CN115304541B - Preparation method of 3-chloro-4- (2-pyridylmethoxy) aniline - Google Patents
Preparation method of 3-chloro-4- (2-pyridylmethoxy) aniline Download PDFInfo
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- CN115304541B CN115304541B CN202211032792.1A CN202211032792A CN115304541B CN 115304541 B CN115304541 B CN 115304541B CN 202211032792 A CN202211032792 A CN 202211032792A CN 115304541 B CN115304541 B CN 115304541B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- XCAPJQSICQSUJP-UHFFFAOYSA-N 3-chloro-4-(pyridin-2-ylmethoxy)aniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=CC=N1 XCAPJQSICQSUJP-UHFFFAOYSA-N 0.000 title description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000006722 reduction reaction Methods 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 31
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 27
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- -1 2-pyridylmethoxy Chemical group 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 75
- 239000012065 filter cake Substances 0.000 claims description 50
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 238000001914 filtration Methods 0.000 claims description 31
- 238000006467 substitution reaction Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical group O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940032296 ferric chloride Drugs 0.000 description 1
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DISPOJHKKXSCLS-UHFFFAOYSA-N n-diaminophosphorylmethanamine Chemical compound CNP(N)(N)=O DISPOJHKKXSCLS-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 3-chloro-4- (2-pyridylmethoxy) anilineThe method. The invention provides a preparation method of a compound I, which comprises the following steps: in a solvent, in the presence of a catalyst, an auxiliary agent and hydrazine hydrate, carrying out a reduction reaction on the compound II to obtain a compound I. The preparation method has high yield, good product purity, low cost and easy industrialized production;
Description
Technical Field
The invention relates to a preparation method of 3-chloro-4- (2-pyridylmethoxy) aniline.
Background
3-chloro-4- (2-pyridylmethoxy) aniline as a structural fragment of various oncology drugs has the following structure:
the synthesis of compound I was first reported in WO 9615118A 1, which uses expensive Pt/C as a catalyst and has high industrial production cost. The synthesis method comprises the following steps:
WO2009033581 A1, WO2012136099 A1, CN102766068 a modified the process to prepare compound I by reduction under acidic conditions using zinc powder, stannous chloride, and iron powder, respectively, as reducing agents. The three methods can greatly reduce the production cost of using the noble metal catalyst, but the post-treatment operation is complex, and a large amount of solid waste is produced in industrial production, which is not beneficial to environmental protection.
WO 2006064196A 1 discloses the preparation of compound I by reacting compound III with compound IV in 97% yield. Although the method does not use a noble metal catalyst, the price of the compound IV is far higher than the preparation cost of the compound II, so that commercial production is difficult to realize. The route is as follows:
in WO2005065266 A2, compound III is reacted with compound V to produce compound I, which uses compound V at a lower cost, but in a reaction yield of only 34%, which is not suitable for commercial production.
Disclosure of Invention
The invention aims to solve the technical problems of less preparation method, high cost and complicated post-treatment steps of the existing 3-chloro-4- (2-pyridylmethoxy) aniline. For this purpose, the invention provides a method for preparing 3-chloro-4- (2-pyridylmethoxy) aniline. The method provided by the invention has the advantages of high yield, easy separation of products, good product purity, low catalyst cost and good application prospect.
The invention provides a preparation method of a compound I, which comprises the following steps: in a solvent, carrying out reduction reaction on a compound II in the presence of a catalyst, an auxiliary agent and hydrazine hydrate to obtain a compound I;
in the reduction reaction, the solvent is an organic solvent conventional in the art, preferably C 1 -C 4 Alcohols or C 4 The epoxy compound, more preferably, the solvent is ethanol.
In the reduction reaction, the catalyst is a catalyst conventional in the art, preferably, the catalyst is ferric chloride, more preferably, the catalyst is ferric chloride hexahydrate.
In the reduction reaction, the auxiliary agent is an auxiliary agent conventional in the art such as activated carbon.
In one scheme, the catalyst is ferric trichloride hexahydrate, and the auxiliary agent is activated carbon.
In the reduction reaction, the mass-to-volume ratio of the compound II to the solvent is a mass-to-volume ratio which is conventional in such a reaction in the art, preferably, the mass-to-volume ratio is 20g/L to 300g/L, more preferably, the mass-to-volume ratio is 100g/L or 250g/L.
In the reduction reaction, the molar ratio of the compound II to the catalyst is a molar ratio conventional in such reactions in the art, preferably from 2:1 to 100:1, more preferably 5:1 to 100:1; further preferably 10:1.
In the reduction reaction, the mass ratio of the catalyst to the auxiliary agent is a mass ratio conventional in such reactions in the art, preferably, the mass ratio is 0.01:1 to 0.5:1, more preferably, the mass ratio is 0.05:1 to 0.4:1, and further, the mass ratio is 0.2:1.
In the reduction reaction, the molar ratio of the compound II to the hydrazine hydrate is a molar ratio conventional in such reactions in the art, preferably the molar ratio is 1:1.5 to 1:20, more preferably the molar ratio is 1:2 to 1:10, further more the molar ratio is 1:3.
In the reduction reaction, the reaction temperature is a reaction temperature conventional in such a reaction in the art, preferably, the reaction temperature is a reflux temperature, the reflux temperature means a boiling point of the solvent + -5 deg.c, more preferably, the reaction temperature is 60-100 deg.c, and further, when the solvent is ethanol, the reaction temperature is preferably 75 deg.c to 80 deg.c.
In the reduction reaction, the reaction may be carried out in a shielding gas, for example, in nitrogen.
In the reduction reaction, the progress of the reaction can be detected using conventional monitoring methods of such reactions in the art (e.g., HPLC, LCMS), typically with the end point of the reaction when the compound II is lost or no longer reacted. The reaction time is a reaction time conventional in the art for such reactions, for example 1 hour.
In the reduction reaction, the reaction preferably includes the following post-treatment steps after completion: after the reaction is finished, the reaction solution is filtered (for example, the temperature is reduced to 30-60 ℃ for filtration), and a filter cake containing the catalyst and the auxiliary agent is washed (for example, the filter cake is washed by ethanol); concentrating the filtrate, adding water for crystallization (for example, adding water at 50-60 ℃, cooling to 20-30 ℃ for crystallization), filtering, washing the filter cake (for example, washing with an aqueous solution of ethanol (the volume ratio of ethanol to water is 1:8)), and drying the filter cake (for example, vacuum drying) to obtain the compound I.
In a certain scheme, the filter cake containing the catalyst and the auxiliary agent obtained in the post-treatment step is applied to the next reaction; preferably, the number of applications is from 1 to 10, for example 10.
In the post-treatment step, the concentration of the filtrate step gives a ratio of the volume of the concentrate to the mass of the compound II in the starting material of N mL/g, preferably N of 3.5 to 4.5, more preferably N of 4.
In the post-treatment step, the water adding amount in the crystallization step is the conventional water amount in the reaction in the field, and the ratio of the water adding volume to the mass of the compound II in the raw material is preferably M mL/g; wherein m= (N-1) ×m, M may be 0 to 4, N is defined as above, preferably 2 to 4, further preferably 3.
In one embodiment, the reduction reaction preferably comprises the steps of: mixing the compound II, the catalyst and the auxiliary agent with the solvent under the protection of nitrogen, and adding the hydrazine hydrate at 75-80 ℃ for reduction reaction; and after the reaction is finished, filtering the reaction liquid, washing a filter cake, concentrating the filtrate, adding water for crystallization, filtering, washing the filter cake, and drying to obtain the compound I.
In one embodiment, the materials for the reduction reaction are the compound II, the ferric trichloride hexahydrate, the activated carbon, the hydrazine hydrate and the solvent.
In one embodiment, the preparation method of the compound I further comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction on a compound VI and a compound V to obtain a compound II;
in the substitution reaction, the solvent is an aprotic solvent conventional in such a reaction in the art, preferably, the solvent is one or more of a nitrile solvent (e.g., acetonitrile), a ketone solvent (e.g., acetone, N-methylpyrrolidone or 1, 3-dimethyl-2-imidazolidinone), a nitrogen-containing compound solvent (e.g., N-dimethylformamide, N-dimethylacetamide or methylphosphoric triamide), and a sulfur-containing compound solvent (e.g., dimethylsulfoxide, sulfolane); more preferably, the solvent is N, N-dimethylformamide.
In the substitution reaction, the mass-to-volume ratio of the compound VI to the solvent is a mass-to-volume ratio which is conventional in such reactions in the art, preferably the mass-to-volume ratio is 50 to 1000g/L, more preferably the mass-to-volume ratio is 200g/L.
In the substitution reaction, the base may be a salt of an alkali metal, such as an alkali metal hydroxide, an alkali metal phosphate or an alkali metal carbonate, the alkali metal not including lithium, preferably, the base is potassium carbonate.
In the substitution reaction, the molar ratio of the compound VI to the base is a molar ratio conventional in such reactions in the art, for example 1:1 to 1:10, preferably 1:2.5.
