CN108516982B - Method for preparing rifampicin by using microchannel reaction device - Google Patents
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 title claims abstract description 50
- 229960001225 rifampicin Drugs 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 title claims description 118
- BTVYFIMKUHNOBZ-ZDHWWVNNSA-N Rifamycin S Natural products COC1C=COC2(C)Oc3c(C)c(O)c4C(=O)C(=CC(=O)c4c3C2=O)NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C BTVYFIMKUHNOBZ-ZDHWWVNNSA-N 0.000 claims abstract description 36
- BTVYFIMKUHNOBZ-ODRIEIDWSA-N Rifamycin S Chemical compound O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-ODRIEIDWSA-N 0.000 claims abstract description 36
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims description 250
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 228
- 238000002156 mixing Methods 0.000 claims description 103
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 84
- 238000005086 pumping Methods 0.000 claims description 49
- 239000012295 chemical reaction liquid Substances 0.000 claims description 40
- RJWLLQWLBMJCFD-UHFFFAOYSA-N 4-methylpiperazin-1-amine Chemical compound CN1CCN(N)CC1 RJWLLQWLBMJCFD-UHFFFAOYSA-N 0.000 claims description 37
- 229930189077 Rifamycin Natural products 0.000 claims description 33
- 229960003292 rifamycin Drugs 0.000 claims description 33
- UKOYDJAIEJKTHU-UHFFFAOYSA-N [tert-butyl(hydroxymethyl)amino]methanol Chemical compound CC(C)(C)N(CO)CO UKOYDJAIEJKTHU-UHFFFAOYSA-N 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- YEIALCAMQYZNAT-UHFFFAOYSA-N 3-tert-butyl-2,4-dihydro-1,3-oxazine Chemical compound C(C)(C)(C)N1COC=CC1 YEIALCAMQYZNAT-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 16
- 239000012153 distilled water Substances 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012498 ultrapure water Substances 0.000 claims description 2
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000012043 crude product Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 65
- 230000035484 reaction time Effects 0.000 description 31
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 30
- 238000004364 calculation method Methods 0.000 description 19
- 239000007791 liquid phase Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 13
- 238000001035 drying Methods 0.000 description 10
- 239000011268 mixed slurry Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000003860 storage Methods 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012456 homogeneous solution Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002365 anti-tubercular Effects 0.000 description 2
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical compound O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 description 2
- HDFQQSOMZYAQCS-UHFFFAOYSA-M rifamycin s sodium Chemical class [Na+].O=C1C(C([O-])=C2C)=C3C(=O)C=C1NC(=O)C(C)=CC=CC(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)C=COC1(C)OC2=C3C1=O HDFQQSOMZYAQCS-UHFFFAOYSA-M 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 238000004065 wastewater treatment Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- UHSMYBHUSYABFW-UHFFFAOYSA-N n-(2-oxo-1h-pyridin-3-yl)acetamide Chemical compound CC(=O)NC1=CC=CN=C1O UHSMYBHUSYABFW-UHFFFAOYSA-N 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a method for preparing rifampicin by using a microchannel reactor, which directly obtains a rifampicin crude product by taking rifamycin S as a raw material through cyclization, hydrolysis, condensation and crystallization processes without a post-treatment process through the microchannel reactor. The invention realizes the complete continuity of rifampicin production, has high yield, low cost, high profit, environmental protection, energy saving and high efficiency, and is suitable for industrial application.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing rifampicin by using a microchannel reaction device.
Background
The invention of rifampicin was in 1965, the discovery of rifampicin has made a significant leap on the treatment of tuberculosis, some experts have very high evaluation on the anti-tuberculosis effect of rifampicin, and it is considered that the anti-tuberculosis treatment has entered the rifampicin era now, and it is considered that tuberculosis to be treated by surgery in the past can be completely controlled without surgery by rifampicin.
In the "preparation method of high quality rifampicin" disclosed in chinese patent 101486716a, rifamycin S sodium salt is first produced into N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin, which is then reacted with 1-methyl-4-amino-piperazine to produce rifampicin. Because of different reaction solvents, crude products of the N-tertin-1, 3-oxazine (5, 6-C) rifamycin products obtained in the first step need to be obtained and can be dissolved by N-butyl alcohol for continuous reaction. The N-tertin-1, 3-oxazine (5, 6-C) rifamycin generated by frequently replacing the solvent has poor quality and more byproducts, and the effect of the next reaction is influenced, so that the whole reaction yield is influenced; meanwhile, the solvent cost, the heat energy cost and the wastewater treatment cost are huge, so that the maximization of the benefit of the industrialization of the whole process is not facilitated. Meanwhile, if the reaction is carried out directly without replacing the solvent in the conventional kettle type reaction, the yield is extremely low or even no reaction is carried out. In the patent, acetic acid is used for hydrolyzing sodium salt in the step of generating N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin by rifamycin S sodium salt, although acetic acid is not strong, reaction is mild, but the using amount is large, and cost is high.
In French patent 2245631, the production of rifampicin from N-tertin-1, 3-oxazine (5, 6-C) rifamycin requires 4-5 times the amount of 1-methyl-4-amino-piperazine for the reaction. In the chinese patent 101486716a, 2-2.4 times of 1-methyl-4-amino-piperazine is required for the reaction. Since 1-methyl-4-amino-piperazine is expensive, the cost and expense have a great influence on the profit.
A microreactor is a three-dimensional structural element which can be used for carrying out chemical reactions and which is manufactured in a solid matrix by means of special microfabrication techniques. Microreactors generally contain small channel sizes (equivalent diameters less than the desired range of 10 μm to 1000 μm) and channel multiplicity, e.g., zig-zag, heart, etc., in which fluids flow and in which the desired reactions are desired to occur. This results in a very large surface area to volume ratio in a micro-structured chemical device, thereby creating a large mass and heat transfer effect, thousands or even tens of thousands of times that of conventional reactions, which avoids the conventional drawbacks of local overheating, uneven mixing, etc. Wiebmeier et al describe microchannel reactors for heterogeneous catalytic reactions at the international conference on microreaction technology. Thereafter, a number of documents have reported the use of microreactors for oxidation, substitution, addition, polymerization, and the like.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing rifampicin by using a microchannel reaction device, so as to reduce the post-treatment process, directly obtain finished products, improve the reaction yield, reduce the use amount of solvents and raw materials, reduce side reactions and reduce the raw materials and the environmental cost.
In order to solve the technical problem, the technical scheme provided by the invention is as follows:
a method for preparing rifampicin by using a microchannel reaction device comprises the following steps:
(1) dissolving rifamycin S in N, N-dimethylformamide and acetic acid to obtain a homogeneous liquid A;
(2) dissolving N, N-dimethylol tert-butylamine in N, N-dimethylformamide to obtain a homogeneous liquid B;
(3) dissolving 1-amino-4-methyl-piperazine in N, N-dimethylformamide to obtain a homogeneous liquid C;
(4) dissolving acetic acid in water until the pH value is within the range of 4-7 to obtain homogeneous liquid D; or the homogeneous liquid D is water;
(5) respectively and simultaneously pumping the homogeneous liquid A and the homogeneous liquid B into a first mixing valve of a microchannel reaction device, uniformly mixing, and introducing into a first microchannel reactor of the microchannel reaction device for reaction to obtain a reaction solution containing N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin;
(6) respectively and simultaneously pumping the reaction liquid containing the N-tertin-1, 3-oxazine (5, 6-C) rifamycin obtained in the step (5) and the homogeneous phase liquid C into a second mixing valve of the microchannel reaction device, uniformly mixing, and introducing the mixture into a second microchannel reactor of the microchannel reaction device for reaction to obtain reaction liquid containing rifampicin;
(7) and (4) pumping the reaction liquid containing the rifampicin obtained in the step (6) and the homogeneous phase liquid D into a third mixing valve of the microchannel reaction device respectively and simultaneously, mixing uniformly, introducing into a third microchannel reactor of the microchannel reaction device for crystallization, collecting effluent liquid, and performing suction filtration to obtain the rifampicin.
