CN103254153B - Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine - Google Patents
Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine Download PDFInfo
- Publication number
- CN103254153B CN103254153B CN201310199797.8A CN201310199797A CN103254153B CN 103254153 B CN103254153 B CN 103254153B CN 201310199797 A CN201310199797 A CN 201310199797A CN 103254153 B CN103254153 B CN 103254153B
- Authority
- CN
- China
- Prior art keywords
- piperazine
- ethyl
- solvent
- hydroxy ethoxy
- preparation
- 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.)
- Active
Links
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 200
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 239000002904 solvent Substances 0.000 claims abstract description 39
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 claims abstract description 33
- LECMBPWEOVZHKN-UHFFFAOYSA-N 2-(2-chloroethoxy)ethanol Chemical compound OCCOCCCl LECMBPWEOVZHKN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 15
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 230000006837 decompression Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 239000002798 polar solvent Substances 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 8
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 abstract 2
- 150000001875 compounds Chemical class 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 45
- 229910052739 hydrogen Inorganic materials 0.000 description 26
- 239000001257 hydrogen Substances 0.000 description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 125000004193 piperazinyl group Chemical group 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 11
- -1 glycol ether ester Chemical class 0.000 description 10
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 239000007789 gas Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- CAFAOQIVXSSFSY-UHFFFAOYSA-N 1-ethoxyethanol Chemical group CCOC(C)O CAFAOQIVXSSFSY-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 150000001793 charged compounds Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- 238000004064 recycling Methods 0.000 description 5
- 230000009183 running Effects 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000006103 sulfonylation Effects 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229960004431 quetiapine Drugs 0.000 description 2
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 2
- 229960005197 quetiapine fumarate Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- CNDXYOPJWQPUMU-UHFFFAOYSA-N CCOC(N1CCN(CCOCCO)CC1)=O Chemical compound CCOC(N1CCN(CCOCCO)CC1)=O CNDXYOPJWQPUMU-UHFFFAOYSA-N 0.000 description 1
- JKGLAGPKYJOXSZ-UHFFFAOYSA-N OCCOCCN(CC1)CCN1C(OCCCC[ClH]CCOCCO)=O Chemical compound OCCOCCN(CC1)CCN1C(OCCCC[ClH]CCOCCO)=O JKGLAGPKYJOXSZ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine, which comprises the following preparation steps: 1) reacting piperazine and piperazine dihydrochloride in solvent to prepare piperazine monohydrochloride; 2) reacting the piperazine monohydrochloride and 2-(2-chloroethoxy)ethanol in solvent; 3) after the reaction is finished, filtering to recover piperazine dihydrochloride, and drying for repeated use; 4) evaporating the filtrate to remove the solvent, thus obtaining a high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine crude product; and 5) performing vacuum reduced pressure rectification on the 1-[2-(2-hydroxyethoxy)ethyl]piperazine crude product, and collecting the 1-[2-(2-hydroxyethoxy)ethyl]piperazine fraction to obtain the high-purity product. The invention effectively solves the problem that the disubstituted compound impurity content is high and improves the product purity; and the cost of the raw materials is low, the process cost is greatly lowered, and the process is greener and more environment-friendly, thereby ensuring that the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine; Be specifically related to prepare intermediate 1-[2-(2-hydroxy ethoxy) ethyl of anti-mental disease therapeuticing medicine quetiapine fumarate] preparation method of piperazine.
Background technology
1-[2-(2-hydroxy ethoxy) ethyl] piperazine, be called for short HEEP, outward appearance is colourless to light yellow viscous liquid, and CAS registration number is [13349-82-1], and molecular structure is as general formula I:
General formula I
Synthetic quetiapine fumarate has the report of multiple route, but route the most practical, that have economic worth is most the use dibenzo [b reporting in patent EP240228, f] [1,4] sulphur azatropylidene-11-ketone makes the scheme of Quetiapine after chloro with key intermediate HEEP condensation, and HEEP is most important intermediate in Quetiapine preparation process.
The simplest synthetic route of HEEP is taking piperazine as starting material and 2-(2-chloroethoxy) ethanol under alkaline condition, condensation reaction occurs and makes.Reaction formula is as follows.
