CN111574416A - Method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate - Google Patents
Method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate Download PDFInfo
- Publication number
- CN111574416A CN111574416A CN202010475715.8A CN202010475715A CN111574416A CN 111574416 A CN111574416 A CN 111574416A CN 202010475715 A CN202010475715 A CN 202010475715A CN 111574416 A CN111574416 A CN 111574416A
- Authority
- CN
- China
- Prior art keywords
- pleuromutilin
- tiamulin
- preparing
- isothiourea
- methylbenzenesulfonate
- 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
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 title claims abstract description 83
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 title claims abstract description 71
- 229960004885 tiamulin Drugs 0.000 title claims abstract description 71
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 58
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 36
- 150000002541 isothioureas Chemical class 0.000 title claims abstract description 31
- 238000005406 washing Methods 0.000 claims abstract description 33
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 28
- -1 p-toluenesulfonic acid pleuromutilin ester Chemical class 0.000 claims abstract description 26
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 17
- QMSVNDSDEZTYAS-UHFFFAOYSA-N 1-bromo-1-chloroethane Chemical compound CC(Cl)Br QMSVNDSDEZTYAS-UHFFFAOYSA-N 0.000 claims abstract description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000007935 neutral effect Effects 0.000 claims abstract description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 9
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims abstract 2
- 229960003750 ethyl chloride Drugs 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000012071 phase Substances 0.000 claims description 27
- XWJCLVYTQULGAW-UHFFFAOYSA-N 2-(diethylamino)ethylthiourea hydrochloride Chemical compound [Cl-].C(C)N(CCNC(S)=[NH2+])CC XWJCLVYTQULGAW-UHFFFAOYSA-N 0.000 claims description 24
- HOJIHIFXRHMKLL-UHFFFAOYSA-N 1-chloroethanamine Chemical compound CC(N)Cl HOJIHIFXRHMKLL-UHFFFAOYSA-N 0.000 claims description 17
- 239000012528 membrane Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 5
- 238000005191 phase separation Methods 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims 1
- YBDSNEVSFQMCTL-UHFFFAOYSA-N 2-(diethylamino)ethanethiol Chemical compound CCN(CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-N 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- YXQXDXAHCSEVSD-GCYNEOGWSA-N dynamutilin Chemical compound OC(=O)\C=C\C(O)=O.CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 YXQXDXAHCSEVSD-GCYNEOGWSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940092292 tiamulin fumarate Drugs 0.000 description 3
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- 241000221198 Basidiomycota Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000222350 Pleurotus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003014 ion exchange membrane Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000005501 phase interface Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
- C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a chemical synthesis method of veterinary bulk drug tiamulin, in particular to a method for preparing tiamulin by using isothiourea salt and p-toluenesulfonic acid pleuromutilin ester. The method comprises the steps of reacting chloroethane prepared from bromochloroethane and diethylamine with thiourea to prepare isothiourea salt, reacting pleuromutilin with p-toluenesulfonyl chloride to prepare p-toluenesulfonate pleuromutilin ester, adding isothiourea salt into the p-toluenesulfonate pleuromutilin ester, and extracting reaction liquid through alkaline washing, neutral washing, phase inversion and the like to prepare the high-purity tiamulin. The invention completely avoids the supervised dangerous intermediate diethylaminoethanethiol, adopts a milder route to prepare tiamulin, greatly reduces the product control cost, and has easily obtained raw materials, thereby being very suitable for application of industrial mass production.
Description
Technical Field
The invention relates to a chemical synthesis method of bulk drugs for veterinary use, in particular to a method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate.
Background
Tiamulin fumarate is an antibiotic special for pleuromutilis animals, has an antibacterial spectrum similar to that of macrolide antibiotics, and is mainly used for preventing and treating respiratory diseases of poultry. The tiamulin fumarate has the advantages of rapid absorption, high blood concentration, wide distribution in vivo, low residue, difficult generation of drug resistance, no pollution to the environment and the like, so the tiamulin fumarate is popularized and used in the global range, and the veterinary antibiotic ranks in ascending order have great market demand.
Tiamulin is a semisynthetic compound, which is synthesized by taking diethylaminoethanethiol as a raw material through the following steps. The method comprises the following steps: 200510122952.1, published in 8/9/2006, "preparation method of raw material containing pleuromutilin in tiamulin production process", discloses the method for extracting pleuromutilin from Basidiomycetes of higher fungus Pleurotus by fermentation. Step two: 201210169854.3 'a method for synthesizing pleuromutilin p-toluenesulfonate ester' disclosed in 2013, 12, 18 and discloses a method for preparing pleuromutilin p-toluenesulfonate ester by the synthetic reaction of pleuromutilin and p-toluenesulfonyl chloride under the catalysis of inorganic base. Step three: 201210169855.8 'a method for synthesizing tiamulin' disclosed in 2013, 12, 18 and discloses that pleuromutilin p-toluenesulfonate and diethylaminoethanethiol are subjected to nucleophilic substitution reaction under the catalysis of inorganic base to obtain the tiamulin. The main problem of the process is that the intermediate diethylaminoethanethiol has large toxicity and strong pungent odor, is the main raw material for synthesizing the nitrogen mustard gas of chemical weapons, so the second type of monitoring chemicals which are specified as tight control by the convention of prohibited chemical weapons are strictly monitored for purchase and use.
In order to get rid of the restriction of purchase and use of diethylaminoethanethiol, a series of methods for preparing tiamulin which diethylaminoethanethiol is avoided as a raw material are developed. For example, 201410842597.4 published on 25.3.2015, "one-pot method" for synthesizing tiamulin, which directly mixes three raw materials for producing tiamulin, pleuromutilin p-toluenesulfonate, diethylamine and thiirane together for reaction. The method avoids the direct use of diethylaminoethanethiol, but has many impurities and can not be separated, has extremely low tiamulin yield, stays in the laboratory research stage, and has no any significance in industrial production.
For example, 201310068656.2 "a method for preparing tiamulin base" disclosed in 2013, 5, month and 22, reacts with thiourea after chlorination of hydroxy group in pleuromutilin to obtain pleuromutilin thiourea salt, and then adds diethylaminoethanol to obtain tiamulin base. 201510231192.1 discloses a synthesis method of tiamulin on 9.9.2015, which is characterized in that pleuromutilin ester p-toluenesulfonate, thiourea and sodium metabisulfite are used for preparing thio-pleuromutilin, and diethylaminoethane derivatives and salts thereof are added for preparing the tiamulin. 201710943351.X, published 3, 14 and 2018, discloses a preparation method of tiamulin, which takes a compound pleuromutilin as a raw material, and the pleuromutilin is subjected to p-toluene sulfonylation, nucleophilic substitution reaction with beta-mercaptoethanol, activation by a halogenating reagent or a sulfonylating reagent, and finally reaction with diethylamine to synthesize the tiamulin. Although the three methods successfully avoid the diethylaminoethanethiol, the yield of the tiamulin is far lower than that of the traditional method using the diethylaminoethanethiol; new management and control chemicals, such as diethylaminoethanol, diethylaminoethane derivatives, mercaptoethanol, have also been introduced; a chlorination process of strict management of the national security supervision department is adopted; therefore, the above three methods are not significant in industrial production.
Disclosure of Invention
The invention aims to solve the problem of avoiding the use of monitoring chemicals and provide a safe and environment-friendly synthetic method of tiamulin suitable for industrial production.
In order to solve the problems, the invention uses diethylamine and bromochloroethane to react, and then thiourea is added to react to generate isothiourea salt; pleuromutilin reacts with paratoluensulfonyl chloride to generate pleuromutilin p-toluenesulfonate ester; adding isothiourea salt into p-toluenesulfonic acid pleuromutilin ester to react to generate tiamulin, and the specific technical scheme is as follows: a, preparing amino chloroethane, namely adding bromochloroethane into a reactor, heating, then gradually adding diethylamine, wherein the feeding time of diethylamine is less than 1 hour, the reaction temperature is 80-120 ℃, the reaction time is maintained for 1-3 hours, the reaction liquid is cooled to room temperature, the pH value is not less than 12.0, washing is carried out, then the pH value is controlled to be 6.0-7.5, washing is carried out, and the water phase is discarded to obtain the amino chloroethane. b, preparing diethylaminoethyl isothiourea hydrochloride, namely adding thiourea and water into the amino chloroethane obtained in the step a, reacting at the temperature of 60-80 ℃, and maintaining the reaction for 1.5-2.5 hours to generate 60-70% diethylaminoethyl isothiourea hydrochloride solution. c, preparing the pleuromutilin p-toluenesulfonate ester, namely adding a ketone or benzene organic solvent into a reactor, adding pleuromutilin, p-toluenesulfonyl chloride and an inorganic base, maintaining the pH value of a reaction system to be not less than 12, reacting at the temperature of 50-60 ℃ for 0.5-1 hour, and then discarding the water phase to obtain the pleuromutilin p-toluenesulfonate ester solution. d, reacting isothiourea salt with p-methyl benzene sulfonic acid pleuromutilin ester, putting the diethylamino ethyl isothiourea hydrochloride solution prepared in the step b into the p-methyl benzene sulfonic acid pleuromutilin ester solution prepared in the step c, adding tetrabutyl ammonium bromide and inorganic base, and reacting for 0.5-1 hour at the reaction temperature of 50-60 ℃ to obtain the tiamulin reaction liquid. e, extracting tiamulin: the tiamulin reaction liquid is separated to remove a water phase, then the impurities are removed through processes of alkaline washing, neutral washing, phase inversion and the like in sequence, the pH value of the alkaline washing is not less than 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the tiamulin reaction liquid is transferred into the water phase under the pH value of not more than 3.0 and then is transferred back to an organic phase again, the diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, the phase separation interface is clear, the tiamulin reaction liquid is washed by using a mixture liquid of methanol and water to remove the impurities, and finally the solvent is evaporated under reduced pressure for recycling, so that the tiamulin is obtained.
Specifically, in the step a, in the preparation of the amino chloroethane, the molar ratio of the bromochloroethane to the diethylamine is 1: 1.0-1.3.
Specifically, in the preparation of diethylaminoethyl isothiourea hydrochloride in the step b, the molar ratio of the addition amount of thiourea to the addition amount of bromochloroethane in the step a is 1: 1.0-1.1.
Specifically, the ketone organic solvent is methyl isobutyl ketone or methyl ethyl ketone, and the benzene organic solvent is toluene or xylene.
Specifically, in the step c, the preparation of the pleuromutilin p-toluenesulfonate ester comprises the step of preparing the pleuromutilin and the p-toluenesulfonyl chloride in a molar ratio of 1: 1.02-1.10.
In the step d, in the reaction of the isothiourea salt and the pleuromutilin p-methylbenzenesulfonate, the molar ratio of the pleuromutilin p-methylbenzenesulfonate to the diethylaminoethyl isothiourea hydrochloride is 1:1.1-1.3
Specifically, in the step d, in the preparation of tiamulin from the isothiourea salt and the pleuromutilin p-toluenesulfonate, the addition amount of tetrabutylammonium bromide is 0.5-1% of the addition amount of the pleuromutilin p-toluenesulfonate.
Specifically, the inorganic base is 32% of ionic membrane base, in the step c of preparing the pleuromutilin p-toluenesulfonate, the addition amount of the 32% of ionic membrane base is 45% -55% of the addition amount of pleuromutilin, in the step d of preparing the tiamulin by using the isothiourea salt and the pleuromutilin p-toluenesulfonate, the addition amount of the 32% of ionic membrane base is 30-40% of the addition amount of the pleuromutilin p-toluenesulfonate.
Specifically, in the purification of tiamulin in the step e, the adding amount of a matching solution of methanol and water is not less than 75% of the tiamulin.
Specifically, the methanol content of the mixture of methanol and water is 10-40%.
The tiamulin is prepared by the reaction of isothiourea salt and p-toluenesulfonic acid pleuromutilin ester, the use of a monitoring chemical, namely diethylaminoethanethiol, is completely avoided, and the yield of the tiamulin is similar to that of a diethylaminoethanethiol way.
Detailed Description
The method adopted by the invention is as follows:
a, preparing amino chloroethane: bromochloroethane was added to the reactor, the temperature was raised, and then diethylamine was added stepwise. The feeding time of the diethylamine is less than 1 hour, the feeding molar ratio of the bromochloroethane to the diethylamine is 1:1.0-1.3, the reaction temperature is 80-120 ℃, the reaction time is maintained for 1-3 hours, and the reaction liquid is cooled to the room temperature. Adjusting pH to 12.0, washing, controlling pH to 6.0-7.5, and removing water phase to obtain amino chloroethane.
b, preparing diethylaminoethyl isothiourea hydrochloride: adding thiourea and water into the amino chloroethane in the step a, wherein the molar ratio of the addition amount of the thiourea to the addition amount of the bromochloroethane in the step a is 1: 1.0-1.1, the reaction temperature is 60-80 ℃, the reaction time is maintained for 1.5-2.5 hours, and 60-65% diethylaminoethyl isothiourea hydrochloride solution is generated.
c, preparation of pleuromutilin p-toluenesulfonate: adding ketones or benzenes as organic solvent into the reactor, wherein the ketones can be methyl isobutyl ketone and methyl ethyl ketone, and the benzenes can be toluene, xylene and the like. And adding pleuromutilin, paratoluensulfonyl chloride and inorganic base, wherein the feeding molar ratio of pleuromutilin to paratoluensulfonyl chloride is 1:1.02-1.10, the inorganic base can be strong base such as sodium hydroxide, potassium hydroxide and the like, and is preferably ion membrane base prepared by electrolysis through an ion exchange membrane method, the adding amount of the ion membrane base is 45-55% of the adding amount of pleuromutilin, the pH value of a reaction system is maintained to be not less than 12, the reaction temperature is 50-60 ℃, the reaction time is 0.5-1 hour, and the water phase is discarded to obtain the pleuromutilin p-methyl benzene sulfonate ester solution.
d, reaction of isothiourea salts with pleuromutilin p-toluenesulfonate: and c, putting the diethylaminoethyl isothiourea hydrochloride solution prepared in the step b into the p-toluenesulfonic acid pleuromutilin ester solution prepared in the step c, adding tetrabutylammonium bromide and inorganic base serving as catalysts, wherein the molar ratio of the p-toluenesulfonic acid pleuromutilin ester to the diethylaminoethyl isothiourea hydrochloride is 1:1.1-1.3, wherein the inorganic base is preferably ion membrane base, the addition amount of the inorganic base is 30-40% of the addition amount of pleuromutilin, and the tiamulin reaction solution is obtained after the reaction is carried out at the reaction temperature of 50-60 ℃ for 0.5-1 hour.
e, extracting tiamulin: firstly, the tiamulin reaction solution is separated to remove the water phase, then the processes of alkaline washing, neutral washing, phase inversion and the like are sequentially carried out to extract and remove impurities, the pH value of the alkaline washing is not less than 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the tiamulin reaction solution is transferred into the water phase under the condition that the pH value is less than or equal to 3.0 and then is transferred back to the organic phase again, the diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, and the phase separation interface is clear. And washing with a mixture of methanol and water to remove impurities, wherein the content of methanol is 10-40%, and the addition amount of the mixture of methanol and water is not less than 75% of the amount of tiamulin. And finally, evaporating the solvent under reduced pressure for recycling to obtain the high-purity tiamulin. The generated waste liquid is collected in a waste water tank for centralized treatment, and then can be recycled for solution preparation or washing.
Example 1
To a 500ml reactor equipped with a stirring and condensing reflux device was added 143g of bromochloroethane, followed by addition ofThe temperature was raised to 80 ℃ and 73g of diethylamine was gradually added over 1 hour, and then the reaction was maintained at 120 ℃ for 1 hour, and the reaction solution was cooled to room temperature. With 250ml30% K2CO3Washing, controlling the pH value of the washing solution to be 6.0-7.5 by using 50ml of water, and removing the water phase to obtain the amino chloroethane.
Adding 80ml of water and 69.2g of thiourea into the amino chloroethane, keeping the reaction temperature at 60-75 ℃ for 2 hours to generate diethylaminoethyl isothiourea hydrochloride solution, and detecting the content of isothiourea salt to be 61.21% for later use.
Adding 200ml of methyl isobutyl ketone solvent into a 500ml reactor with a stirrer, adding 30g of pleuromutilin, 16g of p-toluenesulfonyl chloride and 15g of 32% ionic membrane caustic soda, maintaining the pH value of a reaction system to be equal to or more than 12, reacting at the temperature of 50 ℃, reacting for 1 hour, discarding the water phase to obtain 228ml of pleuromutilin p-toluenesulfonate solution, and detecting that the content of pleuromutilin p-toluenesulfonate is 18.28%.
Adding 35g of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide as a catalyst and 15g of 32% ionic membrane caustic soda into a ketone solution of pleuromutilin p-methylbenzenesulfonate, and reacting at the temperature of 60 ℃ for 0.5 hour to obtain a reaction solution of tiamulin.
And (3) discarding the water phase of the tiamulin reaction solution, adjusting the pH value to be not less than 12.0, washing, adjusting the pH value to be 6.0-7.5, carrying out neutral washing, transferring into the water phase at the pH value of not more than 3.0, and then transferring back to the organic phase again, wherein the temperature of diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, and the phase separation interface is clear. Then washing with 30ml of 25 percent methanol aqueous solution, and evaporating the solvent under the conditions of 95 ℃ and-0.095 MPa under reduced pressure to obtain 36.08g of tiamulin with the detection purity of 96.12 percent.
Example 2
143g of bromochloroethane was charged into a 500ml reactor equipped with a stirring and condensing reflux apparatus, heated to 80 ℃ and 93g of diethylamine was gradually added over 1 hour, and then the reaction was maintained at 100 ℃ for 3 hours and the reaction solution was cooled to room temperature. With 250ml of 30% K2CO3Washing, controlling pH value of 50ml water at 6.0-7.5, and discarding water phase to obtain amino chloroethane.
Adding 80ml of water and 75g of thiourea into the amino chloroethane, keeping the reaction at the temperature of between 65 and 80 ℃ for 1.5 hours to generate diethylaminoethyl isothiourea hydrochloride solution, and detecting the content of isothiourea salt to be 62.03 percent for later use.
Adding 200ml of methyl isobutyl ketone solvent into a 500ml reactor with a stirrer, adding 30g of pleuromutilin, 15.5g of p-toluenesulfonyl chloride and 15g of 32% ionic membrane caustic soda, maintaining the pH value of a reaction system to be equal to or larger than 12, reacting at the temperature of 60 ℃ for 0.5 hour, discarding the water phase to obtain 231ml of pleuromutilin p-toluenesulfonate solution, and detecting that the content of pleuromutilin p-toluenesulfonate is 18.14%.
Adding 30g of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide as a catalyst and 15g of 32% ionic membrane caustic soda into a ketone solution of pleuromutilin p-methylbenzenesulfonate, and reacting at the temperature of 50 ℃ for 1 hour to obtain a tiamulin reaction solution.
And (3) discarding the water phase of the tiamulin reaction solution, adjusting the pH value to be not less than 12.0, washing, adjusting the pH value to be 6.0-7.5, carrying out neutral washing, transferring into the water phase at the pH value of not more than 3.0, and then transferring back to the organic phase again, wherein the temperature of diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, and the phase separation interface is clear. Then washed by 26ml of 35 percent methanol aqueous solution, and the solvent is distilled off under the conditions of 95 ℃ and 0.095MPa under reduced pressure to obtain 35.98g of tiamulin with the detection purity of 96.01 percent.
Example 3
143g of bromochloroethane was charged into a 500ml reactor equipped with a stirring and condensing reflux apparatus, heated to 80 ℃ and 93g of diethylamine was gradually added over 1 hour, and then the reaction was maintained at 100 ℃ for 3 hours and the reaction solution was cooled to room temperature. With 250ml of 30% K2CO3Washing, controlling pH value of 50ml water at 6.0-7.5, and discarding water phase to obtain amino chloroethane.
Adding 80ml of water and 72.6g of thiourea into the amino chloroethane, keeping the reaction at the temperature of between 65 and 80 ℃ for 1.5 hours to generate diethylaminoethyl isothiourea hydrochloride solution, and detecting the content of isothiourea salt to be 62.03 percent for later use.
Adding 200ml of toluene serving as a solvent into a 500ml reactor with a stirrer, adding 30g of pleuromutilin, 16g of p-toluenesulfonyl chloride and 15g of 32% of ionic membrane caustic soda, reacting at 50 ℃ for 1 hour, discarding the water phase to obtain 224ml of pleuromutilin p-toluenesulfonate ester solution, and detecting that the content of pleuromutilin p-toluenesulfonate ester is 18.5%.
Adding 30g of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide as a catalyst and 15g of 32% ionic membrane caustic soda into a ketone solution of pleuromutilin p-methylbenzenesulfonate, and reacting at the temperature of 50 ℃ for 1 hour to obtain a tiamulin reaction solution.
And (3) discarding the water phase of the tiamulin reaction solution, adjusting the pH value to be not less than 12.0, washing, adjusting the pH value to be 6.0-7.5, carrying out neutral washing, transferring into the water phase at the pH value of not more than 3.0, and then transferring back to the organic phase again, wherein the separated phase interface is clear at the temperature of 40-45 ℃ of diethylaminoethyl isothiourea hydrochloride. Then 35ml of 15 percent methanol aqueous solution is used for washing, and the solvent is distilled off under the conditions of 95 ℃ and 0.095MPa under reduced pressure to obtain 36.33g of tiamulin with the detection purity of 95.83 percent.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. The invention discloses a method for preparing tiamulin by using isothiourea salt and pleuromutilin p-methylbenzenesulfonate, which comprises the steps of reacting chloroethane and thiourea prepared from bromochloroethane and diethylamine, and reacting pleuromutilin and p-toluenesulfonyl chloride, and is characterized in that:
a, preparing amino chloroethane, namely adding bromochloroethane into a reactor, heating, then gradually adding diethylamine, wherein the feeding time of diethylamine is less than 1 hour, the reaction temperature is 80-120 ℃, the reaction time is maintained for 1-3 hours, the reaction liquid is cooled to room temperature, the pH value is not less than 12.0, washing is carried out, then the pH value is controlled to be 6.0-7.5, washing is carried out, and the water phase is discarded to obtain the amino chloroethane;
b, preparing diethylaminoethyl isothiourea hydrochloride, namely adding thiourea and water into the amino chloroethane prepared in the step a, reacting at the temperature of 60-80 ℃, and maintaining the reaction time for 1.5-2.5 hours to generate 60-70% diethylaminoethyl isothiourea hydrochloride solution;
c, preparing pleuromutilin p-toluenesulfonate ester, namely adding a ketone or benzene organic solvent into a reactor, adding pleuromutilin, p-toluenesulfonyl chloride and an inorganic base, maintaining the pH value of a reaction system to be not less than 12, reacting at the temperature of 50-60 ℃ for 0.5-1 hour, and then discarding the water phase to obtain a pleuromutilin p-toluenesulfonate ester solution;
d, reacting isothiourea salt with p-methyl benzene sulfonic acid pleuromutilin ester, putting the diethylaminoethyl isothiourea hydrochloride solution prepared in the step b into the p-methyl benzene sulfonic acid pleuromutilin ester solution prepared in the step c, adding tetrabutyl ammonium bromide and inorganic base, and reacting at the temperature of 50-60 ℃ for 0.5-1 hour to obtain tiamulin reaction liquid;
e, extracting tiamulin: and (2) discarding the water phase of the tiamulin reaction solution, sequentially removing impurities through processes of alkaline washing, neutral washing, phase inversion and the like, wherein the pH value of the alkaline washing is not less than 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the tiamulin reaction solution is transferred into the water phase and then is transferred back to the organic phase again under the pH value of not more than 3.0, the temperature of a system is kept at 40-45 ℃ in the whole extraction process, a phase separation interface is clear, the tiamulin reaction solution is washed by using a methanol-water mixture liquid to remove impurities, and finally a solvent is evaporated under reduced pressure for recycling to obtain the tiamulin.
2. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the step a, in the preparation of the amino chloroethane, the molar ratio of the bromochloroethane to the diethylamine is 1: 1.0-1.3.
3. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the preparation of diethylaminoethyl isothiourea hydrochloride in the step b, the molar ratio of the addition amount of thiourea to the addition amount of bromochloroethane in the step a is 1: 1.0-1.1.
4. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: the ketone organic solvent is methyl isobutyl ketone or methyl ethyl ketone, and the benzene organic solvent is toluene or xylene.
5. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the step c, the preparation of the pleuromutilin p-toluenesulfonate ester, the molar ratio of the pleuromutilin to the p-toluenesulfonyl chloride is 1: 1.02-1.10.
6. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the reaction of the isothiourea salt and the pleuromutilin p-toluenesulfonate, the molar ratio of the pleuromutilin p-toluenesulfonate to the diethylaminoethyl isothiourea hydrochloride is 1: 1.1-1.3.
7. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the step d, in the preparation of tiamulin by using the isothiourea salt and the pleuromutilin p-methylbenzenesulfonate, the addition amount of tetrabutylammonium bromide is 0.5-1% of the addition amount of the pleuromutilin p-methylbenzenesulfonate.
8. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: and d, preparing tiamulin from the isothiourea salt and the p-toluenesulfonic acid pleuromutilin ester in the step d, wherein the 32% of ion membrane base is 30-40% of the p-toluenesulfonic acid pleuromutilin ester.
9. The method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate as claimed in claim 1, wherein: in the purification of tiamulin in the step e, the adding amount of a matching liquid of methanol and water is not less than 75% of the amount of tiamulin.
10. A process for the preparation of tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate according to claim 1 or 9, wherein: the methanol content is 10-40% of the mixture of methanol and water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010475715.8A CN111574416B (en) | 2020-05-29 | 2020-05-29 | Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010475715.8A CN111574416B (en) | 2020-05-29 | 2020-05-29 | Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111574416A true CN111574416A (en) | 2020-08-25 |
| CN111574416B CN111574416B (en) | 2024-05-03 |
Family
ID=72121874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010475715.8A Active CN111574416B (en) | 2020-05-29 | 2020-05-29 | Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111574416B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402431A (en) * | 2021-06-18 | 2021-09-17 | 青岛科技大学 | Preparation method of binary system tiamulin by one-pot method |
| CN120271487A (en) * | 2025-04-03 | 2025-07-08 | 山东胜利生物工程有限公司 | Preparation method of diethylaminoethyl isothiourea salt and preparation method of tiamulin |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BG104156A (en) * | 2000-02-15 | 2001-08-31 | Любомир БОГДАНОВ | Method for the preparation of 2-diethylaminoethylisothiouronium chloride hydrochloride |
| BG105644A (en) * | 2001-06-25 | 2003-04-30 | "Биовет" Ад | Method for the preparation of thiamulin |
| CN101250145A (en) * | 2008-04-02 | 2008-08-27 | 苏州科技学院 | The preparation method of diethylaminoethanethiol |
| CN102675172A (en) * | 2012-04-27 | 2012-09-19 | 宁夏泰瑞制药股份有限公司 | Preparation method of tiamulin base |
| CN107759502A (en) * | 2017-10-11 | 2018-03-06 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of Tiamulin |
| CN108137621A (en) * | 2016-05-03 | 2018-06-08 | 株式会社Lg化学 | A New Method for Preparation of Aminosilane Compounds |
-
2020
- 2020-05-29 CN CN202010475715.8A patent/CN111574416B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BG104156A (en) * | 2000-02-15 | 2001-08-31 | Любомир БОГДАНОВ | Method for the preparation of 2-diethylaminoethylisothiouronium chloride hydrochloride |
| BG105644A (en) * | 2001-06-25 | 2003-04-30 | "Биовет" Ад | Method for the preparation of thiamulin |
| CN101250145A (en) * | 2008-04-02 | 2008-08-27 | 苏州科技学院 | The preparation method of diethylaminoethanethiol |
| CN102675172A (en) * | 2012-04-27 | 2012-09-19 | 宁夏泰瑞制药股份有限公司 | Preparation method of tiamulin base |
| CN108137621A (en) * | 2016-05-03 | 2018-06-08 | 株式会社Lg化学 | A New Method for Preparation of Aminosilane Compounds |
| CN107759502A (en) * | 2017-10-11 | 2018-03-06 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of Tiamulin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402431A (en) * | 2021-06-18 | 2021-09-17 | 青岛科技大学 | Preparation method of binary system tiamulin by one-pot method |
| CN120271487A (en) * | 2025-04-03 | 2025-07-08 | 山东胜利生物工程有限公司 | Preparation method of diethylaminoethyl isothiourea salt and preparation method of tiamulin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111574416B (en) | 2024-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102432478B (en) | Preparation process of glycine | |
| CN110452136A (en) | A method of preparing taurine | |
| CN111574416A (en) | Method for preparing tiamulin from isothiourea salt and pleuromutilin p-methylbenzenesulfonate | |
| CN111925323B (en) | Synthetic method of 2-aminosulfonyl-N, N-dimethylnicotinamide | |
| CN105254575B (en) | A kind of synthetic method of sulphadiazine | |
| CN113120925A (en) | Method for recovering iodide from isophorone cracking material | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN105418494B (en) | A kind of preparation method of clodinafop-propargyl | |
| CN109627183A (en) | A kind of preparation method of chloroacetaldehyde oxime | |
| CN104098462B (en) | The method for splitting of the diphenyl-propionic acid racemoid of 2 hydroxyl, 3 methoxyl group 3,3 | |
| CN112250600B (en) | Technological method for improving yield of N, N' -diisopropylcarbodiimide product | |
| CN117986162B (en) | Preparation method of ethyl sulfonyl chloride | |
| CN102382050A (en) | Preparation method of substituted 1, 2, 3 and 4- tetrahydroquinoline -4-one hydrochloride | |
| CN106565621B (en) | A kind of synthetic method of isoxaflutole | |
| CN111362957B (en) | A kind of preparation method of icotinib key intermediate | |
| CN115505622A (en) | Method for preparing UDCA isomer of 3 alpha, 7 beta-dihydroxy-5 alpha-H | |
| CN117417340B (en) | A preparation method of 6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile | |
| CN113735747B (en) | Method for producing tiamulin by diethylaminoethanethiol synthetic solution | |
| CN112479951A (en) | Continuous synthesis method of carboxyethyl sulfosuccinate | |
| CN106008321B (en) | A kind of preparation method of UV292 | |
| CN105175294A (en) | Method for synthesizing sulfanilamide by using chlorobenzene as raw material | |
| CN108752216A (en) | A kind of high purity N, the environment-friendly preparation method thereof of N`- dibenzyl-ethylenediamin diacetates | |
| CN104829502B (en) | A kind of preparation method of biological buffer | |
| US9604895B2 (en) | Lactate production process | |
| CN118184528A (en) | Preparation method of sarcosine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information |
Address after: 832000 No.3, Tianshan Road, No.94 community, Shihezi Development Zone, Shihezi City, Xinjiang Uygur Autonomous Region Applicant after: Xinjiang Shangni Biotechnology Co.,Ltd. Address before: 832000 No.3, Tianshan Road, No.94 community, Shihezi Development Zone, Shihezi City, Xinjiang Uygur Autonomous Region Applicant before: Xinjiang Zheda sunshine Biotechnology Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |