aniline compound by using microchannel reaction device |
| CN107445851A (en) * | 2017-06-21 | 2017-12-08 | 南京工业大学 | Method for continuously synthesizing quaternary ammonium salt by using micro-reaction device |
| CN109369722A (en) * | 2018-12-14 | 2019-02-22 | 中国海洋石油集团有限公司 | A kind of preparation method of bis-phosphite |
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| CN114746399A (en) * | 2019-11-29 | 2022-07-12 | 武汉远大弘元股份有限公司 | Preparation method of carbocisteine |
| CN114746399B (en) * | 2019-11-29 | 2024-05-24 | 武汉远大弘元股份有限公司 | Preparation method of carbocisteine |
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