But this synthetic method is owing to sending on piperazine two imido grpup chemical environments identical, condensation reaction meeting produces a large amount of di-substituted impurity that waits, total recovery only has 55%, gas phase purity is lower than 85%, for addressing this problem, need to adopt the repeatedly mode of rectifying removal of impurities, each purification approximately will be lost the finished product of 5-8%, cause like this products production cost very high, on market, lack competitive power.
Some researchs think that this may be that halogen reactive behavior causes too by force, and reaction is improved, and use Tosyl chloride (TsCl) to react with glycol ether, generate the glycol ether ester of sulfonylation, make next step form monosubstituted thing control condition comparatively easy.Reaction formula is as follows.
But this method does not have the basic problem that solves reaction yet, be first that glycol ether ester and the piperazine reaction of sulfonylation still has dibasic problem.Secondly; Tosyl chloride (TsCl) reacts itself and also can produce the situation of disulfonyl with glycol ether; the raw material of the glycol ether ester of the sulfonylation using itself just has dibasic problem; also can produce corresponding impurity; react downwards and prepare HEEP with such raw material, impurity situation is below more complicated.
For solving dibasic problem, patent Be556239 has reported a kind of method, using piperazinecarboxylic acid ethyl ester as raw material, under alkaline condition, makes HEEP with the ethanol condensed hydrolysis again of 2-(2-chloroethoxy).Reaction formula is as follows.
This route is first protected one side of piperazine; avoid the generation of disubstitution product impurity; but starting raw material piperazinecarboxylic acid ethyl ester is difficult to obtain; raw materials cost is higher; secondly reaction scheme extends relatively; total recovery is low, and the insufficient of hydrolysis reaction also will introduce new impurity simultaneously, and these have all limited the suitability for industrialized production of this route.
In above multiple preparation method, all have different defects, or in product, the impurity such as piperazine raw material, two substituted-piperazinyl, hydroxyethyl piperazine exceeds standard seriously, or raw material sources are difficult to obtain, high expensive, the shortage market competitiveness.
Summary of the invention
The object of the present invention is to provide a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine; The present invention has solved the high problem of di-substituted foreign matter content in existing commercially available prod effectively, and product purity increases substantially; And cost of material is cheap, wide material sources, process costs significantly reduces; The piperazine dihydrochloride that reaction treatment reclaims is reusable, and three wastes treatment capacity is reduced greatly, makes technique environmental protection more, is applicable to suitability for industrialized production.
For achieving the above object, technical scheme of the present invention is:
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise and be prepared as follows step:
1) adopt piperazine and piperazine dihydrochloride to react in solvent and produce piperazine mono-hydrochloric salts;
2) utilize the piperazine mono-hydrochloric salts of preparing in step 1) to react in solvent with 2-(2-chloroethoxy) ethanol;
3) reaction finishes rear filtered and recycled piperazine dihydrochloride, can reuse after drying;
4) will after the filtrate steaming removal solvent after step 3) filtration, obtain highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product;
5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, collect 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) cut obtain high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product.
Described step 1) in the mol ratio that adds of piperazine and piperazine dihydrochloride be 1:0.8-1.2; In described step 1), solvent adopts the one in water and alcoholic solvent; And the add-on of solvent, calculates with envelope-bulk to weight ratio mL/g, be 1.8-2.2 times of piperazine add-on.
The mol ratio that adds of described piperazine and piperazine dihydrochloride is preferably 1:0.91.And the add-on of solvent, calculates with envelope-bulk to weight ratio mL/g, be 2.0 times of piperazine add-on.
Described alcoholic solvent adopts the one in methyl alcohol, ethanol, Virahol.
Described step 2) in the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol be (1.8-2.2): 1; Described step 2) in solvent adopt the one in polar solvent and non-polar solvent; And the add-on of solvent, calculates with weight ratio g/g, be 1.2-2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Described step 2) in temperature of reaction be 40-120 DEG C; Reaction times is 2-8 hour.
The mol ratio that adds of described piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is preferably 1.82:1; And the add-on of solvent, calculates with weight ratio g/g, be 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Temperature of reaction is preferably 80 DEG C; Reaction times is preferably 5.5 hours.
Described polar solvent adopts the one in water and alcoholic solvent; Described non-polar solvent adopts the one in methylene dichloride, chloroform, hexanaphthene, normal hexane, toluene, dimethylbenzene.