In the substitution reaction, the molar ratio of the compound VI to the compound V is a molar ratio conventional in such reactions in the art, for example, 1:1 to 1:2, preferably 1:1.1.
In the substitution reaction, the reaction temperature is a reaction temperature conventional in such a reaction in the art, for example, 50 to 100 ℃, preferably 60 to 65 ℃.
In the substitution reaction, the reaction may be carried out in a shielding gas, for example, in nitrogen.
In the substitution reaction, the progress of the reaction can be detected by methods conventional in the art for monitoring such reactions (e.g., HPLC, LCMS), typically with the end point of the reaction when the compound VI is lost or no longer reacted. The reaction time is conventional in the art for such reactions, for example 16 hours.
In the substitution reaction, the reaction preferably includes the following post-treatment steps after completion: after the reaction, the reaction mixture is cooled (e.g., 20 to 30 ℃), water is added (e.g., water is added at 0 to 60 ℃), filtration is performed (e.g., filtration is performed after stirring for 2 to 4 hours at 20 to 30 ℃), the cake is washed (e.g., washed with water), and the compound II is obtained by drying.
In the substitution reaction, in the post-treatment step, the volume ratio of the added water to the solvent may be 1:1 to 10:1, preferably 2:1.
in one embodiment, the substitution reaction preferably comprises the steps of: mixing the compound VI, the compound V and the potassium carbonate with the solvent under the protection of nitrogen, and reacting at 60-65 ℃; and after the reaction is finished, adding water, filtering, washing a filter cake, and drying to obtain the compound II.
In one embodiment, the materials for the reduction reaction are the compound VI, the compound V, the base (potassium carbonate) and the solvent.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method provided by the invention has the advantages of simple post-treatment operation and high reaction yield, and the activated carbon used in the preparation method can be recycled, and the reaction byproducts are nitrogen and water, so that the preparation method is environment-friendly.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE Synthesis of Compound II
120g (0.68 mol,1 eq.) of Compound VI,82g (0.75 mol,1.1 eq.) of Compound V,236g (1.71 mol,2.5 eq.) of anhydrous potassium carbonate powder, and 600mL of DMF are added to the reaction vessel under nitrogen, heated to 60-65℃with stirring, and then reacted for 16 hours. The reaction mixture was cooled to 20-30℃and 1200mL of water (not less than twice the volume of DMF) was added dropwise with stirring at a temperature of not more than 60 ℃. After the dripping is finished, stirring for 2-4 hours at the temperature of 20-30 ℃ and filtering. The filter cake was rinsed with 600-1800mL of water until the filtrate was colorless, and dried under vacuum to constant weight to give 175g (0.66 mol) of a yellowish solid with a yield of 96.7% and a purity of 99.7%.
EXAMPLE two Synthesis of Compound II
150g of compound II,15.3g of ferric trichloride hexahydrate, 76.5g of activated carbon and 1500mL of ethanol were added to the reaction vessel under nitrogen protection, and the temperature was raised to 75-80℃with stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. The reaction is carried out for 1 hour after the dripping is finished; cooling to 30-60 deg.c, filtering, and rinsing the filter cake with 300mL ethanol. All the filtrates are combined, and after the filtrate is concentrated to about 4 times of the volume of the compound II (namely about 600 mL), 1350mL of water is added dropwise for crystallization at the temperature of 50-60 ℃; cooling to 20-30deg.C, filtering, rinsing the filter cake with 550mL ethanol-water solution (volume ratio=1:8); the filter cake was dried in vacuo to give 120g of a white solid in 90.2% yield and 100.0% purity.
Example three catalyst recycle
2g of Compound II,0.20g of ferric trichloride hexahydrate, 1.02g of activated carbon and 20mL of ethanol were added to a reaction flask under nitrogen atmosphere, and the temperature was raised to 75-80℃with stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, and the central control shows that the reaction is complete; cooling to 30-60 ℃, filtering, and rinsing the filter cake with 4mL of ethanol.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, the central control shows that the reaction is complete, the temperature is reduced to 30-60 ℃, the filtration is carried out, and 4mL of ethanol is used for rinsing the filter cake.
The monitoring of the experimental process and the reaction process shows that the catalyst ferric trichloride hexahydrate and the activated carbon keep activity in 10 recycling experiments, and can catalyze the complete conversion of materials.
Example IV
5g of compound II,0.051g of ferric trichloride hexahydrate, 5.11g of activated carbon and 20mL of ethanol are added to a reaction flask under nitrogen protection, and the mixture is heated to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. The reaction was incubated for 28 hours after the completion of the dropwise addition, and the completion of the reaction was indicated by the central control.
5g of Compound II,2.56g of ferric trichloride hexahydrate, 5.11g of activated carbon and 20mL of ethanol were added to a reaction flask under nitrogen atmosphere, and the temperature was raised to 75-80℃with stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. The reaction was kept at the end of the dropwise addition for 1 hour, and the reaction was completed by central control.
Example five
20g of Compound II,2.0g of ferric trichloride hexahydrate, 10.2g of activated carbon and 200mL of ethanol were added to a reaction flask under nitrogen atmosphere, and the temperature was raised to 75-80℃with stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, and the central control shows that the reaction is complete; cooling to 30-60 deg.c, filtering, and rinsing with 40mL ethanol to obtain filter cake containing catalyst (ferric trichloride hexahydrate) and assistant (active carbon). Concentrating under reduced pressure to about 80mL, and dropwise adding 180mL of water at the temperature of 50-60 ℃ for crystallization; cooling to 20-30deg.C, filtering, rinsing filter cake with 70-80mL ethanol-water solution (volume ratio=1:8); the filter cake was dried in vacuo to give 16.2g of a white solid in 91.3% yield with 99.9% purity.
Under the protection of nitrogen, 20g of compound II, the activated carbon filter cake obtained in the reaction, 200mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under stirring. 3 equivalents of aqueous solution of hydrazine hydrate are slowly added dropwise under the condition of controlling the temperature to be 75-80 ℃. After the dripping is finished, the reaction is kept for 1 hour, and the central control shows that the reaction is complete; cooling to 30-60 ℃, filtering, and rinsing the filter cake with 40mL of ethanol. Concentrating under reduced pressure to about 80mL, and dropwise adding 180mL of water at the temperature of 50-60 ℃ for crystallization; cooling to 20-30deg.C, filtering, rinsing filter cake with 70-80mL ethanol-water solution (volume ratio=1:8); the filter cake was dried in vacuo to give 17.3g of a white solid in 97.6% yield and 99.9% purity.
Claims (19)
1. A process for the preparation of compound I, characterized in that it comprises the steps of:
in a solvent, under the action of alkali, carrying out substitution reaction on a compound VI and a compound V to obtain a compound II;
in the substitution reaction, the reaction temperature is 60-65 ℃;
in the substitution reaction, the solvent is a nitrogen-containing compound solvent;
in a solvent, carrying out reduction reaction on a compound II in the presence of a catalyst, an auxiliary agent and hydrazine hydrate to obtain a compound I;
in the reduction reaction, the catalyst is ferric trichloride;
in the reduction reaction, the auxiliary agent is active carbon.
2. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the reduction reaction, the solvent is C 1 -C 4 An alcohol;
(2) In the reduction reaction, the mass-volume ratio of the compound II to the solvent is 20g/L to 300g/L;
(3) In the reduction reaction, the molar ratio of the compound II to the catalyst is 2:1 to 100:1;
(4) In the reduction reaction, the mass ratio of the catalyst to the auxiliary agent is 0.01:1 to 0.5:1;
(5) In the reduction reaction, the molar ratio of the compound II to the hydrazine hydrate is 1:1.5 to 1:20;
(6) The temperature of the reduction reaction is reflux temperature, wherein the reflux temperature refers to the boiling point of the solvent plus or minus 5 ℃;
(7) The reduction reaction is carried out in a shielding gas.
3. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the reduction reaction, the solvent is ethanol;
(2) In the reduction reaction, the catalyst is ferric trichloride hexahydrate;
(3) In the reduction reaction, the mass-volume ratio of the compound II to the solvent is 100g/L or 250g/L;
(4) In the reduction reaction, the molar ratio of the compound II to the catalyst is 5:1 to 100:1;
(5) In the reduction reaction, the molar ratio of the compound II to the hydrazine hydrate is 1:2 to 1:10;
(6) The temperature of the reduction reaction is 60-100 ℃;
(7) The reduction reaction is carried out under nitrogen;
(8) In the reduction reaction, the mass ratio of the catalyst to the auxiliary agent is 0.05:1 to 0.4:1.
4. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the reduction reaction, the molar ratio of the compound II to the catalyst is 10:1;
(2) In the reduction reaction, the molar ratio of the compound II to the hydrazine hydrate is 1:3;
(3) In the reduction reaction, when the solvent is ethanol, the reaction temperature is 75-80 ℃;
(4) In the reduction reaction, the mass ratio of the catalyst to the auxiliary agent is 0.2:1.
5. The preparation method according to any one of claims 1 to 4, wherein the preparation method satisfies one or more of the following conditions:
(1) In the reduction reaction, the catalyst is ferric trichloride hexahydrate, and the auxiliary agent is activated carbon;
(2) In the reduction reaction, the reaction comprises the following post-treatment steps: after the reaction is finished, filtering the reaction liquid, and washing a filter cake containing the catalyst and the auxiliary agent; concentrating the filtrate, adding water for crystallization, filtering, washing a filter cake, and drying the filter cake to obtain the compound I;
(3) The materials of the reduction reaction are the compound II, ferric trichloride hexahydrate, activated carbon, hydrazine hydrate and the solvent.
6. The production method according to any one of claims 1 to 4, wherein the reduction reaction comprises the steps of: mixing the compound II, the catalyst and the auxiliary agent with the solvent under the protection of nitrogen, and adding the hydrazine hydrate at 75-80 ℃ for reduction reaction; and after the reaction is finished, filtering the reaction liquid, washing a filter cake, concentrating the filtrate, adding water for crystallization, filtering, washing the filter cake, and drying to obtain the compound I.
7. The method of claim 5, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the post-treatment step, the concentration of the filtrate step is carried out to obtain a ratio of the volume of the concentrated solution to the mass of the compound II in the raw material of N mL/g, wherein N is 3.5 to 4.5;
(2) And in the post-treatment step, the obtained filter cake containing the catalyst and the auxiliary agent is applied to the next reaction.
8. The method of claim 7, wherein the method of preparation satisfies one or more of the following conditions:
(1) The ratio of the volume of the concentrated solution obtained in the step of concentrating the filtrate to the mass of the compound II in the raw material is N mL/g, and N is 4;
(2) In the post-treatment step, the obtained filter cake containing the catalyst and the auxiliary agent is applied to the next reaction, and the application frequency is 1 to 10 times.
9. The method according to claim 7, wherein in the post-treatment step, the obtained filter cake containing the catalyst and the auxiliary agent is applied to the next reaction, and the number of times of the application is 10.
10. The production method according to claim 7 or 8, wherein in the post-treatment step, a ratio of a volume of the added water to a mass of the compound II in the raw material in the crystallization step is MmL/g; wherein m= (N-1) ×m, M is 0 to 4; n is as defined in claim 7 or 8.
11. The method of claim 10, wherein m is 2 to 4.
12. The method of claim 10, wherein m is 3.
13. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the substitution reaction, the mass-volume ratio of the compound VI to the solvent is 50-1000g/L;
(2) In the substitution reaction, the base is a salt of an alkali metal, the alkali metal not including lithium;
(3) In the substitution reaction, the molar ratio of the compound VI to the base is 1:1-1:10;
(4) In the substitution reaction, the molar ratio of the compound VI to the compound V is 1:1-1:2;
(5) The substitution reaction is carried out in a shielding gas.
14. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the substitution reaction, the solvent is N, N-dimethylformamide;
(2) In the substitution reaction, the mass-volume ratio of the compound VI to the solvent is 200g/L;
(3) In the substitution reaction, the alkali is hydroxide of alkali metal, phosphate of alkali metal or carbonate of alkali metal, and the alkali metal does not comprise lithium;
(4) In the substitution reaction, the molar ratio of the compound VI to the base is 1:2.5;
(5) In the substitution reaction, the molar ratio of the compound VI to the compound V is 1:1.1;
(6) The substitution reaction was carried out under nitrogen.
15. The method of claim 13, wherein in the substitution reaction, the base is potassium carbonate.
16. The preparation method according to claim 1 or any one of claims 13 to 15, wherein the preparation method satisfies one or more of the following conditions:
(1) The substitution reaction comprises the following post-treatment steps after the reaction is finished: after the reaction is finished, cooling the reaction liquid, adding water, filtering, washing a filter cake, and drying to obtain the compound II;
(2) The materials of the substitution reaction are the compound VI, the compound V, the alkali and the solvent.
17. The method of claim 1, wherein the substitution reaction comprises the steps of: mixing the compound VI, the compound V and the potassium carbonate with the solvent under the protection of nitrogen, and reacting at 60-65 ℃; and after the reaction is finished, adding water, filtering, washing a filter cake, and drying to obtain the compound II.
18. The method of claim 16, wherein in the post-treatment step, the volume ratio of the added water to the solvent is 1:1 to 10:1.
19. the method of claim 16, wherein in the post-treatment step, the volume ratio of the added water to the solvent is 2:1.
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