In the step (1), the molar ratio of the rifamycin S to the acetic acid is 1: 0.5-8, preferably 1: 2-5; the concentration of the rifamycin S in the N, N-dimethylformamide is 0.05-1 g/ml, preferably 0.2-0.5 g/ml.
In order to ensure the reaction effect, the purity of the rifamycin S is more than 90%, the purity of the acetic acid is more than 90%, and the purity of the N, N-dimethylformamide is more than 90%.
In the step (2), the concentration of the N, N-dimethylol tert-butylamine in the N, N-dimethylformamide is 0.013-0.25 g/ml or the solvent N, N-dimethylformamide is not added, and preferably 0.2-0.25 g/ml or the solvent is not added.
Preferably, the purity of the N, N-dimethylol tert-butylamine is 98% or more, and the purity of the N, N-dimethylformamide is 99.5% or more.
In the step (3), the concentration of the 1-amino-4-methylpiperazine in the N, N-dimethylformamide is 0.1 to 1.5g/ml, preferably 0.3 to 1.0 g/ml.
Preferably, the purity of the 1-amino-4-methylpiperazine is 98% or more and the purity of the N, N-dimethylformamide is 99.5% or more.
In the step (4), the water is distilled water, deionized water or high-purity water, acetic acid is dropwise added into the water, and the obtained pH range is 4-7, preferably 5-6.
In the step (5), the flow rate of the homogeneous phase liquid A pumped into the first mixing valve is 0.05-0.5 ml/min, preferably 0.1-0.3 ml/min; the flow rate of the homogeneous phase liquid B pumped into the first mixing valve is 0.33-1.5 ml/min, preferably 0.6-1 ml/min; the volume of the first microchannel reactor is 5-50 ml, preferably 15-40 ml, the diameter of a pipeline is 0.5-4 mm, preferably 0.5-1 mm, the reaction temperature of the first microchannel reactor is 40-100 ℃, preferably 60-80 ℃, the reaction residence time is 5-30 min, preferably 20-30 min, and the molar ratio of rifamycin S to N, N-dihydroxymethyl tert-butylamine in the first microchannel reactor before reaction is 1: 1 (1-1.9), preferably 1: 1.2-1.5.
In the step (6), the flow rate of the homogeneous phase liquid C pumped into the second mixing valve is 0.5-3 ml/min, preferably 1.5-2.5 ml/min; the volume of the second microchannel reactor is 10-80 ml, preferably 30-60 ml, the diameter of a pipeline is 0.5-4 mm, preferably 0.5-1 mm, the reaction temperature of the second microchannel reactor is 40-100 ℃, preferably 70-90 ℃, the reaction residence time is 5-30 min, preferably 15-25 min, and the molar ratio of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine before reaction in the second microchannel reactor is 1: 1 (1-1.8), preferably 1: 1.2-1.5.
In the step (7), the flow rate of the homogeneous liquid D pumped into the third mixing valve is 5-40 ml/min, preferably 15-25 ml/min, the flow rate ratio of the reaction liquid containing rifampicin to the acetic acid aqueous solution is 1: 2.5-15, preferably 1: 5-10, the volume of the third microchannel reactor is 500-1500 ml, preferably 1000-1200 ml, the diameter of the pipeline is more than 2mm, the reaction temperature of the third microchannel reactor is 15-40 ℃, preferably 25 ℃, and the reaction residence time is 30-90 min, preferably 50-70 min.
The microchannel reaction device comprises a first mixing valve, a first microchannel reactor, a second mixing valve, a second microchannel reactor, a third mixing valve, a third microchannel reactor and a receiving tank which are sequentially connected in series, wherein a first material storage tank and a second material storage tank are respectively connected with the first mixing valve in a parallel connection mode, the third material storage tank is connected with the second mixing valve in a parallel connection mode with the first microchannel reactor, and a fourth material storage tank is connected with the third mixing valve in a parallel connection mode with the second microchannel reactor.
The first material storage tank is used for placing homogeneous phase solution A, the second material storage tank is used for placing homogeneous phase solution B, the third material storage tank is used for placing homogeneous phase solution C, and the fourth material storage tank is used for placing homogeneous phase solution D.
The first mixing valve, the second mixing valve and the third mixing valve are respectively a T-shaped mixer, a Y-shaped mixer, an inverted Y-shaped mixer or an extrusion mixer, and preferably an inverted Y-shaped mixer.
The first mixing valve, the second mixing valve, the third mixing valve and the microchannel reactor are of a vapourtec R4 series reactor, the length of a connecting pipe between the mixing valve and the microchannel reactor I and II is 10-25 cm, the inner diameters of the connecting pipes are 0.5-5 mm, the length of a connecting pipe between the mixing valve and the microchannel reactor III is 10-25 cm, and the inner diameters of the connecting pipes are 2-8 mm.
The reaction liquid entering the microchannel reaction device is homogeneous liquid, if more particles exist in the liquid, the reactor is blocked, the pressure drop of the container is increased, and even the reaction can not be effectively carried out. In the prior art, after the rifamycin sodium salt and the dimethylol tert-butylamine react under the N, N-dimethylformamide, the solvent needs to be replaced to precipitate a solid, the solvent is replaced by N-butanol again, and the next reaction is continued.
The reaction utilizes the micro-flow field technology to accurately control the reaction temperature, the reaction time of the whole process is short, the toxicity and the pollution are small, the side reaction is small, the selectivity is better than that of the conventional process, the yield of the rifampicin in each step can reach more than 80%, most importantly, the whole rifampicin synthesis process and the crystallization process can be seamlessly connected together, a series of post-treatment operations such as solvent replacement, solid precipitation and the like of the traditional process are not needed, the cost of heat energy, solvent and acid for solvent replacement and the cost of wastewater treatment are greatly saved, and the consumption of N, N-dimethylol tert-butylamine and 1-amino-4-methylpiperazine is reduced, so that the cost of raw materials is greatly saved.
Has the advantages that: the invention completely realizes the continuous production of rifampicin, has the advantages of good product quality, low cost, high profit, environmental protection, energy saving and high efficiency, and is suitable for industrial application.
Drawings
FIG. 1 is a schematic diagram of the apparatus of the present invention;
FIG. 2 shows the reaction equation of the present invention.
Detailed Description
The microchannel reactor apparatus used in the following examples is shown in FIG. 1 and comprises a first mixer, a microchannel reactor I, a second mixer, a microchannel reactor II, a third mixer, a microchannel reactor III, and a receiving tank, which are connected in series in this order, a first material tank (homogeneous solution A) and a second material tank (homogeneous solution B) being connected in parallel to the first mixer, respectively, a third material tank (homogeneous solution C) being connected in parallel to the microchannel reactor I to the second mixer, and a fourth material tank (homogeneous solution D) being connected in parallel to the microchannel reactor II to the third mixing valve.
The types of the microchannel reactor are all Vapourtac R series, which is purchased from Dexiang International science and technology. The pipe diameters of the microchannel reactors I and II in the reaction are both 1mm, and the pipe diameters of the microchannel reactor III are both 2 mm; the length of a connecting pipe between the mixer and the microchannel reactors I and II is 25cm, the inner diameters of the connecting pipes are 1mm, the length of a connecting pipe between the mixer and the microchannel reactor III is 25cm, and the inner diameters of the connecting pipes are 2 mm; the purity of acetic acid used was 99.5%, that of N, N-dimethylformamide 99.5%, that of dimethylol tert-butylamine 98%, and that of 1-methyl-4-amino-piperazine 98%.
Example 1
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 87.05 percent by utilizing high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 8g of red powder is weighed, the yield of the step is 92%, and the purity is 93.9%.
Example 2
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; 3.2ml of N, N-dimethylol tert-butylamine with the purity of 98% and 97ml of N, N-dimethylformamide with the purity of 98% are mixed to form 100ml of homogeneous liquid B; 2.04ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.2mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.8mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I together, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.7 in the reaction. The yield of the step is 74.36 percent by utilizing high performance liquid chromatography; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 83.97% by using high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 6.7g of red powder is weighed, the yield of the step is 91 percent, and the purity is 92.8 percent.
Example 3
10g of rifamycin S with the purity of 97 percent, 7.5ml of acetic acid with the mass percent concentration of 99.5 percent and 14ml of N, N-dimethylformamide with the purity of 98 percent are mixed into 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.12ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 81.61 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 85.64% by using high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 7.55g of red powder is weighed, the yield of the step is 91.3 percent, and the purity is 92.1 percent.
Example 4
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 30mL, the reaction temperature is 75 ℃, the reaction time is 30min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 85.1 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 87.08% by utilizing high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 8.05g of red powder is weighed, the yield of the step is 92%, and the purity is 91.9%.
Example 5
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.12ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 60 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 77.97 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 81.05% by using high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 6.75g of red powder is weighed, the yield of the step is 90.3 percent, and the purity is 92 percent.
Example 6
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 10.5ml of N, N-dimethylformamide with a purity of 98% were mixed to form 12.5ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 0.5mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 90.27% by using high performance liquid phase calculation; pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 15mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 7.8g of red powder is weighed, the yield of the step is 87%, and the purity is 91.9%.
Example 7
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 50mL, the reaction temperature is 80 ℃, the reaction time is 25min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 87.35% by using high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 8g of red powder is weighed, the yield of the step is 92 percent, and the purity is 92.2 percent.
Example 8
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 90 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 85.97 percent by utilizing high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 7.88g of red powder is weighed, the yield of the step is 91.6 percent, and the purity is 92.3 percent.
Example 9
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; taking 1L of distilled water as homogeneous liquid D; pumping homogeneous liquid A by a pump A at a flow rate of 0.885mL/min, pumping homogeneous liquid B by a pump B at a flow rate of 0.115mL/min, fully mixing the homogeneous liquid A and the homogeneous liquid B by an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor I, wherein the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is a mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3. the yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 87.05 percent by utilizing high performance liquid phase calculation; pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1000mL, the reaction temperature is 25 ℃, the reaction time is 50min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 7.6g of red powder is weighed, the yield of the step is 88 percent, and the purity is 92.7 percent.
Example 10
Taking 10g of rifamycin S with the purity of 97 percent, mixing with 3.75ml of acetic acid with the mass percentage concentration of 99.5 percent and 10ml of N, N-dimethylformamide with the purity of 98 percent to obtain 25ml of homogeneous liquid A; taking 2.44ml of N, N-dimethylol tert-butylamine with the purity of 98 percent without adding a solvent to form homogeneous liquid B; 2.31ml of 1-amino-4-methylpiperazine with a purity of 98% and 22.5ml of N, N-dimethylformamide with a purity of 98% were mixed to 25ml of homogeneous liquid C; dissolving 0.087mL of acetic acid in 1L of distilled water to obtain a homogeneous liquid D; the homogeneous phase liquid A is pumped by a pump A at the flow rate of 0.885mL/min, the homogeneous phase liquid B is pumped by a pump B at the flow rate of 0.115mL/min, the homogeneous phase liquid A and the homogeneous phase liquid B are fully mixed by an inverted Y-shaped mixing valve and then are pumped into a microchannel reactor I, the volume of the microchannel reactor is 20mL, the reaction temperature is 75 ℃, the reaction time is 20min, the outflow reaction liquid is the mixed liquid of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin and N, N-dimethylformamide, and the actual molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine is 1: 1.3 in the reaction. The yield of the step is 84.52 percent by utilizing high performance liquid phase calculation; pumping liquid in the homogeneous phase liquid C by a pump C at the flow rate of 1mL/min, mixing the liquid with the mixed liquid by using an inverted Y-shaped mixing valve, pumping the mixed liquid into a microchannel reactor II, wherein the volume of the microreactor is 30mL, the reaction temperature is 80 ℃, the reaction time is 15min, the outflow reaction liquid is a mixed liquid of rifampicin and N, N-dimethylformamide, the molar ratio of the actual N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1.7, and the yield of the step is 87.05 percent by utilizing high performance liquid phase calculation; and pumping the liquid in the homogeneous phase liquid D by a pump D at the flow rate of 20mL/min, mixing the liquid with the mixed liquid by using a Y-shaped mixing valve, pumping the mixed liquid and the mixed liquid into a microchannel reactor III, wherein the volume of the microreactor is 1200mL, the reaction temperature is 25 ℃, the reaction time is 60min, and the effluent reaction liquid is mixed slurry liquid of N, N-dimethylformamide and water for separating out rifampicin solids. After suction filtration and drying, 8g of red powder is weighed, the yield of the step is 92 percent, and the purity is 89.2 percent.
Example 11
As in example 1, except that,
in the step (1), the molar ratio of the rifamycin S to the acetic acid is 1: 0.5; the rifamycin S concentration in N, N-dimethylformamide is 0.05 g/ml.
In the step (2), the concentration of the N, N-dimethylol tert-butylamine in the N, N-dimethylformamide is 0.013 g/ml.
In the step (3), the concentration of the 1-amino-4-methylpiperazine in the N, N-dimethylformamide is 0.1 g/ml.
In the step (5), the flow rate of the pump A is 0.05 ml/min; the flow rate of the pump B is 0.33 ml/min; the volume of the microchannel reactor I is 5ml, the diameter of a pipeline is 0.5mm, the reaction temperature of the microchannel reactor I is 40 ℃, the reaction residence time is 30min, and the molar ratio of the rifamycin S to the N, N-dihydroxymethyl tert-butylamine in the microchannel reactor I before reaction is 1: 1.
In the step (6), the flow rate of the pump C is 0.5 ml/min; the volume of the microchannel reactor II is 10ml, the diameter of a pipeline is 0.5mm, the reaction temperature of the microchannel reactor II is 40 ℃, the reaction residence time is 30min, and the molar ratio of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine is 1: 1 in the microchannel reactor II before reaction.
In the step (7), the flow rate of the pump D is 5ml/min, the flow rate ratio of the reaction liquid containing rifampicin to the acetic acid aqueous solution is 1: 2.5, the volume of the microchannel reactor III is 500ml, the reaction temperature of the microchannel reactor III is 15 ℃, and the reaction residence time is 90 min.
Example 12
As in example 1, except that,
in the step (1), the molar ratio of the rifamycin S to the acetic acid is 1: 8; the rifamycin S is present in N, N-dimethylformamide at a concentration of 1 g/ml.
In the step (2), the concentration of the N, N-dimethylol tert-butylamine in the N, N-dimethylformamide is 0.25 g/ml.
In the step (3), the concentration of the 1-amino-4-methylpiperazine in the N, N-dimethylformamide is 1.5 g/ml.
In the step (5), the flow rate of the pump A is 0.5 ml/min; the flow rate of the pump B is 1.5 ml/min; the volume of the microchannel reactor I is 50ml, the diameter of a pipeline is 4mm, the reaction temperature of the microchannel reactor I is 100 ℃, the reaction residence time is 5min, and the molar ratio of the rifamycin S to the N, N-dihydroxymethyl tert-butylamine in the microchannel reactor I before reaction is 1: 1.9.
In the step (6), the flow rate of the pump C is 3 ml/min; the volume of the microchannel reactor II is 80ml, the diameter of a pipeline is 4mm, the reaction temperature of the microchannel reactor II is 100 ℃, the reaction residence time is 5min, and the molar ratio of N-tertin-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine before reaction in the microchannel reactor II is 1: 1.8.
In the step (7), the flow rate of the pump D is 40ml/min, the flow rate ratio of the reaction liquid containing rifampicin to the acetic acid aqueous solution is 1: 15, the volume of the microchannel reactor III is 1500ml, the reaction temperature of the microchannel reactor III is 40 ℃, and the reaction residence time is 30 min.
Claims (10)
1. A method for preparing rifampicin by using a microchannel reaction device is characterized by comprising the following steps:
(1) dissolving rifamycin S in N, N-dimethylformamide and acetic acid to obtain a homogeneous liquid A; the concentration of the rifamycin S in the N, N-dimethylformamide is 0.05-1 g/ml;
(2) dissolving N, N-dimethylol tert-butylamine in N, N-dimethylformamide to obtain a homogeneous liquid B;
(3) dissolving 1-amino-4-methyl-piperazine in N, N-dimethylformamide to obtain a homogeneous liquid C;
(4) dissolving acetic acid in water until the pH value is within the range of 4-7 to obtain homogeneous liquid D; or the homogeneous liquid D is water;
(5) respectively and simultaneously pumping the homogeneous liquid A and the homogeneous liquid B into a first mixing valve of a microchannel reaction device, uniformly mixing, and introducing into a first microchannel reactor of the microchannel reaction device for reaction to obtain a reaction solution containing N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin; the flow rate of the homogeneous phase liquid A pumped into the first mixing valve is 0.05-0.5 ml/min; the flow rate of the homogeneous phase liquid B pumped into the first mixing valve is 0.33-1.5 ml/min; the diameter of the pipeline of the first microchannel reactor is 0.5-4 mm;
(6) respectively and simultaneously pumping the reaction liquid containing the N-tertin-1, 3-oxazine (5, 6-C) rifamycin obtained in the step (5) and the homogeneous phase liquid C into a second mixing valve of the microchannel reaction device, uniformly mixing, and introducing the mixture into a second microchannel reactor of the microchannel reaction device for reaction to obtain reaction liquid containing rifampicin; the diameter of the pipeline of the second microchannel reactor is 0.5-4 mm;
(7) pumping the reaction liquid containing the rifampicin obtained in the step (6) and the homogeneous phase liquid D into a third mixing valve of the microchannel reaction device respectively and simultaneously, mixing uniformly, introducing into a third microchannel reactor of the microchannel reaction device for crystallization, collecting effluent liquid, and performing suction filtration to obtain rifampicin; the flow rate of the third mixing valve is 5-40 ml/min, the volume of the third micro-channel reactor is 500-1500 ml, and the diameter range of the pipeline is 2-8 mm.
2. The method of claim 1, wherein the molar ratio of rifamycin S to acetic acid in step (1) is 1 (0.5-8).
3. The method according to claim 1, wherein in the step (2), the concentration of the N, N-dimethylol tert-butylamine in the N, N-dimethylformamide is 0.013 to 0.25g/ml or the solvent N, N-dimethylformamide is not added.
4. The method according to claim 1, wherein in the step (3), the concentration of the 1-amino-4-methylpiperazine in the N, N-dimethylformamide is 0.1 to 1.5 g/ml.
5. The method according to claim 1, wherein in the step (4), the water is distilled water, deionized water or high-purity water.
6. The method according to claim 1, wherein in the step (5), the volume of the first microchannel reactor is 5-50 ml, the reaction temperature of the first microchannel reactor is 40-100 ℃, the reaction residence time is 5-30 min, and the molar ratio of the rifamycin S to the N, N-dimethylol tert-butylamine in the first microchannel reactor before the reaction is 1 (1-1.9).
7. The method according to claim 1, wherein in the step (6), the flow rate of the homogeneous liquid C pumped into the second mixing valve is 0.5-3 ml/min; the volume of the second microchannel reactor is 10-80 ml, the reaction temperature of the second microchannel reactor is 40-100 ℃, the reaction residence time is 5-30 min, and the molar ratio of N-tert-butyl-1, 3-oxazine (5, 6-C) rifamycin to 1-methyl-4-amino-piperazine before reaction in the second microchannel reactor is 1 (1-1.8).
8. The method as claimed in claim 1, wherein in the step (7), the flow rate ratio of the rifampicin reaction solution to the acetic acid aqueous solution is 1 (2.5-15), the reaction temperature of the third microchannel reactor is 15-40 ℃, and the reaction residence time is 30-90 min.
9. The process of any one of claims 1 to 8 wherein the microchannel reactor device comprises a first mixing valve, a first microchannel reactor, a second mixing valve, a second microchannel reactor, a third mixing valve, a third microchannel reactor, and a receiving tank connected in series in that order, the first material tank and the second material tank being connected in parallel with the first mixing valve, respectively, the third material tank being connected in parallel with the first microchannel reactor with the second mixing valve, and the fourth material tank being connected in parallel with the second microchannel reactor with the third mixing valve.
10. The method of claim 9, wherein the first, second, and third mixing valves are a T-mixer, a Y-mixer, an inverted Y-mixer, or a die mixer, respectively.
Priority Applications (1)
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