Described alcoholic solvent adopts the one in methyl alcohol, ethanol, Virahol.
In described step 5), rectification under vacuum temperature is 120-160 DEG C, and vacuum tightness is 10-30mmHg.
The reaction equation the present invention relates to is as follows:
The invention has the beneficial effects as follows: 1, the present invention is by using piperazine mono-hydrochloric salts for the main raw material reaction that feeds intake; the impact of having protected the one end on piperazine ring not reacted, thus the high serious problems of di-substituted foreign matter content in existing commercially available prod effectively solved.The crude product purity of its HEEP of preparation method provided by the invention can reach more than 98%, has improved product purity, and has also improved transformation efficiency and the yield of reaction, and yield can reach more than 75%, and process costs is significantly reduced.
2, the raw material of piperazine mono-hydrochloric salts can be produced with piperazine dihydrochloride and piperazine easily; compared with being starting raw material with the glycol ether ester of the tosylation of existing bibliographical information or piperazinecarboxylic acid ethyl ester; this cost of material is cheap, and wide material sources are applicable to suitability for industrialized production.
3, the piperazine dihydrochloride that reaction treatment reclaims can be without processing, after being only dried, can repeat to apply mechanically, and three wastes treatment capacity is reduced greatly, makes technique environmental protection more.
Brief description of the drawings
Fig. 1 is 1-[2-(2-hydroxy ethoxy) ethyl prepared by the present invention] infrared spectrogram of piperazine;
Fig. 2 is 1-[2-(2-hydroxy ethoxy) ethyl prepared by the present invention] mass spectrum of piperazine;
Fig. 3 is 1-[2-(2-hydroxy ethoxy) ethyl prepared by the present invention] the nucleus magnetic hydrogen spectrum figure of piperazine;
Fig. 4 is 1-[2-(2-hydroxy ethoxy) ethyl prepared by the present invention] the nuclear-magnetism carbon spectrogram of piperazine;
Fig. 5 is the gas chromatogram of the embodiment of the present invention 1;
Fig. 6 is the gas chromatogram of the embodiment of the present invention 2;
Fig. 7 is the gas chromatogram of the embodiment of the present invention 3;
Fig. 8 is the gas chromatogram of the embodiment of the present invention 4;
Fig. 9 is the gas chromatogram of the embodiment of the present invention 5.
Embodiment
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl of the present embodiment] preparation method of piperazine, comprise and be prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the mol ratio that adds of piperazine and piperazine dihydrochloride is 1:0.91(piperazine dihydrochloride 168g(1.06mol); Piperazine 100g(1.16mol)), in methyl alcohol, (add-on of methyl alcohol, calculates with envelope-bulk to weight ratio mL/g, 2.0 times of piperazine add-on) be heated with stirring to back flow reaction 1.2 hours, be cooled to 13 DEG C, suction filtration, filter cake is drained by a small amount of methanol wash, and filter cake is dried 5.5 hours at 75 DEG C; Obtain the about 245g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts prepared in step 1) and 2-(2-chloroethoxy) ethanol in 500ml reaction flask, add solvent reaction, wherein the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 1.82:1(piperazine mono-hydrochloric salts 90g(734.5mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) middle solvent employing polar solvent methyl alcohol; And the add-on of methyl alcohol, calculates with weight ratio g/g, be 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 80 DEG C; Insulation reaction 5.5 hours at this temperature.3) after reaction finishes, remove the about 50g of half quantity of methyl alcohol lower than 60 DEG C of underpressure distillation, be cooled to 18 DEG C, filter, filter cake is piperazine dihydrochloride by a small amount of methanol wash, and 53 DEG C are dried after 7.5 hours with regard to recyclable recycling.4) filtrate after step 3) filtration is slowly heated to 95 DEG C, after vacuum decompression distillation for removing methanol and residual piperazine, obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product.5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=148 DEG C, vacuum tightness=15mmHg) be colorless transparent viscous liquid, 53.8g, molar yield 76.9%, is high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product.Analytical results is shown in shown in Fig. 1-5, and in Fig. 1 infrared spectra, 3390.81 absorption peak can be confirmed the hydroxyl in HEEP, and 1119.10 can confirm the ehter bond in HEEP, can obtain thus the conclusion that contains ethoxy ethanol structure in sample HEEP molecular structure.In Fig. 2 mass spectrum, 174 molecular ion peak can obviously be confirmed the molecular weight of HEEP, and 84 peak shows piperazine fragment peak, and can obtain thus sample is the conclusion of the HEEP of molecular weight 174 really.In Fig. 3 nucleus magnetic hydrogen spectrum, 3.71 is fignal centers of hydroxyl hydrogen, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.Fig. 5 records purity (GC) 99.7%.
Embodiment 2
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl of the present embodiment] preparation method of piperazine, comprise and be prepared as follows step: 1) in reaction flask, add the piperazine dihydrochloride after piperazine and embodiment 1 reclaim; Wherein the mol ratio that adds of the piperazine dihydrochloride after piperazine and recovery is 1:0.91(piperazine dihydrochloride 180g(1.06mol); Piperazine 100g(1.16mol)), in ethanol, (add-on of ethanol, calculates with envelope-bulk to weight ratio mL/g, 1.8 times of piperazine add-on) be heated with stirring to back flow reaction 1.2 hours, be cooled to 13 DEG C, suction filtration, filter cake is drained by a small amount of washing with alcohol, and filter cake is dried 5.5 hours at 85 DEG C; Obtain the about 238g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts prepared in step 1) and 2-(2-chloroethoxy) ethanol in 500ml reaction flask, add solvent reaction, wherein the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 1.93:1(piperazine mono-hydrochloric salts 95g(774.6mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) middle solvent employing polar solvent water; And the add-on of water, calculates with weight ratio g/g, be 1.2 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 78 DEG C; Insulation reaction 6.5 hours at this temperature.3) after reaction finishes, the about 40g of the half water yield is removed in 75 DEG C of underpressure distillation, is cooled to 18 DEG C, filters, and filter cake is piperazine dihydrochloride, and 65 DEG C are dried after 7.5 hours with regard to recyclable recycling.4) filtrate after step 3) filtration is slowly heated to 95 DEG C, after vacuum decompression dephlegmate and residual piperazine, obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product.5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=155 DEG C, vacuum tightness=17mmHg) be colorless transparent viscous liquid, 55.4g, molar yield 79.2%, be high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product, analytical results is shown in shown in Fig. 1-4 and Fig. 6, in Fig. 1 infrared spectra, 3390.81 absorption peak can be confirmed the hydroxyl in HEEP, 1119.10 can confirm the ehter bond in HEEP, can obtain thus the conclusion that contains ethoxy ethanol structure in sample HEEP molecular structure.In Fig. 2 mass spectrum, 174 molecular ion peak can obviously be confirmed the molecular weight of HEEP, and 84 peak shows piperazine fragment peak, and can obtain thus sample is the conclusion of the HEEP of molecular weight 174 really.In Fig. 3 nucleus magnetic hydrogen spectrum, 3.71 is fignal centers of hydroxyl hydrogen, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.Fig. 6 records purity (GC) 99.7%.
Embodiment 3
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl of the present embodiment] preparation method of piperazine, comprise and be prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the mol ratio that adds of piperazine and piperazine dihydrochloride is 1:0.8(piperazine dihydrochloride 158g(0.93mol); Piperazine 100g(1.16mol)), in water, (add-on of water, calculates with envelope-bulk to weight ratio mL/g, is 2.2 times of piperazine add-on) is heated with stirring to back flow reaction 1 hour, is cooled to 10 DEG C, suction filtration, filter cake is dried 5 hours at 70 DEG C; Obtain the about 225g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts prepared in step 1) and 2-(2-chloroethoxy) ethanol in 500ml reaction flask, add solvent reaction, wherein the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.0:1(piperazine mono-hydrochloric salts 98.4g(802.8mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) middle solvent employing polar solvent ethanol; And the add-on of ethanol, calculates with weight ratio g/g, be 2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 40 DEG C; Insulation reaction 2 hours at this temperature.3) after reaction finishes, remove the about 30g of half amount of alcohol lower than 60 DEG C of underpressure distillation, be cooled to 15 DEG C, filter, filter cake is piperazine dihydrochloride by a small amount of washing with alcohol, and 50 DEG C are dried after 7 hours with regard to recyclable recycling.4) filtrate after step 3) filtration is slowly heated to 90 DEG C, after vacuum decompression distillation for removing methanol and residual piperazine, obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product.5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=120 DEG C, vacuum tightness=10mmHg) be colorless transparent viscous liquid, 54.7g, molar yield 78.2%, is high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product.Analytical results is shown in that, shown in Fig. 1-4 and Fig. 7, in Fig. 1 infrared spectra, 3390.81 absorption peak can be confirmed the hydroxyl in HEEP, and 1119.10 can confirm the ehter bond in HEEP, can obtain thus the conclusion that contains ethoxy ethanol structure in sample HEEP molecular structure.In Fig. 2 mass spectrum, 174 molecular ion peak can obviously be confirmed the molecular weight of HEEP, and 84 peak shows piperazine fragment peak, and can obtain thus sample is the conclusion of the HEEP of molecular weight 174 really.In Fig. 3 nucleus magnetic hydrogen spectrum, 3.71 is fignal centers of hydroxyl hydrogen, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.8% by Fig. 7.
Embodiment 4
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl of the present embodiment] preparation method of piperazine, comprise and be prepared as follows step: 1) in reaction flask, add the piperazine dihydrochloride after piperazine and embodiment 3 reclaim; Wherein the mol ratio that adds of the piperazine dihydrochloride after piperazine and recovery is 1:1.2(piperazine dihydrochloride 236g(1.39mol); Piperazine 100g(1.16mol)), in Virahol, (add-on of Virahol, calculates with envelope-bulk to weight ratio mL/g, 2.1 times of piperazine add-on) in be heated with stirring to back flow reaction 1.5 hours, be cooled to 20 DEG C, suction filtration, filter cake is drained by a small amount of washed with isopropyl alcohol, and filter cake is dried 6 hours at 90 DEG C; Obtain the about 250g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts prepared in step 1) and 2-(2-chloroethoxy) ethanol in 500ml reaction flask, add solvent reaction, wherein the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.2:1(piperazine mono-hydrochloric salts 102.1g(883.1mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) middle solvent employing polar solvent Virahol; And the add-on of Virahol, calculates with weight ratio g/g, be 1.8 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 120 DEG C; Insulation reaction 8 hours at this temperature.3) after reaction finishes, the about 60g of half Virahol amount is removed in 80 DEG C of underpressure distillation, is cooled to 20 DEG C, filters, and filter cake is with being piperazine dihydrochloride after a small amount of washed with isopropyl alcohol, and 70 DEG C are dried after 8 hours with regard to recyclable recycling.4) filtrate after step 3) filtration is slowly heated to 100 DEG C, after vacuum decompression dephlegmate and residual piperazine, obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product.5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=165 DEG C, vacuum tightness=25mmHg) be colorless transparent viscous liquid, 55.8g, molar yield 79.7%, is high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product.Analytical results is shown in that, shown in Fig. 1-4 and Fig. 8, in Fig. 1 infrared spectra, 3390.81 absorption peak can be confirmed the hydroxyl in HEEP, and 1119.10 can confirm the ehter bond in HEEP, can obtain thus the conclusion that contains ethoxy ethanol structure in sample HEEP molecular structure.In Fig. 2 mass spectrum, 174 molecular ion peak can obviously be confirmed the molecular weight of HEEP, and 84 peak shows piperazine fragment peak, and can obtain thus sample is the conclusion of the HEEP of molecular weight 174 really.In Fig. 3 nucleus magnetic hydrogen spectrum, 3.71 is fignal centers of hydroxyl hydrogen, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.7% by Fig. 8.
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl of the present embodiment] preparation method of piperazine, comprise and be prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the mol ratio that adds of piperazine and piperazine dihydrochloride is 1:1.05(piperazine dihydrochloride 193g(1.22mol); Piperazine 100g(1.16mol)), in water, (add-on of water, calculates with envelope-bulk to weight ratio mL/g, is 1.9 times of piperazine add-on) is heated with stirring to back flow reaction 1.1 hours, is cooled to 12 DEG C, suction filtration, filter cake is dried 5.3 hours at 70 DEG C; Obtain the about 232g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts prepared in step 1) and 2-(2-chloroethoxy) ethanol in 500ml reaction flask, add solvent reaction, wherein the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.12:1(piperazine mono-hydrochloric salts 104.3g(851.0mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) middle solvent employing non-polar solvent methylene dichloride (described non-polar solvent methylene dichloride also can adopt the one in chloroform, hexanaphthene, normal hexane, toluene, dimethylbenzene to replace, and the effect playing is all identical); And the add-on of non-polar solvent, calculates with weight ratio g/g, be 2.2 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 100 DEG C; Insulation reaction 3 hours at this temperature.3) after reaction finishes, the about 55g of half quantity of dichloromethane is removed in 70 DEG C of underpressure distillation, is cooled to 18 DEG C, filters, and filter cake is piperazine dihydrochloride by a small amount of washed with dichloromethane, and 52 DEG C are dried after 7.4 hours with regard to recyclable recycling.4) filtrate after step 3) filtration is slowly heated to 94 DEG C, after vacuum decompression distillation for removing methanol and residual piperazine, obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) crude product.5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=160 DEG C, vacuum tightness=20mmHg) be colorless transparent viscous liquid, 52.5g, molar yield 75.0%, be high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product, analytical results is shown in shown in Fig. 1-4 and Fig. 9, in Fig. 1 infrared spectra, 3390.81 absorption peak can be confirmed the hydroxyl in HEEP, 1119.10 can confirm the ehter bond in HEEP, can obtain thus the conclusion that contains ethoxy ethanol structure in sample HEEP molecular structure.In Fig. 2 mass spectrum, 174 molecular ion peak can obviously be confirmed the molecular weight of HEEP, and 84 peak shows piperazine fragment peak, and can obtain thus sample is the conclusion of the HEEP of molecular weight 174 really.In Fig. 3 nucleus magnetic hydrogen spectrum, 3.71 is fignal centers of hydroxyl hydrogen, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on side chain.Can obtain HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.7% by Fig. 9.
Claims (7)
1. 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine, it is characterized in that comprising being prepared as follows step:
1) adopt piperazine and piperazine dihydrochloride to react in solvent and produce piperazine mono-hydrochloric salts;
2) utilize the piperazine mono-hydrochloric salts of preparing in step 1) to react in solvent with 2-(2-chloroethoxy) ethanol;
3) reaction finishes rear filtered and recycled piperazine dihydrochloride, can reuse after drying;
4) will after the filtrate steaming removal solvent after step 3) filtration, obtain highly purified 1-[2-(2-hydroxy ethoxy) ethyl] piperazine crude product;
5) 1-[2-(2-hydroxy ethoxy) ethyl step 4) being obtained] rectifying under vacuum decompression of piperazine crude product, collect 1-[2-(2-hydroxy ethoxy) ethyl] piperazine cut obtain high purity 1-[2-(2-hydroxy ethoxy) ethyl] piperazine product;
Described step 1) in the mol ratio that adds of piperazine and piperazine dihydrochloride be 1:0.8-1.2; In described step 1), solvent adopts the one in water and alcoholic solvent; And the add-on of solvent, calculates with envelope-bulk to weight ratio mL/g, be 1.8-2.2 times of piperazine add-on;
Described step 2) in the mol ratio that adds of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol be (1.8-2.2): 1; Described step 2) in solvent adopt the one in polar solvent and non-polar solvent; And the add-on of solvent, calculates with weight ratio g/g, be 1.2-2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Described step 2) in temperature of reaction be 40-120 DEG C; Reaction times is 2-8 hour.
2. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 1] preparation method of piperazine, it is characterized in that described piperazine and the mol ratio that adds of piperazine dihydrochloride are 1:0.91; And the add-on of solvent, calculates with envelope-bulk to weight ratio mL/g, be 2.0 times of piperazine add-on.
3. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 1] preparation method of piperazine, it is characterized in that described alcoholic solvent adopts the one in methyl alcohol, ethanol, Virahol.
4. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 1] preparation method of piperazine, it is characterized in that described piperazine mono-hydrochloric salts and the mol ratio that adds of 2-(2-chloroethoxy) ethanol are 1.82:1; And the add-on of solvent, calculates with weight ratio g/g, be 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Temperature of reaction is 80 DEG C; Reaction times is 5.5 hours.
5. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 1] preparation method of piperazine, it is characterized in that described polar solvent adopts the one in water and alcoholic solvent; Described non-polar solvent adopts the one in methylene dichloride, chloroform, hexanaphthene, normal hexane, toluene, dimethylbenzene.
6. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 5] preparation method of piperazine, it is characterized in that described alcoholic solvent adopts the one in methyl alcohol, ethanol, Virahol.
7. a kind of 1-[2-(2-hydroxy ethoxy) ethyl as claimed in claim 1] preparation method of piperazine, it is characterized in that in described step 5), rectification under vacuum temperature is 120-160 DEG C, vacuum tightness is 10-30mmHg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310199797.8A CN103254153B (en) | 2013-05-24 | 2013-05-24 | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310199797.8A CN103254153B (en) | 2013-05-24 | 2013-05-24 | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103254153A CN103254153A (en) | 2013-08-21 |
| CN103254153B true CN103254153B (en) | 2014-06-04 |
Family
ID=48958419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310199797.8A Active CN103254153B (en) | 2013-05-24 | 2013-05-24 | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103254153B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237496A (en) * | 2015-10-27 | 2016-01-13 | 济南大学 | A new method for synthesizing N-tert-butoxycarbonylpiperazine |
| CN106083761A (en) * | 2016-06-16 | 2016-11-09 | 盐城工学院 | The preparation method of the monosubstituted piperazine compounds of a kind of N and application |
| CN106045941A (en) * | 2016-06-16 | 2016-10-26 | 盐城工学院 | Method for preparing piperazine hydrochloride |
| CN112321533A (en) * | 2020-11-09 | 2021-02-05 | 扬州市普林斯医药科技有限公司 | Preparation method of 1- [2- (2-hydroxyethoxy) ethyl ] piperazine |
| CN116143724A (en) * | 2023-01-06 | 2023-05-23 | 中国科学院宁波材料技术与工程研究所 | A kind of preparation method and application of piperazine chloride |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU227192B1 (en) * | 2006-11-13 | 2010-10-28 | Richter Gedeon Nyrt | Process for the preparation of 2-[2-(1-piperazinyl)-ethoxy]-ethanol |
| CN102558097B (en) * | 2011-12-27 | 2014-05-28 | 辅仁药业集团有限公司 | Improved method for synthesizing ranolazine |
-
2013
- 2013-05-24 CN CN201310199797.8A patent/CN103254153B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103254153A (en) | 2013-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103254153B (en) | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine | |
| CN103193594B (en) | Method for separating ethylene glycol and 1, 2-butanediol | |
| CN101501000B (en) | Purification process of montelukast and its amine salts | |
| CN108484666B (en) | Synthetic method of refined glufosinate-ammonium | |
| CN107805205A (en) | A kind of preparation method of (R) 3 amino butanol | |
| EP1730132A2 (en) | Process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof | |
| WO2009009751A1 (en) | A crystalline synthetic intermediate for preparation of a dpp-iv inhibitor and method of purification thereof | |
| US20230092227A1 (en) | Preparation method for synthesizing chiral nicotine from chiral tert-butylsulfenamide | |
| CN113999142A (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| WO2007069266A2 (en) | A novel process for the synthesis of bisodprolol and its intermediate | |
| KR20090037445A (en) | Montelukast Purification Method | |
| CN109776316A (en) | A kind of production method of environment-friendly plasticizer dibenzoic diglycol laurate | |
| WO2008139492A2 (en) | A process for the preparation of highly pure ranolazine base | |
| CN101412672B (en) | Chemical synthesis method for R-2-hydroxy-4-phenylbutanoate | |
| EP3176155B1 (en) | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate for the synthesis of same | |
| CN109575070A (en) | A kind of upper limb totally disappeared the calixarenes phosphate derivative and preparation method thereof that lower edge replaces entirely | |
| CA2412543C (en) | Process for the preparation of quinoline derivatives | |
| CN101343248B (en) | Fine purification method for key intermediate of Donepezil Hydrochloride | |
| CN101638378B (en) | Synthetic method of N-alkyl substituted-3-piperidones | |
| CN109836374B (en) | Environment-friendly preparation method of vitamin B6 | |
| KR20170074895A (en) | Preparation of a sorbate ester | |
| CN100526275C (en) | Synthetic method of 1-chlorine-3-methoxy propane | |
| CN114874104B (en) | Cationic liposome SM-102 and preparation method of Lipid5 | |
| CN111662293B (en) | A kind of preparation method of zeatin | |
| CN114716341B (en) | A one-pot method for preparing dimethochlor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |