CN116554120B - Preparation method of 2-amino-2-thiazoline - Google Patents
Preparation method of 2-amino-2-thiazoline Download PDFInfo
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- REGFWZVTTFGQOJ-UHFFFAOYSA-N 4,5-dihydro-1,3-thiazol-2-amine Chemical compound NC1=NCCS1 REGFWZVTTFGQOJ-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 195
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 75
- 238000003756 stirring Methods 0.000 claims abstract description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000010438 heat treatment Methods 0.000 claims abstract description 27
- 239000012452 mother liquor Substances 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 239000008213 purified water Substances 0.000 claims abstract description 16
- 238000007259 addition reaction Methods 0.000 claims abstract description 15
- 238000010992 reflux Methods 0.000 claims abstract description 15
- 238000001704 evaporation Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 188
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 48
- 238000000605 extraction Methods 0.000 claims description 34
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 24
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 239000010413 mother solution Substances 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 8
- 238000006555 catalytic reaction Methods 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009835 boiling Methods 0.000 abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 23
- 238000004321 preservation Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 230000001276 controlling effect Effects 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 S- (2-aminoethyl) isothiourea hydrobromide hydrochloride Chemical compound 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- HCFPRFJJTHMING-UHFFFAOYSA-N ethane-1,2-diamine;hydron;chloride Chemical compound [Cl-].NCC[NH3+] HCFPRFJJTHMING-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- QDGRANVCLYGLDL-UHFFFAOYSA-N 2-(2-sulfanylethyl)guanidine;hydrochloride Chemical compound [Cl-].NC([NH3+])=NCCS QDGRANVCLYGLDL-UHFFFAOYSA-N 0.000 description 1
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical compound NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 description 1
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 1
- CKCQXLZVTHFENO-UHFFFAOYSA-N 2-hydroxyethyl carbamimidothioate Chemical compound NC(=N)SCCO CKCQXLZVTHFENO-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a preparation method of 2-amino-2-thiazoline, which belongs to the technical field of organic synthesis and comprises the following steps: an addition reaction and a chloro addition reaction; adding reaction mother liquor, thionyl chloride and N, N-dimethylformamide into a reaction kettle, heating to reflux, preserving heat for 3-5 hours, then adding purified water, adjusting ph to 7 by using sodium hydroxide aqueous solution, stirring, extracting, evaporating to dryness, recovering solvent, and drying to obtain 2-amino-2-thiazoline; the method does not need to additionally add acid for catalysis, has single reaction solvent and low boiling point of the solvent, is favorable for recovering the solvent, reduces the cost, has strong reaction selectivity, low-price and environment-friendly raw materials, can reduce the generation of waste ammonium salt, and has strong economical efficiency, environmental protection and high reaction yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2-amino-2-thiazoline.
Background
The compound 2-amino-2-thiazoline is an effective intermediate of levamisole, which is a broad-spectrum anthelmintic, is mainly used for expelling roundworms and colluders, and can improve the resistance of patients to bacterial and viral infections. The traditional Chinese medicine composition is mainly used as an auxiliary treatment after lung cancer, breast cancer operation or acute leukemia or malignant lymphoma chemotherapy. In addition, the traditional Chinese medicine composition can also be used for autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, upper sense, infantile respiratory tract infection, hepatitis, bacillary dysentery, sore furuncles, abscess and the like, and has obvious recent curative effect on refractory bronchial asthma through preliminary test.
Chinese patent CN101417985A discloses a synthesis method of 2-aminothiazoline, which comprises the steps of firstly directly carrying out chlorination reaction on ethanolamine and thionyl chloride in an organic solvent to obtain 2-aminoethylamine hydrochloride, and then carrying out cyclization reaction on the 2-aminoethylamine hydrochloride and thiourea to obtain 2-amino-2-thiazoline, wherein the purity of the product is 99.2%, and the reaction yield can reach 76%. But the ethanolamine is used as a raw material, the price is relatively high, and the economical efficiency is poor; the process has high reaction temperature and long reaction time, and causes higher energy consumption; finally, one molecule of ammonia is removed in the cyclization stage, and a large amount of waste ammonium salt is generated.
Green Chem, 2011, 13, 1648-1651 discloses that thiazoline is obtained by serial S-alkylation-cyclodeaminic reaction of thioamide/haloamine, and the reaction is carried out for 2.5h by using thiourea and 2-bromoethylamine hydrobromide to generate 2-amino-2-thiazoline, wherein the reaction yield can reach 88%. In the process reaction, halogen bromine participates in, so that certain influence is caused on the environment; also, this process removes a molecule of ammonia during the reaction to produce waste ammonium salts.
J. Am. chem, soc, 1957, 79, 21, 5667-5671 and Chemistry of Heterocyclic Compounds, 1262-1266 (1987) all disclose the use of S- (2-aminoethyl) isothiourea hydrobromide hydrochloride to react with 1- (2-mercaptoethyl) guanidine hydrochloride as starting material, but all produce waste ammonium salts by stripping off intramolecular ammonia during the reaction and environmental damage when the halogen salt is bromine.
Chem. Ber. 115, 1247-1251 (1982) discloses the use of thiourea to react with cyclic ethylamine to prepare 2-amino-2-thiazoline, which likewise gives rise to a large amount of waste ammonium salts, and the cyclic ethylamine has poor material stability and is difficult to obtain.
J. Am. chem. Soc. 1941, 63, 11, 3124-3126 use the preparation of 2-amino-2-thiazoline by the aqueous solution of beta-bromoethylamine and potassium thiocyanate. The technology needs to use diethyl ether for extraction operation, diethyl ether is extremely volatile, has extremely strong anesthetic action, and has great potential safety hazard in industrial production; meanwhile, the reaction yield is lower, the reaction yield is about 70%, and bromine atoms carried by raw materials have certain damage to the environment.
Chinese patent CN110698469A discloses a tebipenem ester intermediate and a synthesis method and application thereof, wherein ethylamine and triethylamine are used as raw materials, the ethylamine and the triethylamine are added into DMF, chloroacetamide is then added dropwise to prepare a first reaction product, then sodium hydroxide aqueous solution is added, potassium ferricyanide deionized water solution is used as catalysis, and 2-amino-2-thiazoline is produced by stirring. However, potassium ferricyanide deionized water solution is used as a catalyst for reaction, so that the price of potassium ferricyanide and DMF is high, and the economical efficiency is poor.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the preparation method of the 2-amino-2-thiazoline, which does not need to additionally add acid for catalysis, has single reaction solvent, low boiling point of the solvent, low cost, strong reaction selectivity, low price and environmental protection of raw materials, capability of reducing the generation of waste ammonium salt, strong economy of a process route, environmental protection and high reaction yield, and is beneficial to the recovery of the solvent.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
in a dichloromethane solvent system, thiourea and ethylene oxide are subjected to an initiation reaction to obtain S- (2-hydroxyethyl) -isothiourea, then N, N-dimethylformamide is used for catalyzing and carrying out chlorination by thionyl chloride reflux reaction to form a ring, and a 2-amino-2-thiazoline product is obtained.
A preparation method of 2-amino-2-thiazoline comprises the following reaction routes:
the preparation method of the 2-amino-2-thiazoline comprises the following steps: an addition reaction and a chloro addition reaction;
adding dichloromethane and thiourea into a high-pressure reaction container, stirring, closing the high-pressure reaction container, cooling the high-pressure reaction container to-5 ℃, then introducing ethylene oxide, heating the high-pressure reaction container to 40-60 ℃ after the introduction is finished, and preserving heat for 3-5 hours to obtain a reaction mother solution;
in the addition reaction, the mass ratio of dichloromethane to thiourea to ethylene oxide is 90.08-90.41:29.96-30.11:13.86-20.86;
the purity of the dichloromethane is 99%;
the purity of the thiourea is 99%;
the stirring speed during stirring is 400rpm;
adding reaction mother liquor, thionyl chloride and N, N-dimethylformamide into a reaction kettle, heating to reflux, preserving heat for 3-5 hours, then adding purified water, adjusting ph to 7 by using sodium hydroxide aqueous solution, stirring, extracting, evaporating to dryness, recovering solvent, and drying to obtain 2-amino-2-thiazoline;
adding dichloromethane into the water layer for the first time for the second time for extraction, and separating liquid to obtain the water layer; adding dichloromethane into the water layer for the second time to perform the third extraction, and mixing the dichloromethane layer of the second extraction and the dichloromethane layer of the third extraction after separating liquid;
the mass ratio of thiourea in the addition reaction to thionyl chloride, N-dimethylformamide and purified water in the chloro addition reaction is 29.96-30.11:47.24-52.21:0.05-0.07:100.01-100.41;
the mass ratio of the thionyl chloride in the chloro-addition reaction to the dichloromethane added for the first time and the dichloromethane added for the second time in the extraction is 47.24-52.21:100.05-100.77:100.12-100.59;
the purity of the sulfoxide chloride is 98%;
the purity of the N, N-dimethylformamide is 99.5%;
the mass fraction of the sodium hydroxide aqueous solution is 32%;
the stirring speed during stirring is 400rpm;
the temperature at the time of drying was 50 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) Compared with the traditional synthesis method, the preparation method of the 2-amino-2-thiazoline can generate acid to carry out catalytic chlorination reaction in the reaction process, and does not need to additionally add acid to carry out catalysis; the reaction solvent is single, the boiling point of the solvent is low, and the recovery of the solvent is facilitated, so that the cost is reduced; the reaction selectivity is high, the raw materials are low-cost and environment-friendly, the generation of waste ammonium salt can be reduced, and the process route has high economical efficiency;
(2) The preparation method of the 2-amino-2-thiazoline can reduce the production cost and the pollution to the environment, is environment-friendly, and has industrial popularization value;
(3) According to the preparation method of the 2-amino-2-thiazoline, ethylene oxide is selected as a raw material, and the catalyst is not needed for catalytic reaction due to the activity of the ethylene oxide, so that the selectivity is good, the yield is high, and the raw material is cheap and easy to obtain; in the chlorination process, trace DMF is used for catalysis, so that the chlorination rate and the cyclization rate are both improved, the reaction yield is improved, and the economy is improved; acid generated in the reaction process is catalyzed, no additional addition is needed, the use of reagents is reduced, and no waste ammonium salt is generated; the purity of the 2-amino-2-thiazoline prepared by the method can reach 99.21-99.65%, and the reaction yield can reach 72.99-90.98%.
Drawings
FIG. 1 is a liquid mass spectrum of the product prepared in example 1.
Detailed Description
Specific embodiments of the present invention will now be described in order to provide a clearer understanding of the technical features, objects and effects of the present invention.
The reaction yields in examples 1 to 11 were each calculated on the basis of the amount of thiourea used.
Example 1
Adding 90.12g of Dichloromethane (DCM) (AR, 99%) and 30.04g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle, increasing the weight of the high-pressure reaction kettle to 17.63g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, carrying out heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.73g of thionyl chloride (AR, 98%) and 0.06g of N, N-Dimethylformamide (DMF) (AR, 99.5%), heating the water bath to reflux, carrying out heat preservation reaction for 4 hours, adding 100.23g of purified water into the reaction system, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring at the stirring speed of 400rpm for 10 minutes, and extracting and separating the liquid; then adding 100.63g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.12g of DCM is added into the water layer for carrying out the third extraction and separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 36.44g of dried 2-amino-2-thiazoline, the purity is 99.65%, and the reaction yield is 90.98%.
Example 2
Adding 90.26g of DCM (AR, 99%) and 30.02g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle until the weight of the high-pressure reaction kettle increases to 13.86g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, and then carrying out heat preservation reaction for 4 hours to obtain a reaction mother solution; after the reaction is finished, opening a high-pressure reaction kettle, transferring reaction mother liquor into a 500mL four-mouth bottle, adding 49.55g of thionyl chloride (AR, 98%) and 0.05g of DMF (AR, 99.5%), heating in a water bath to reflux, preserving heat for 4 hours, adding 100.13g of purified water into a reaction system after the reaction is finished, adjusting ph=7 by using 32% sodium hydroxide aqueous solution by mass fraction, stirring at a stirring speed of 400rpm for 10 minutes, and extracting and separating liquid; then adding 100.17g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.44g of DCM is added into the water layer for carrying out the third extraction and liquid separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 29.34g of dried 2-amino-2-thiazoline with the purity of 99.23% and the reaction yield of 72.99%.
Example 3
Adding 90.36g of DCM (AR, 99%) and 30.06g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle until the weight of the reaction kettle increases to 20.86g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, and carrying out heat preservation reaction for 4 hours to obtain a reaction mother solution; after the reaction is finished, opening a high-pressure reaction kettle, transferring reaction mother liquor into a 500mL four-mouth bottle, adding 49.86g of thionyl chloride (AR, 98%) and 0.06g of DMF (AR, 99.5%), heating in a water bath to reflux, preserving heat for 4 hours, adding 100.29g of purified water into a reaction system after the reaction is finished, adjusting ph=7 by using a 32% sodium hydroxide aqueous solution, stirring at a stirring speed of 400rpm for 10 minutes, and extracting and separating liquid; then adding 100.52g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.26g of DCM is added into the water layer for carrying out the third extraction and separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 36.26g of dried 2-amino-2-thiazoline with the purity of 99.52 percent and the reaction yield of 90.35 percent.
Example 4
Adding 90.41g of DCM (AR, 99%) and 30.04g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to minus 5 ℃, introducing ethylene oxide into the high-pressure reaction kettle until the weight of the high-pressure reaction kettle increases to 17.26g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, preserving heat for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 47.24g of thionyl chloride (AR, 98%) and 0.06g of DMF (AR, 99.5%) and heating in a water bath to reflux, preserving heat for 4 hours, adding 100.16g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a 32% sodium hydroxide aqueous solution, stirring at 400rpm for 10 minutes, and extracting and separating the liquid; then adding 100.27g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.41g of DCM is added into the water layer for carrying out the third extraction and liquid separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 35.46g of dried 2-amino-2-thiazoline, the purity is 99.49%, and the reaction yield is 88.39%.
Example 5
Into a 250mL autoclave, 90.24g of DCM (AR, 99%) and 30.01g of thiourea (AR, 99%) were added, stirring was started and the stirring speed was controlled to 400rpm, the autoclave was closed, the autoclave was cooled to-5℃and ethylene oxide was introduced into the autoclave until the weight of the autoclave increased by 17.03g. Heating the high-pressure reaction kettle to 50 ℃ in a water bath, carrying out heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 52.21g of sulfoxide chloride (AR, 98%) and 0.07g of DMF (AR, 99.5%), heating the water bath to reflux, carrying out heat preservation reaction for 4 hours, adding 100.01g of purified water into a reaction system after the reaction is finished, regulating ph=7 by using a 32% sodium hydroxide aqueous solution, and extracting and separating liquid after stirring for 10 minutes at a stirring speed of 400rpm; then adding 100.57g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then adding 100.36g of DCM into the water layer for carrying out a third extraction and separation, mixing the obtained DCM layers, evaporating to dryness to recover the solvent, and drying the obtained white solid powder at 50 ℃ to obtain 36.48g of dried 2-amino-2-thiazoline with the purity of 99.43% and the reaction yield of 90.97%.
Example 6
Adding 90.08g of DCM (AR, 99%) and 30.08g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle until the weight of the high-pressure reaction kettle increases to 17.44g, heating the high-pressure reaction kettle in a water bath to 40 ℃ for heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.68g of thionyl chloride (AR, 98%) and 0.07g of DMF (AR, 99.5%) into the reaction kettle, heating the mixture in the water bath for reflux, carrying out heat preservation reaction for 4 hours, adding 100.06g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring for 10 minutes at the stirring speed of 400rpm, and extracting and separating liquid; then adding 100.24g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.48g of DCM is added into the water layer for carrying out the third extraction and separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 35.66g of dried 2-amino-2-thiazoline with the purity of 99.52 percent and the reaction yield of 88.80 percent.
Example 7
Into a 250mL autoclave, 90.21g of DCM (AR, 99%) and 29.96g of thiourea (AR, 99%) were added, stirring was started and the stirring speed was controlled to 400rpm, the autoclave was closed, the autoclave was cooled to-5℃and ethylene oxide was introduced into the autoclave until the weight of the autoclave increased by 16.98g. Heating the high-pressure reaction kettle to 60 ℃ in a water bath, carrying out heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.51g of thionyl chloride (AR, 98%) and 0.06g of DMF (AR, 99.5%), heating the water bath to reflux, carrying out heat preservation reaction for 4 hours, adding 100.28g of purified water into a reaction system after the reaction is finished, regulating ph=7 by using a 32% sodium hydroxide aqueous solution, stirring for 10 minutes at a stirring speed of 400rpm, and extracting and separating the liquid; then adding 100.62g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.50g of DCM was added to the aqueous layer for a third extraction and separation, the obtained DCM layers were mixed, the solvent was recovered by evaporation, and the obtained white solid powder was dried at 50 ℃. 36.24g of dried 2-amino-2-thiazoline was obtained, which had a purity of 99.61% and a reaction yield of 90.68%.
Example 8
Adding 90.18g of DCM (AR, 99%) and 30.11g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle, increasing the weight of the high-pressure reaction kettle to 17.24g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, preserving heat for 3 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 50.11g of thionyl chloride (AR, 98%) and 0.06g of DMF (AR, 99.5%), heating the mixture in the water bath to reflux, preserving heat for 4 hours, adding 100.33g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring at the stirring speed of 400rpm for 10 minutes, and extracting and separating the liquid; then adding 100.33g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.59g of DCM is added into the water layer for carrying out the third extraction and liquid separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, and the obtained white solid powder is dried at 50 ℃ to obtain 35.73g of dried 2-amino-2-thiazoline with the purity of 99.37 percent and the reaction yield of 88.75 percent.
Example 9
Adding 90.36g of DCM (AR, 99%) and 30.08g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle, increasing the weight of the high-pressure reaction kettle to 17.32g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, carrying out heat preservation reaction for 5 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.86g of thionyl chloride (AR, 98%) and 0.07g of DMF (AR, 99.5%), heating the water bath to reflux, carrying out heat preservation reaction for 4 hours, adding 100.41g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring at the stirring speed of 400rpm for 10 minutes, and extracting and separating the liquid; then adding 100.28g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.37g of DCM is added into the water layer for carrying out the third extraction and liquid separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 36.48g of dried 2-amino-2-thiazoline, the purity is 99.57%, and the reaction yield is 90.88%.
Example 10
Adding 90.16g of DCM (AR, 99%) and 30.03g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle, increasing the weight of the high-pressure reaction kettle to 17.26g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, carrying out heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.61g of thionyl chloride (AR, 98%) and 0.06g of DMF (AR, 99.5%) into the reaction kettle, heating the mixture in the water bath to reflux, carrying out heat preservation reaction for 3 hours, adding 100.14g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring at the stirring speed of 400rpm for 10 minutes, and extracting and separating the liquid; adding 100.05g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then 100.34g of DCM is added into the water layer for carrying out the third extraction and liquid separation, the obtained DCM layer is mixed, the solvent is recovered by evaporating, the obtained white solid powder is dried at 50 ℃ to obtain 35.86g of dried 2-amino-2-thiazoline with the purity of 99.21% and the reaction yield of 89.16%.
Example 11
Adding 90.33g of DCM (AR, 99%) and 30.01g of thiourea (AR, 99%) into a 250mL high-pressure reaction kettle, starting stirring, controlling the stirring speed to 400rpm, closing the high-pressure reaction kettle, cooling the high-pressure reaction kettle to-5 ℃, introducing ethylene oxide into the high-pressure reaction kettle, increasing the weight of the high-pressure reaction kettle to 17.29g, heating the high-pressure reaction kettle to 50 ℃ in a water bath, carrying out heat preservation reaction for 4 hours to obtain reaction mother liquor, opening the high-pressure reaction kettle after the reaction is finished, transferring the reaction mother liquor into a 500mL four-mouth bottle, adding 49.63g of thionyl chloride (AR, 98%) and 0.07g of DMF (AR, 99.5%), heating the water bath to reflux, carrying out heat preservation reaction for 5 hours, adding 100.19g of purified water into the reaction system after the reaction is finished, adjusting ph=7 by using a sodium hydroxide aqueous solution with the mass fraction of 32%, stirring at the stirring speed of 400rpm for 10 minutes, and extracting and separating liquid; then adding 100.77g of DCM into the water layer for secondary extraction, and separating to obtain a water layer; then adding 100.52g of DCM into the water layer for carrying out a third extraction and separation, mixing the obtained DCM layers, evaporating to dryness to recover the solvent, and drying the obtained white solid powder at 50 ℃ to obtain 36.46g of dried 2-amino-2-thiazoline with the purity of 99.48% and the reaction yield of 90.96%.
Summary of the results for examples 1-11:
the products prepared in the examples are analyzed through a liquid mass spectrum, and in consideration of the purpose of the liquid mass spectrum to determine that the prepared products are 2-amino-2-thiazoline, while examples 1 to 11 are all reacted under the same process flow, each group of examples only change process parameters, the final reaction result is compared to determine the optimal process condition, under the same process flow, the prepared products are all products, and only the purity of the products and the yield of the reaction are influenced according to the change of the process condition, so that when the liquid mass spectrum is prepared, only the products of the example with the highest yield are selected for analysis, namely the products of example 1 are analyzed, and the obtained liquid mass spectrum is shown in figure 1;
molecular ion peak M/z=103 for m+1 appears in fig. 1, illustrating the relative molecular mass of 102 for the product of example 1; judging according to the nitrogen rule, wherein the molecule contains no nitrogen or even numbers of nitrogen; isotopic ion peaks of M +2 sulfur appear in the spectra, 32 S: 34 s had a natural abundance ratio of 95.0:4.24, so M (M+2). Apprxeq.100:4.5, the abundance ratio was close, demonstrating that the compound contains sulfur, and therefore, according to the analysis, the product structure of example 1 was consistent with that of 2-amino-2-thiazoline.
The percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. The preparation method of the 2-amino-2-thiazoline is characterized by comprising the following steps of: an addition reaction and a chloro addition reaction;
adding dichloromethane and thiourea into a high-pressure reaction container, stirring, closing the high-pressure reaction container, cooling the high-pressure reaction container to-5 ℃, then introducing ethylene oxide, heating the high-pressure reaction container to 40-60 ℃ after the introduction is finished, and preserving heat for 3-5 hours to obtain a reaction mother solution;
in the addition reaction, the mass ratio of dichloromethane to thiourea to ethylene oxide is 90.08-90.41:29.96-30.11:13.86-20.86;
adding reaction mother liquor, thionyl chloride and N, N-dimethylformamide into a reaction kettle, heating to reflux, preserving heat for 3-5 hours, then adding purified water, adjusting ph to 7 by using sodium hydroxide aqueous solution, stirring, extracting, evaporating to dryness, recovering solvent, and drying to obtain 2-amino-2-thiazoline;
the mass ratio of thiourea in the addition reaction to thionyl chloride, N-dimethylformamide and purified water in the chloro addition reaction is 29.96-30.11:47.24-52.21:0.05-0.07:100.01-100.41.
2. The method for producing 2-amino-2-thiazoline according to claim 1, wherein in the addition reaction, the purity of the methylene chloride is 99%;
the thiourea had a purity of 99%.
3. The method for producing 2-amino-2-thiazoline according to claim 1, wherein in the chloroaddition reaction, the extraction is performed by adding methylene dichloride to the aqueous layer for the first time to perform the second extraction, and separating the aqueous layer; and adding dichloromethane into the aqueous layer for the second time to perform the third extraction, and mixing the dichloromethane layers of the second extraction and the third extraction after separating.
4. The process for producing 2-amino-2-thiazoline according to claim 3, wherein the mass ratio of thionyl chloride in the chloroaddition reaction to dichloromethane added for the first time and dichloromethane added for the second time in the extraction is 47.24-52.21:100.05-100.77:100.12-100.59.
5. The method for producing 2-amino-2-thiazoline according to claim 1, wherein in the chloroaddition reaction, the purity of the thionyl chloride is 98%;
the purity of the N, N-dimethylformamide is 99.5%;
the mass fraction of the sodium hydroxide aqueous solution is 32%.
6. The method for producing 2-amino-2-thiazoline according to claim 1, wherein the temperature at the time of drying in the chloro addition reaction is 50 ℃.
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| GB1109150A (en) * | 1966-03-14 | 1968-04-10 | Ici Ltd | Heterocyclic amines |
| JPS6351380A (en) * | 1986-08-21 | 1988-03-04 | Mitsui Toatsu Chem Inc | Production of 2-mercapto-2-thiazoline compound |
| CN101417985A (en) * | 2008-11-24 | 2009-04-29 | 山西新天源医药化工有限公司 | Method for synthesizing 2-amino thizaoline |
| CN110698469A (en) * | 2019-10-28 | 2020-01-17 | 南京红杉生物科技有限公司 | Tebipenem pivoxil intermediate and synthetic method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1109150A (en) * | 1966-03-14 | 1968-04-10 | Ici Ltd | Heterocyclic amines |
| JPS6351380A (en) * | 1986-08-21 | 1988-03-04 | Mitsui Toatsu Chem Inc | Production of 2-mercapto-2-thiazoline compound |
| CN101417985A (en) * | 2008-11-24 | 2009-04-29 | 山西新天源医药化工有限公司 | Method for synthesizing 2-amino thizaoline |
| CN110698469A (en) * | 2019-10-28 | 2020-01-17 | 南京红杉生物科技有限公司 | Tebipenem pivoxil intermediate and synthetic method and application thereof |
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