CN113248413A - Method for continuously preparing thiamphenicol by using micro-reaction system - Google Patents
Method for continuously preparing thiamphenicol by using micro-reaction system Download PDFInfo
- Publication number
- CN113248413A CN113248413A CN202110364353.XA CN202110364353A CN113248413A CN 113248413 A CN113248413 A CN 113248413A CN 202110364353 A CN202110364353 A CN 202110364353A CN 113248413 A CN113248413 A CN 113248413A
- Authority
- CN
- China
- Prior art keywords
- micro
- reaction
- thiamphenicol
- solvent
- methylsulfonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 106
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 title claims abstract description 43
- 229960003053 thiamphenicol Drugs 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 42
- CIAZEFCFQFQJLB-NXEZZACHSA-N (1r,2r)-2-amino-1-(4-methylsulfonylphenyl)propane-1,3-diol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@H](N)CO)C=C1 CIAZEFCFQFQJLB-NXEZZACHSA-N 0.000 claims abstract description 38
- HKMLRUAPIDAGIE-UHFFFAOYSA-N methyl 2,2-dichloroacetate Chemical compound COC(=O)C(Cl)Cl HKMLRUAPIDAGIE-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- 239000000463 material Substances 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 150000005215 alkyl ethers Chemical class 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 150000001555 benzenes Chemical class 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000003068 static effect Effects 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- 239000000758 substrate Substances 0.000 description 17
- 238000001035 drying Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 238000005265 energy consumption Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- -1 polytetrafluoroethylene Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HFOCAQPWSXBFFN-UHFFFAOYSA-N 2-methylsulfonylbenzaldehyde Chemical compound CS(=O)(=O)C1=CC=CC=C1C=O HFOCAQPWSXBFFN-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006500 Brucellosis Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- IWYBVQLPTCMVFO-UHFFFAOYSA-N ethyl 2,2-dichloroacetate Chemical compound CCOC(=O)C(Cl)Cl IWYBVQLPTCMVFO-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a method for continuously preparing thiamphenicol by using a micro-reaction system. The micro-reaction system used in the invention comprises a micro-mixer, a micro-channel reactor and a backpressure device, when in preparation, the solution of the raw material (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and the alkali solution of methyl dichloroacetate are respectively injected into the micro-reactor by a pump simultaneously for condensation reaction, and the reaction product is concentrated, recrystallized, filtered, washed and dried to obtain the thiamphenicol product. The method provided by the invention has the advantages that the reaction time is only a few minutes, the yield of the product thiamphenicol is more than 99%, the purity is more than 99%, the operation is convenient, the method is continuous and controllable, no amplification effect exists, the process efficiency is high, and the method has good industrial application prospects.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a method for continuously preparing thiamphenicol.
Background
Thiamphenicol, shown in chemical structural formula (I), is a beta-aminoalcohol broad-spectrum antibiotic which is artificially synthesized for the first time in 1952 by U.S. Cutler research group (J. Am. Chem. Soc., 1952, 74, 5475-5481）。
Thiamphenicol has the characteristics of strong antibacterial activity, quick absorption, lasting drug effect and low toxicity, and is mainly used for treating typhoid fever, dysentery, respiratory tract infection, urinary tract infection, hepatobiliary system infection, intestinal infection, surgical infection, brucellosis, meningitis and the like clinically. The composition has obvious effect on preventing and treating the epidemic disease of the livestock and poultry, is mainly used for controlling the respiratory tract and gastrointestinal tract infection of cattle and poultry, and is used for treating various infectious diseases of pigs, sheep-Yang and fishes. Cutler research group: (J. Am. Chem. Soc.1953, 75, 4330-4333) report that (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was condensed with methyl dichloroacetate to obtain thiamphenicol in 88% yield, but the reaction was carried out at 100 ℃ and high temperature, which is harsh in reaction conditions and high in energy consumption, and is not suitable for industrial production. Strong in the Lin nationality (Tetrahedron2008, 64, 7822-7827) reported that (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was condensed with ethyl dichloroacetate in the presence of triethylamine to give thiamphenicol in 100% yield and the reaction temperature was lowered to 30 ℃. However, this method requires the addition of a large amount of triethylamine and the reaction time is too long.
In recent years, since many advantages of the micro-reaction system are receiving increasing attention from scientists and research technicians, the micro-reaction system is widely applied to the fields of organic synthesis and pharmacy. Compared with the traditional kettle type reaction equipment, the high-efficiency mass and heat transfer of the microreactor and the fluidity of the whole reaction system promote the high-efficiency conversion of the reaction, and the yield and the purity of the product are greatly improved. In addition, reaction amplification can be easily achieved by increasing the number of the micro-reaction channels, extending the length of the channels, or increasing the inner diameter of the micro-reaction channels. Therefore, based on the existing problems in preparing thiamphenicol, the continuous preparation method with short reaction time, high yield, low preparation cost, low energy consumption and high process efficiency is an urgent need to be solved by the technical personnel in the field.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a method for continuously preparing thiamphenicol by using a micro-reaction system. Compared with the existing preparation method, the method provided by the invention has the advantages that the reaction time is greatly shortened, the automation degree and efficiency of the technological process are obviously improved, the energy consumption is greatly reduced, the safety is greatly improved, and the industrial application is easy. It is to be noted that, as far as the method for continuously producing thiamphenicol using a micro-reaction system is concerned, no literature is reported.
The invention provides a method for continuously preparing thiamphenicol by using a micro-reaction system, wherein the micro-reaction system comprises a micro-mixer, a micro-channel reactor and a back pressure device which are sequentially communicated, and the method comprises the following specific steps:
(1) dissolving (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (II) in an organic solution, simultaneously conveying the organic solution and an alkali solution of methyl dichloroacetate into a micro mixer for mixing, and directly feeding a mixed reaction material flowing out of the micro mixer into a microchannel reactor for continuous condensation reaction;
(2) collecting reaction mixed liquid flowing out of the micro-reaction system, and performing separation and purification treatment to obtain a target product thiamphenicol;
wherein the thiamphenicol is a compound shown in a formula (I), and the (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol is a compound shown in a formula (II); the reaction formula is as follows:
in the present invention, the base may be an inorganic base or an organic base;
preferably, the inorganic base is ammonia or hydrazine hydrate;
preferably, the organic base is selected from methylamine, urea, ethylamine, ethanolamine, ethylenediamine, dimethylamine, trimethylamine, triethylamine, propylamine, isopropylamine, 1, 3-propanediamine, 1, 2-propanediamine, tripropylamine, triethanolamine, butylamine, isobutylamine, tert-butylamine, tributylamine, hexylamine, octylamine, aniline, benzylamine, cyclohexylamine or pyridine.
In the invention, the organic solvent is selected from halogenated hydrocarbon solvents, acetate solvents, alkyl ether solvents and alkanol solvents of C1-C4;
preferably, the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, trichloromethane, carbon tetrachloride and 1, 2-dichloroethane; the acetate solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and tert-butyl acetate; the substituted benzene solvent is toluene and xylene; the alkyl ether solvent is selected from diethyl ether, propyl ether, methyl tert-butyl ether and n-butyl ether; the alkanol solvent of C1-C4 is selected from methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1, 2-propylene glycol, 1, 3-propylene glycol and 1-butanol.
In the invention, the molar ratio of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol to methyl dichloroacetate to alkaline agent is 1: (1-10): (1-10); preferably, the molar ratio of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol, methyl dichloroacetate to alkaline agent is 1: (1.5-6): (1.5-5), the reaction effect is better.
In the invention, the temperature in the micro mixer is controlled to be 25-80 ℃.
In the invention, the temperature in the microchannel reactor is controlled to be 25-100 ℃.
In the invention, the backpressure of the microchannel reactor is 0.1-5 Mpa; preferably, the backpressure of the microchannel reactor is 0.3-2 Mpa, and the reaction effect is better.
In the invention, the residence time of a mixed reaction material formed by mixing the substrate liquid and hydrogen through a micro mixer in a microchannel reactor is controlled to be 1-15 minutes.
In the present invention, the micro mixer is any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a coaxial flow micro mixer, or a flow-focusing micro mixer.
In the invention, the microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor.
In the invention, the inner diameter of the tubular microchannel reactor is 100 micrometers-50 millimeters, preferably 120 micrometers-30 millimeters; or,
the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom, wherein the reaction layer is provided with a reaction fluid channel, and the hydraulic diameter of the reaction fluid channel is 100 micrometers-50 millimeters. More preferably, the hydraulic diameter of the reaction fluid channel is 120 micrometers to 30 millimeters.
In the invention, the step (2) of collecting the reaction mixed solution flowing out from the micro-reaction system and obtaining the target product thiamphenicol through separation and purification treatment specifically comprises the following steps: and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol.
The invention has the beneficial effects that: the preparation method comprises the following steps of carrying out continuous condensation reaction of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and methyl dichloroacetate by adopting a micro reaction system comprising a micro mixer and a microchannel reactor which are sequentially communicated, and preparing thiamphenicol, and compared with the existing synthesis method adopting a traditional batch reaction kettle, the preparation method has the following advantages:
1. the method has the advantages that the continuous synthesis from raw materials to products is realized, the technological process is continuously carried out, the automation degree is high, external intervention is not needed in the middle, the number of operators and the labor intensity are greatly reduced, and the production cost is obviously reduced;
2. the microchannel reactor has excellent mass and heat transfer and material mixing performance, so that the reaction time of the condensation reaction of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and methyl dichloroacetate is greatly shortened, and the reaction time is shortened from hours of the traditional batch kettle type reaction to several minutes;
3. the multiphase mixing, mass transfer and reaction processes in the reaction process are finished in the reaction fluid channels of the micro mixer and the micro channel reactor, a stirring device is not needed, and the energy consumption in the process is greatly reduced.
Drawings
FIG. 1 is a schematic view of a micro-reaction system used in an embodiment of the present invention.
Reference numbers in the figures: 1. The device comprises a feeding pump, 2, a constant-temperature oil bath, 3, a micro mixer, 4, a micro-channel reactor, 5, a back pressure valve, 6 and a storage tank.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
This example provides a method for continuously preparing methylsulfonylbenzaldehyde using a micro-reaction system, as shown in FIG. 1, comprising a micro-mixer 3, a microchannel reactor 4, which are connected in series, a feed pump 1, a constant temperature oil bath 2, a back pressure valve 5 and a storage tank 6, wherein the feed pump 1 is used for regulating and controlling the flow rate of a reaction mixture in the micro-reaction system, the constant temperature oil bath 2 is used for regulating and controlling the reaction temperature of the microchannel reactor 4, and the back pressure valve 5 is used for regulating and controlling the reaction pressure in the micro-reaction system. The micro mixer 3 is a T-shaped micro mixer. The microchannel reactor 4 is a polytetrafluoroethylene tubular microchannel reactor with an inner diameter of 0.8 mm, and the reaction volume is 1 mL. The back pressure valve 5 provides a pressure of 0.5 Mpa. The storage tank 6 is used for collecting reaction liquid. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (10.0 mmol,1.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 77.6 mu L/min; controlling the flow rate of the material 2 to be 22.4 mu L/min; the temperature of the micro mixer is 30 ℃; the temperature of the micro-channel is 30 ℃; the residence time of the reaction was 10 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
1H NMR (400 MHz, CD3OD): δ 7.90 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 6.25 (s, 1H), 5.16 (d, J = 2.8 Hz, 1H), 4.15 (td, J 1 = 6.4 Hz, J 2 = 2.8 Hz, 1H), 3.83 (dd, J 1 = 10.8 Hz, J 2 = 6.8 Hz, 1H), 3.62 (dd, J 1 = 10.8 Hz,J 2 = 6.0 Hz, 1H), 3.10 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD): δ 165.1, 149.0, 139.4, 126.9, 126.8, 70.0, 66.0, 60.8, 57.1, 43.0 ppm. ESI HRMS: calcd. for C12H15Cl2NO5Theoretical value of S + Na: 377.9946, found: 377.9941.
example 2
The embodiment is the same as embodiment 1, except that in the embodiment, the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (10.0 mmol,1.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 155.2 mu L/min; controlling the flow rate of the material 2 to be 44.8 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 5 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 95%.
Example 3
This example is the same as example 1 except that in this example, the back pressure valve 5 provides a pressure of 1.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (10.0 mmol,1.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 155.2 mu L/min; controlling the flow rate of the material 2 to be 44.8 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 5 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Example 4
This example is the same as example 1 except that in this example, the back pressure valve 5 provides a pressure of 2.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (10.0 mmol,1.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 310.4 mu L/min; controlling the flow rate of the material 2 to be 89.6 mu L/min; the temperature of the micro mixer is 60 ℃; the temperature of the micro-channel is 60 ℃; the residence time of the reaction was 2.5 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Example 5
This example is the same as example 1 except that in this example, the back pressure valve 5 provides a pressure of 1.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (20.0 mmol,2.87 g) and triethylamine (10.0 mmol,1.0 g) were added to 5mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 123.9 mu L/min; controlling the flow rate of the material 2 to be 76.1 mu L/min; the temperature of the micro mixer is 30 ℃; the temperature of the micro-channel is 30 ℃; the residence time of the reaction was 5 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Example 6
This example is the same as example 1 except that in this example, the back pressure valve 5 provides a pressure of 2.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (20.0 mmol,2.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 329.7 mu L/min; controlling the flow rate of the material 2 to be 170.3 mu L/min; the temperature of the micro mixer is 30 ℃; the temperature of the micro-channel is 30 ℃; the residence time of the reaction was 2 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 95%.
Example 7
The embodiment is the same as the embodiment 6, except that the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g) was added to 14mL of methanol, and the mixture was dissolved with stirring to give Material 1; methyl dichloroacetate (15.0 mmol,2.15 g) and triethylamine (20.0 mmol,2.0 g) were added to 3mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 329.7 mu L/min; controlling the flow rate of the material 2 to be 170.3 mu L/min; the temperature of the micro mixer is 60 ℃; the temperature of the micro-channel is 60 ℃; the residence time of the reaction was 2 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Example 8
This example is the same as example 1, except that in this example, a static mixer was used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 9
This example is the same as example 1, except that in this example, a Y-type micromixer is used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 10
This example is the same as example 1, except that in this example, a coaxial flow micromixer is used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 11
This example is the same as example 1, except that in this example, a flow focusing micromixer is used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 12
This example is the same as example 1, except that in this example, the base used in the continuous condensation reaction was aqueous ammonia, which is an inorganic base. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 98%.
Example 13
This example is the same as example 1, except that in this example, the base used in the continuous condensation reaction is hydrazine hydrate, which is an inorganic base. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 98%.
Example 14
This example is the same as example 1, except that in this example the base used in the continuous condensation reaction is tert-butylamine. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 15
This example is the same as example 1, except that in this example the base used in the continuous condensation reaction is cyclohexylamine. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 16
This example is the same as example 1, except that in this example, pyridine was used as the base in the continuous condensation reaction. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 97%.
Example 17
This example is the same as example 1, except that in this example, the organic solvent used in the continuous condensation reaction was 2-propanol. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 18
This example is the same as example 1, except that in this example, the organic solvent used in the continuous condensation reaction is 1-butanol. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product thiamphenicol was 99%.
Example 19
This example is the same as example 1 except that in this example, the microchannel reactor 4 is a polytetrafluoroethylene tubular microchannel reactor having an inner diameter of 0.8 mm and a reaction volume of 10 mL. The back pressure valve 5 provides a pressure of 1.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol,12.3 g) was added to 100mL of methanol, and dissolved with stirring to give Material 1; methyl dichloroacetate (150 mmol,21.5 g) and triethylamine (100 mmol,10 g) were added to 30mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 0.63 mL/min; controlling the flow rate of the material 2 to be 0.37 ml/min; the temperature of the micro mixer is 80 ℃; the temperature of the micro-channel is 100 ℃; the residence time of the reaction was 10 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 90%.
Example 20
This example is the same as example 19 except that in this example, the back pressure valve 5 provides a pressure of 2.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol,12.3 g) was added to 100mL of methanol, and dissolved with stirring to give Material 1; methyl dichloroacetate (150 mmol,21.5 g) and triethylamine (100 mmol,10 g) were added to 30mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 0.63 mL/min; controlling the flow rate of the material 2 to be 0.37 ml/min; the temperature of the micro mixer is 80 ℃; the temperature of the micro-channel is 100 ℃; the residence time of the reaction was 10 minutes;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Example 21
This embodiment is the same as embodiment 20, except that in this embodiment, the method includes the steps of:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol,12.3 g) was added to 100mL of methanol, and dissolved with stirring to give Material 1; methyl dichloroacetate (150 mmol,21.5 g) and triethylamine (100 mmol,10 g) were added to 30mL of methanol, and dissolved with stirring to give Material 2;
(2) controlling the flow rate of the material 1 to be 6.3 mL/min; controlling the flow rate of the material 2 to be 3.7 ml/min; the temperature of the micro mixer is 80 ℃; the temperature of the micro-channel is 100 ℃; the residence time of the reaction was 1 minute;
(3) and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product thiamphenicol with the yield of 99%.
Comparative example 1
The preparation method of thiamphenicol by adopting the traditional batch type reaction kettle comprises the following steps: methanol (17 mL), (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol,1.23 g), methyl dichloroacetate (15.0 mmol,2.15 g), and triethylamine (10.0 mmol,1.0 g) were added sequentially in a 100mL round-bottomed flask. The temperature is increased to 30 ℃, and the stirring speed is adjusted to 600 r/min. The reaction was carried out by sampling at regular intervals and analyzing for 3 hours, the conversion of the reaction substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 43%, the conversion of the reaction substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 64% in 6 hours, the conversion of the reaction substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 79% in 9 hours, the conversion of the reaction substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1 in 16 hours, the conversion of 3-diol was about 87%, the conversion of the reaction substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 99% in 24 hours of the reaction, the yield of the product (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was 97%, and the product purity was 96%.
The charge ratio of the comparative example 1 and the example 1 is the same. Compared with the traditional batch kettle type synthesis mode, the method disclosed by the invention has the advantages that the reaction time is greatly shortened, the product yield is high (more than 99%), no stirring device is needed, the energy consumption is greatly reduced, the process is continuously carried out, the operation is simple and convenient, the automation degree is high, and the efficiency is greatly improved. In addition, the excellent mass and heat transfer characteristics of the microchannel reactor can accurately regulate and control the dosage of methyl dichloroacetate and alkali in the condensation reaction process.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A method for continuously preparing thiamphenicol is characterized in that a micro-reaction system is used, the micro-reaction system comprises a micro-mixer, a micro-channel reactor and a back pressure device, and the method comprises the following specific steps:
(1) putting (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (II) in an organic solvent, simultaneously conveying the organic solvent and an alkali solution of methyl dichloroacetate into a micro mixer for mixing, and directly feeding a mixed reaction material flowing out of the micro mixer into a micro-channel reactor for continuous condensation reaction;
(2) collecting the reaction mixed liquid flowing out of the micro-reaction system, and separating and purifying to obtain a target product thiamphenicol (I);
the reaction formula is as follows:
2. the process according to claim 1, wherein the molar ratio of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol, methyl dichloroacetate and base in step (1) is 1: (1-10): (1-10).
3. The method according to claim 1, wherein in the step (1), the temperature in the micro mixer is controlled to be 25-80 ℃, the reaction temperature in the microchannel reactor is controlled to be 25-100 ℃, the residence time of the mixed reaction material in the microchannel reactor is 0.5-30 minutes, and the back pressure of the microchannel reactor is 0.1-5 MPa.
4. The method according to claim 1, wherein the organic solvent in step (1) is a halogenated hydrocarbon solvent, an acetate solvent, a substituted benzene solvent, an alkyl ether solvent or an alkanol of C1-C4.
5. The process according to claim 1, characterized in that said halogenated hydrocarbon solvent is selected from dichloromethane, trichloromethane, carbon tetrachloride and 1, 2-dichloroethane; the acetate solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and tert-butyl acetate; the substituted benzene solvent is selected from toluene and xylene; the alkyl ether solvent is selected from diethyl ether, propyl ether, methyl tert-butyl ether and n-butyl ether; the alkanol solvent of C1-C4 is selected from methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1, 2-propylene glycol, 1, 3-propylene glycol and 1-butanol.
6. The process according to claim 1, wherein the base in step (1) is an inorganic base or an organic base; the inorganic base is ammonia water or hydrazine hydrate; the organic base is selected from methylamine, urea, ethylamine, ethanolamine, ethylenediamine, dimethylamine, trimethylamine, triethylamine, propylamine, isopropylamine, 1, 3-propylenediamine, 1, 2-propylenediamine, tripropylamine, triethanolamine, butylamine, isobutylamine, tert-butylamine, tributylamine, hexylamine, octylamine, aniline, benzylamine, cyclohexylamine, or pyridine.
7. The method of claim 1, wherein the micromixer is any of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, or a flow focusing micromixer.
8. The process of claim 1 wherein the microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor;
the inner diameter of the tubular micro-channel reactor is 100 micrometers-50 millimeters; or,
the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom, wherein the reaction layer is provided with a reaction fluid channel, and the hydraulic diameter of the reaction fluid channel is 100 micrometers-50 millimeters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110364353.XA CN113248413B (en) | 2021-04-05 | 2021-04-05 | Method for continuously preparing thiamphenicol by using micro-reaction system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110364353.XA CN113248413B (en) | 2021-04-05 | 2021-04-05 | Method for continuously preparing thiamphenicol by using micro-reaction system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113248413A true CN113248413A (en) | 2021-08-13 |
| CN113248413B CN113248413B (en) | 2022-07-22 |
Family
ID=77220293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110364353.XA Active CN113248413B (en) | 2021-04-05 | 2021-04-05 | Method for continuously preparing thiamphenicol by using micro-reaction system |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113248413B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743309A (en) * | 2005-08-12 | 2006-03-08 | 中国科学院上海有机化学研究所 | Synthesis of optical active cyanhydrin compound by enzyme chemical process |
| CN102863361A (en) * | 2012-10-17 | 2013-01-09 | 湖北美天生物科技有限公司 | Chiral catalytic synthesis method of thiamphenicol |
| CN208679115U (en) * | 2018-06-20 | 2019-04-02 | 华北电力大学 | A kind of novel micro-mixer |
-
2021
- 2021-04-05 CN CN202110364353.XA patent/CN113248413B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743309A (en) * | 2005-08-12 | 2006-03-08 | 中国科学院上海有机化学研究所 | Synthesis of optical active cyanhydrin compound by enzyme chemical process |
| CN102863361A (en) * | 2012-10-17 | 2013-01-09 | 湖北美天生物科技有限公司 | Chiral catalytic synthesis method of thiamphenicol |
| CN208679115U (en) * | 2018-06-20 | 2019-04-02 | 华北电力大学 | A kind of novel micro-mixer |
Non-Patent Citations (4)
| Title |
|---|
| JIE ZOU 等: "Asymmetric Synthesis of Florfenicol by Dynamic Reductive Kinetic Resolution with Ketoreductases", 《EUR.J.ORG.CHEM.》 * |
| QIONG LI 等: "Stereoselective Synthesis of (−)-Chloramphenicol (＋)-Thiamphenicol and (＋)-Sphinganine via Chiral Tricyclic Iminolactone", 《CHIN.J.CHEM.》 * |
| 刘兆利 等: "微反应器在化学化工领域中的应用", 《化工进展》 * |
| 徐勤丰: "甲砜霉素合成路线概述", 《中国医药工业杂志》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113248413B (en) | 2022-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113264845B (en) | Method for continuously preparing chloramphenicol by using micro-reaction system | |
| CN113307766B (en) | Method for synthesizing pyridine compound by using microchannel reaction device | |
| CN111187324B (en) | Method for continuously preparing emamectin benzoate and intermediate thereof by using microreactor | |
| CN109665963A (en) | A kind of synthetic method of 2,6- dimethyl nitrobenzene | |
| CN108794426B (en) | Heterocyclic dithiocarbamate compound and preparation method thereof | |
| CN110511157A (en) | A method of trifluoroacetamide is prepared using microchannel reaction technology | |
| CN114262296B (en) | Method for synthesizing imidazole compounds by utilizing micro-channel reaction device | |
| CN113248413B (en) | Method for continuously preparing thiamphenicol by using micro-reaction system | |
| CN112876389A (en) | Method for synthesizing aromatic nitro compound by using microchannel reactor | |
| CN113181850A (en) | Microchannel preparation method of indole compound | |
| CN116063363B (en) | Process for synthesizing emamectin benzoate intermediate by using intermittent microchannel reactor | |
| CN109082450B (en) | Method for producing sitagliptin free base by using continuous flow technology | |
| CN112778146B (en) | Method for preparing p-hydroxyphenylglycine in pulse tubular reactor | |
| CN116283952A (en) | Vitamin B 1 Is a fully continuous flow preparation method | |
| CN108191736B (en) | 2, 3-disubstituted indole derivatives and preparation method thereof | |
| CN113149876A (en) | Method for continuously preparing florfenicol based on micro-reaction system | |
| CN113264892B (en) | Method for continuously preparing florfenicol key intermediate by using micro-reaction system | |
| CN214088354U (en) | Preparation system containing 3-amino-2-formamide pyridine structure compound | |
| CN116396302B (en) | Indole compound and preparation method thereof | |
| CN115536568B (en) | Method for continuously synthesizing chlorfenapyr | |
| CN112321524B (en) | Method for continuously preparing 3, 4-bis (4 '-aminofurazan-3' -yl) furoxan by adopting microchannel reactor | |
| CN112028830B (en) | Synthetic method of 2-H indazole and derivatives thereof | |
| CN114524777B (en) | Synthesis method of dihydro-oxazole compound | |
| CN114702460B (en) | Method for synthesizing 2H-1, 3-oxazine compound by utilizing micro-channel reaction device | |
| CN219111575U (en) | Production system for synthesizing benzonitrile compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |