CN106749326A - Method for continuously producing and preparing rifampicin from rifamycin S sodium salt - Google Patents
Method for continuously producing and preparing rifampicin from rifamycin S sodium salt Download PDFInfo
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- CN106749326A CN106749326A CN201611060961.7A CN201611060961A CN106749326A CN 106749326 A CN106749326 A CN 106749326A CN 201611060961 A CN201611060961 A CN 201611060961A CN 106749326 A CN106749326 A CN 106749326A
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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 55
- 229960001225 rifampicin Drugs 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 19
- 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 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 168
- RJWLLQWLBMJCFD-UHFFFAOYSA-N 4-methylpiperazin-1-amine Chemical compound CN1CCN(N)CC1 RJWLLQWLBMJCFD-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000243 solution Substances 0.000 claims description 198
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 82
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 56
- 159000000000 sodium salts Chemical class 0.000 claims description 48
- -1 dihydroxymethyl tert-butyl Chemical group 0.000 claims description 34
- 239000012043 crude product Substances 0.000 claims description 25
- 229930189077 Rifamycin Natural products 0.000 claims description 18
- 229960003292 rifamycin Drugs 0.000 claims description 17
- 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 claims description 17
- YKJGSTOEKNIXMW-UHFFFAOYSA-N 2-butyl-2H-1,3-oxazine Chemical compound CCCCC1N=CC=CO1 YKJGSTOEKNIXMW-UHFFFAOYSA-N 0.000 claims description 9
- 238000005194 fractionation Methods 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 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 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 238000010523 cascade reaction Methods 0.000 claims description 2
- 230000001186 cumulative effect Effects 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000007787 solid Substances 0.000 abstract description 3
- 238000010924 continuous production Methods 0.000 abstract 2
- 230000003321 amplification Effects 0.000 abstract 1
- 238000005265 energy consumption Methods 0.000 abstract 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 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical compound O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 80
- 239000012071 phase Substances 0.000 description 56
- 238000002156 mixing Methods 0.000 description 38
- 238000001914 filtration Methods 0.000 description 35
- 230000035484 reaction time Effects 0.000 description 25
- 238000009835 boiling Methods 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 23
- 239000007791 liquid phase Substances 0.000 description 23
- 239000007788 liquid Substances 0.000 description 15
- 238000007792 addition Methods 0.000 description 13
- 238000007086 side reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 238000005852 acetolysis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 description 1
- 229940081192 rifamycins Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention provides a method for continuously producing and preparing rifampicin by rifamycin S sodium salt, which takes rifamycin sodium salt, dimethylol tert-butylamine and 1-methyl-4-amino-piperazine as raw materials and realizes the continuous production of rifampicin by connecting a kettle type and a microreactor in series. Compared with the prior art, the invention realizes the continuous production of rifampicin, omits the steps of solvent replacement, solid precipitation and the like in the reaction, greatly saves raw materials and heat energy, saves cost and increases profit. Meanwhile, the invention utilizes the characteristics of high-efficiency heat and mass transfer capability and easy direct amplification of the microchannel reactor, improves the conversion rate of rifampicin to more than 85 percent on the premise of reducing one third of the raw material 1-methyl-4-amino-piperazine, has good product quality and low energy consumption, is a green, environment-friendly and high-efficiency method for synthesizing rifampicin, and is suitable for industrial application.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to one kind should be filled using still reaction device with microchannel plate
Put the method that cascade reaction prepares rifampin.
Background technology
Rifampin invention makes treatment lungy there occurs once great leap, has in nineteen sixty-five, the discovery of rifampin
Expert it is very high to the treating tuberculosis evaluation of effect of rifampin, it is believed that present Anti-TB treatment has been enter into the rifampin epoch, and thinks
Past wants the tuberculosis of operative treatment, has rifampin to be not required to perform the operation and get off Morbidity control completely.
In Chinese patent 101486716A, in open " preparation method of good quality benemicin ", sodium salt for rifainycin S generation N-
Special butyl- 1,3- oxazines (5,6-C) rifamycin and N- spy's butyl- 1,3- oxazines (5,6-C) rifamycin generation step of rifampin two, by
It is different in the solvent of reaction, it is necessary to obtain product N- spy's butyl- 1 of first step reaction, 3- oxazines (5,6-C) rifamycin it is thick
Product, then could continue reaction with n-Butanol soluble.Frequently changing solvent causes N- spies butyl- 1,3- oxazines (5,6-C) profits for producing
Good fortune mycin is second-rate, and accessory substance is more, under the influence of single step reaction effect so that influence whole reaction yield；Simultaneously solvent into
Originally, heat energy cost and cost for wastewater treatment are huge, are unfavorable for the industrialized benefit of whole piece technique.Meanwhile, if
In conventional still reaction, solvent direct reaction is changed without, yield is extremely low not to react even.
In Chinese patent 101486716A, in open " preparation method of good quality benemicin ", sodium salt for rifainycin S generation N-
Special butyl- 1, uses acetolysis sodium salt in 3- oxazines (5,6-C) rifamycin step, form sodium salt for rifainycin S free
Rifamycin, although acetic acid is not acid strong, and reaction is gentle but usage amount is larger, relatively costly.
In French Patent (FRP) 2245631, N- spy butyl- 1,3- oxazines (5,6-C) rifamycin generation rifampin this step in need
4~5 times of 1- methyl -4- amino-piperazine is wanted to be reacted.And in Chinese patent 101486766A, disclosure be " good quality benemicin
In preparation method ", the 1- methyl -4- amino-piperazine for needing also remain for 2~2.4 times is reacted.Due to 1- methyl -4- amino-piperazine
Costly, cost is still affected greatly piperazine price to income.
Microreactor is a kind of to be chemically reacted with can be used for of manufacturing of solid matrix by means of special micro-processing
Three-dimensional structure element.Microreactor usually contain small channel size (equivalent diameter less than require at 10 μm -1000 μm) and
Passage diversity is for example, zigzag, heart etc., fluid flows in these passages, and requirement occurs to want in these passages
The reaction asked.Which results in having very big surface area/volume ratio rate in the chemical device of micro-structure, thus produce
Huge mass-and heat-transfer effect, is thousand times even ten thousand times of popular response, avoiding problems hot-spot, incomplete mixing etc.
Normal defect.G.WieBmeier et al. describes the microchannel for heterogeneous catalytic reaction in micro-reacting tcchnology international conference
Reactor.Afterwards, lot of documents reports application of the microreactor at aspects such as oxidation, substitution, addition, polymerizations.
The content of the invention
The technical problems to be solved by the invention are：One kind is provided by sodium salt for rifainycin S continuous system for rifampin
Method, fast and safely synthesize rifampin, improve yield, reduce solvent, raw material usage amount, reduce side reaction.
In order to solve the above technical problems, the present invention is adopted the technical scheme that：One kind is continuously produced by sodium salt for rifainycin S
The method for preparing rifampin, comprises the following steps：
(1) sodium salt for rifainycin S is placed in the DMF of sulfur acid, it is mould that reaction obtains free sharp good fortune
Element, reaction solution is filtered, and obtains homogeneous phase solution；
(2) homogeneous phase solution obtained in step (1) is mixed with dihydroxymethyl tert-butyl amine, reaction obtains N- tertiary butyl -1,
3- oxazines (5,6-C) rifamycin solution；
(3) solution fractionation obtained in step (2) is boiled off into dihydroxymethyl tert-butyl amine, DMF, is obtained
N- tertiary butyl -1,3- oxazine (5,6-C) rifamycin of concentration；
(4) N- spy butyl- 1,3- oxazine (5,6-C) rifamycin that will be obtained in step (3) is dissolved in N, N- dimethyl formyls
In amine, homogeneous phase solution is obtained；
(5) 1- methyl -4- amino-piperazine is dissolved in DMF, obtains homogeneous phase solution；
(6) in the reaction unit of microchannel, step (4) is neutralized into the homogeneous phase solution that will be obtained in step (6) respectively from pump A
With pump B while in pumping into blender, after being sufficiently mixed, mixed solution is with constant flow pump reactor reaction in a subtle way；Collect outflow
Liquid, as rifampin crude product.
In step (3), the fractionation in vacuum -0.08~-0.1mpa, carried out under the conditions of 60~85 DEG C, it is preferred that
In vacuum -0.08~-0.1mpa, carried out at 80~85 DEG C, dihydroxymethyl tert-butyl amine and N, N- dimethyl methyl that fractionation is boiled off
The cumulative volume of acid amides accounts for the 20~80% of original solution volume, preferably 30~70%, more preferably 62.5~70%.Step
(1) in, the mass percent purity of the sodium salt for rifainycin S is 72~95%, and the mass percent concentration of the sulfuric acid is
More than 98%；Described sodium salt for rifainycin S and the mol ratio of sulfuric acid are 1:0.5~1, preferably 1:0.5~0.9；Described
Concentration of the sodium salt for rifainycin S in DMF is 0.3~1g/mL, preferably 0.6~1g/mL；The reaction
Temperature be 20~40 DEG C, preferably 25~40 DEG C；The time of the reaction is 0.5~1h.
In step (2), the mass percent concentration of the dihydroxymethyl tert-butyl amine is more than 98%, and the dihydroxymethyl is special
The mol ratio of the rifamycin obtained in butylamine and step (1) is 1.2~1.6:1, preferably 1.3~1.5:1；The reaction
Temperature is 40~60 DEG C；The time of the reaction is 1~4h.
In step (4), the homogeneous phase solution concentration is 0.1~0.7mol/L, preferably 0.146~0.584mol/L.
In step (5), described 1- methyl -4- amino-piperazine mass percent purity is more than 98%, N, N- dimethyl methyls
Acid amides mass percent purity is more than 99.5%, and the homogeneous phase solution concentration for obtaining is 0.264~2.11mol, preferably
0.43~1.0512mol/L.
In step (6), the homogeneous phase solution obtained in described step (4) pumps into flow velocity for 0.333~1.332mL/min,
Preferably 0.333~0.666mL/min；The homogeneous phase solution obtained in described step (5) pump into flow velocity for 0.666~
2.664mL/min, preferably 0.666~1.333mL/min, N- spies butyl- 1,3- oxazines (5,6-C) Li Fu in the mixed solution
Mycin is 1 with the mol ratio of 1- methyl -4- amino-piperazine:1~1.8, preferably 1:1.5~1.8.It is described micro- in step (6)
Pathway reaction device includes pump A, pump B, micro-mixer, microreactor and reception device, and pump A and pump B is with parallel way by connecting
Adapter and micro-mixer connection, micro-mixer, microreactor and reception device are connected by connecting tube in a series arrangement；It is described micro-
Reactor volume is 5~50mL；The heating-up temperature of the microreactor is 75~100 DEG C；The residence time of the reaction be 4~
25min；The length of a diameter of 0.5~4mm of the connecting tube, the pump A or the connecting tube between pump B and micro-mixer is 10
~50cm；Connection length of tube between the microreactor and reception device is 10~70cm.
Homogeneous phase solution is necessary in step (5) and (6) described reaction solution, solvent of the present invention is DMF,
Preferably purity is more than 99.5% N,N-dimethylformamide.
The present invention utilizes miniflow field technology precise control reaction temperature, and the whole technological reaction time is short, and toxicity and pollution are small,
Side reaction is few, and selectivity ratios common process is good, and, up to more than 80%, optimal yield is more than 85% for rifampin yield；The present invention
Can be by sodium salt for rifainycin S generation N- spy's butyl- 1,3- oxazines (5,6-C) rifamycins and N- spies butyl- 1,3- oxazines (5,6-C)
Rifamycin generation rifampin two step is seamlessly connected together, it is not necessary to the replacing solvent of traditional handicraft, separates out solid etc. and is
Row post-processing operation, makes solvent wastage in bulk or weight reduce 50%, valuable raw material 1- methyl -4- aminopiperazines reduce consumption 30% with
On, acid amount reduces more than 50%, reduces side reaction, decreases the pollution of waste water, used heat to environment, with application well
Prospect.
Beneficial effect：Reaction time of the invention is short, and side reaction is few, selective number, and toxicity and pollution are small, environment-friendly, tool
There is good prospects for commercial application.
Brief description of the drawings
Fig. 1 is the schematic diagram of reaction unit of the present invention and flow, wherein 1 is the first still reaction device, 2 is the second autoclave
Reaction unit, 3 is pump A, and 4 is pump B, and 5 micro-mixers, 8 are microreactor, and 7 is reception device.
Fig. 2 is reaction equation of the invention.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
Apply the content described by example and be merely to illustrate the present invention, without should also without limitation on sheet described in detail in claims
Invention.
Micro passage reaction model vapourtac R series used in the present invention, is purchased from the auspicious International Technology of moral public
Department.Caliber internal diameter used in reaction is all 1mm, and feed liquor length of tube is 15cm, the connection between mixing valve and microreactor
Length of tube is 25cm, and the connection length of tube between microreactor and outlet is 20cm
In following embodiments, the concentration of sulfuric acid used is 98.3%, and the purity of DMF is 99.5%, two
The purity of methylol tert-butyl amine is that 98%, 1- methyl -4- amino-piperazine purity is 98%.
Embodiment 1
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed with T-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 90.0%.
Embodiment 2
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 1.55mL (0.0292mol) sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filter
Cheng Hou, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；
By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution (0.584mol/l) to stir；Flask after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In C, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, stream are extracted by pump A
Speed is 0.666mL/min, and the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, by the two with T-shaped
During mixing valve mixing together pumps into microreactor, microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is
20min, connects reaction solution as rifampin crude product, is calculated using efficient liquid phase, and yield is 85.0%.
Embodiment 3
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 51.3mL
(0.666mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 62.5% of reaction solution, adds 70mLN,
Dinethylformamide, it is homogeneous phase solution to stir；Flask after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In C, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, stream are extracted by pump A
Speed is 0.666mL/min, and the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, by the two with T-shaped
During mixing valve mixing together pumps into microreactor, microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is
20min, connects reaction solution as rifampin crude product, is calculated using efficient liquid phase, and yield is 90.9%.
Embodiment 4
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 102.6mL
(1.332mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 78.5% of reaction solution, adds 70mLN,
Dinethylformamide, it is homogeneous phase solution to stir；Flask after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In C, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, stream are extracted by pump A
Speed is 0.666mL/min, and the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, by the two with T-shaped
During mixing valve mixing together pumps into microreactor, microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is
20min, connects reaction solution as rifampin crude product, is calculated using efficient liquid phase, and yield is 88.7%.
Embodiment 5
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 11.38mL0.0876mol dihydroxymethyl tert-butyl amines, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 88.6%.
Embodiment 6
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 1h is stirred at 60 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 85.9%.
Embodiment 7
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 4h is stirred at 40 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 82.9%.
Embodiment 8
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 1h at 40 DEG C, by reacting liquid filtering；
After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, at 45 DEG C
Stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- bis-
NMF, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C,
Addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 88.0%.
Embodiment 9
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is mixed with inverted Y-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 88.9%.
Embodiment 10
Take 72% sodium salt for rifainycin S 42g0.0584mol to be placed in there-necked flask A, add 70mL (0.908mol) N, N-
Dimethylformamide and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；After the completion of filtering,
Filtrate is placed in three mouthfuls of beaker bottle B, 9.86mL0.0759mol is added) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will be anti-
Liquid -0.08 is answered to -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, add 70mLN, dinethylformamide,
It is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, 193mLN is added,
Dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is 0.666mL/min,
Solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed into together pump with T-shaped mixing valve
Enter in microreactor, microreactor volume is 40mL, reaction temperature is 80 DEG C, and the reaction time is 20min, connects reaction solution and is profit
The flat crude product of good fortune, is calculated using efficient liquid phase, and yield is 75.2%.
Embodiment 11
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
93mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is 1mL/
Min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1mL/min, and the two is mixed into together pump with T-shaped mixing valve
Enter in microreactor, microreactor volume is 40mL, reaction temperature is 80 DEG C, and the reaction time is 20min, connects reaction solution and is profit
The flat crude product of good fortune, is calculated using efficient liquid phase, and yield is 79.9%.
Embodiment 12
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.333mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 0.666mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 20mL, and reaction temperature is 80 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 80.2%.
Embodiment 13
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
1.332mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 2.664mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 10min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 82.2%.
Embodiment 14
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 10mL, and reaction temperature is 80 DEG C, and the reaction time is 5min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 78.6%.
Embodiment 15
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 20mL, and reaction temperature is 80 DEG C, and the reaction time is 10min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 81.4%..
Embodiment 16
Take the sodium salt for rifainycin S 42g0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL (0.908mol)
DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reacting liquid filtering；Filtering is completed
Afterwards, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 2h is stirred at 45 DEG C；Will
Reaction solution -0.08 arrives -0.1mpa, is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N- dimethyl formyls
Amine, it is homogeneous phase solution to stir；After 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again in flask C, add
193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A, flow velocity is
0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T-shaped mixing
Valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 90 DEG C, and the reaction time is 20min, is connect
Reaction solution is rifampin crude product, is calculated using efficient liquid phase, and yield is 83.4%.
Embodiment 17
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed with T-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 50mL, and reaction temperature is 80 DEG C, and the reaction time is 25min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 89.7%.
Embodiment 18
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed with T-shaped
Close during valve mixing together pumps into microreactor, microreactor volume is 50mL, and reaction temperature is 100 DEG C, the reaction time is
25min, connects reaction solution as rifampin crude product, is calculated using efficient liquid phase, and yield is 81.3%.
Embodiment 19
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 45min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 30% of reaction solution, adds 30mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed with T-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 50mL, and reaction temperature is 80 DEG C, and the reaction time is 25min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 77.4%.
Embodiment 20
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 30min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Burnt after 6.66mL0.0573mol 1- methyl -4- amino-piperazine is placed in into three again
In bottle C, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B is extracted by pump A,
Flow velocity is 0.666mL/min, and the solution in there-necked flask C is directly extracted by pump B, and flow velocity is 1.333mL/min, and the two is used into T
During the mixing of type mixing valve together pumps into microreactor, microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is
20min, connects reaction solution as rifampin crude product, is calculated using efficient liquid phase, and yield is 72.0%.
Embodiment 21
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 30min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 70mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 12mL0.0341mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 0.666mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1.333mL/min, the two is mixed with T-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 91.0%.
Embodiment 22
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 30min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 170mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 1mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 1mL/min, and the two is mixed with T-shaped mixing valve
Together pump into microreactor, microreactor volume is 40mL, reaction temperature is 80 DEG C, and the reaction time is 20min, connects reaction solution
As rifampin crude product, is calculated using efficient liquid phase, and yield is 81.2%.
Embodiment 23
Take the sodium salt for rifainycin S 42g 0.0584mol of purity 95% to be placed in there-necked flask A, add 70mL
(0.908mol) DMF and 2.84mL0.0533mol sulfuric acid, after stirring 30min under normal temperature, by reaction solution mistake
Filter；After the completion of filtering, filtrate is placed in three mouthfuls of beaker bottle B, adds 9.86mL0.0759mol) dihydroxymethyl tert-butyl amine, 45 DEG C
Lower stirring 2h；By reaction solution -0.08 to -0.1mpa, it is fractionated at 80 DEG C, after boiling off the 70% of reaction solution, adds 370mLN, N-
Dimethylformamide, it is homogeneous phase solution to stir；Flask C after 10mL0.086mol 1- methyl -4- amino-piperazine is placed in into three again
In, addition 193mLN, dinethylformamide, it is homogeneous phase solution to stir；Reaction solution in there-necked flask B, flow velocity are extracted by pump A
It is 1.333mL/min, the solution in there-necked flask C is directly extracted by pump B, flow velocity is 0.666mL/min, the two is mixed with T-shaped
Conjunction valve mixing is together pumped into microreactor, and microreactor volume is 40mL, and reaction temperature is 80 DEG C, and the reaction time is 20min,
Reaction solution as rifampin crude product is connect, is calculated using efficient liquid phase, yield is 73.4%.
Claims (10)
1. it is a kind of by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that comprise the following steps：
(1) sodium salt for rifainycin S is placed in the DMF of sulfur acid, reaction obtains free rifamycin,
Reaction solution is filtered, homogeneous phase solution is obtained；
(2) homogeneous phase solution obtained in step (1) is mixed with dihydroxymethyl tert-butyl amine, reaction obtains N- tertiary butyl -1,3- Evil
Piperazine (5,6-C) rifamycin solution；
(3) solution fractionation obtained in step (2) is boiled off into dihydroxymethyl tert-butyl amine, DMF, is concentrated
N- spy butyl- 1,3- oxazine (5,6-C) rifamycin；
(4) N- tertiary butyl -1,3- oxazine (5,6-C) rifamycin that will be obtained in step (3) is dissolved in N,N-dimethylformamide
In, obtain homogeneous phase solution；
(5) 1- methyl -4- amino-piperazine is dissolved in DMF, obtains homogeneous phase solution；
(6) in the reaction unit of microchannel, step (4) is neutralized into the homogeneous phase solution that will be obtained in step (5) respectively while pumping into
In blender, after being sufficiently mixed, mixed solution is with constant flow pump reactor reaction in a subtle way；Trickle is collected, as sharp good fortune
Flat crude product.
2. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(3) in, the fractionation vacuum is carried out in -0.08~-0.1mpa under the conditions of 60~85 DEG C, and the dihydroxymethyl that fractionation is boiled off is special
The cumulative volume of butylamine and N,N-dimethylformamide accounts for the 20~80% of original solution volume.
3. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(1) in, the mass percent purity of the sodium salt for rifainycin S is 72~95%, and the mass percent concentration of the sulfuric acid is
More than 98%；Described sodium salt for rifainycin S and the mol ratio of sulfuric acid are 1:0.5~1；Described sodium salt for rifainycin S in N,
Concentration in dinethylformamide is 0.3~1g/mL；The temperature of the reaction is 20~40 DEG C；The time of the reaction is
0.5~1h.
4. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(2) in, the mass percent concentration of the dihydroxymethyl tert-butyl amine is more than 98%, the dihydroxymethyl tert-butyl amine and step
(1) mol ratio of the rifamycin obtained in is 1.2~1.6:1；The temperature of the reaction is 40~60 DEG C；The reaction when
Between be 1~4h.
5. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(4) in, the homogeneous phase solution concentration for obtaining is 0.1~0.7mol/L.
6. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(5) in, described 1- methyl -4- amino-piperazine mass percent purity is more than 98%, and the homogeneous phase solution concentration is 0.264
~2.1mol/L.
7. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(6) in, the homogeneous phase solution obtained in described step (4) pumps into flow velocity for 0.333~1.332mL/min, described step (5)
In the homogeneous phase solution that obtains pump into flow velocity for 0.666~2.664mL/min, N- spies butyl- 1 in the mixed solution, 3- oxazines (5,
6-C) rifamycin and the mol ratio of 1- methyl -4- amino-piperazine are 1:1~1.8.
8. as claimed in claim 1 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that step
(6) in, the microchannel reaction unit includes pump A, pump B, micro-mixer, microreactor and reception device, and pump A and pump B are with simultaneously
Connection mode is connected by connecting tube and micro-mixer, and micro-mixer, microreactor and reception device are in a series arrangement by connection
Pipe is connected.
9. as claimed in claim 8 by sodium salt for rifainycin S continuous system for rifampin method, it is characterised in that it is described
Microreactor volume is 5~50mL；The heating-up temperature of the microreactor is 75~100 DEG C；The residence time of the reaction is 4
~25min.
10. rifampin is prepared using still reaction device and microchannel reaction unit cascade reaction as described in claim 8 or 9
Method, it is characterised in that a diameter of 0.5~4mm of the connecting tube, the pump A or the connecting tube between pump B and micro-mixer
Length be 10~50cm；Connection length of tube between the microreactor and reception device is 10~70cm.
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| CN108516982A (en) * | 2018-05-25 | 2018-09-11 | 南京工业大学 | Method for preparing rifampicin by using microchannel reaction device |
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| CN108516982A (en) * | 2018-05-25 | 2018-09-11 | 南京工业大学 | Method for preparing rifampicin by using microchannel reaction device |
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