CN115304541A - 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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- CN115304541A CN115304541A CN202211032792.1A CN202211032792A CN115304541A CN 115304541 A CN115304541 A CN 115304541A CN 202211032792 A CN202211032792 A CN 202211032792A CN 115304541 A CN115304541 A CN 115304541A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 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 abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 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 43
- 239000002904 solvent Substances 0.000 claims abstract description 43
- 238000006722 reduction reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 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 25
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 125
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 76
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 50
- 239000012065 filter cake Substances 0.000 claims description 48
- 238000006467 substitution reaction Methods 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [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
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- -1 nitrogen-containing compound Chemical class 0.000 claims description 4
- 230000001681 protective effect Effects 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
- 239000002994 raw material Substances 0.000 claims description 3
- 239000004593 Epoxy Substances 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 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
- 239000012295 chemical reaction liquid Substances 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
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 10
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000004321 preservation Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008034 disappearance Effects 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
- 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
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 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
- 206010028980 Neoplasm Diseases 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
- 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
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- DISPOJHKKXSCLS-UHFFFAOYSA-N n-diaminophosphorylmethanamine Chemical compound CNP(N)(N)=O DISPOJHKKXSCLS-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery 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
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 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)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (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) aniline. The present invention provides a process for the preparation of compound I, comprising the steps of: 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. The preparation method has high yield, good product purity, low cost and easy industrial production;
Description
Technical Field
The invention relates to a preparation method of 3-chloro-4- (2-pyridylmethoxy) aniline.
Background
The structure of the structural fragment of the 3-chloro-4- (2-pyridylmethoxy) aniline which is used as a plurality of tumor drugs is as follows:
WO 9615118A 1 reports a synthesis method of a compound I for the first time, and the method uses expensive Pt/C as a catalyst, so that the industrial production cost is high. The synthesis method comprises the following steps:
WO 2009033581A 1, WO 2012136099A 1 and CN 102766068A are improved on the method, and zinc powder, stannous chloride and iron powder are respectively used as reducing agents to prepare the compound I through reduction under acidic conditions. The three methods can greatly reduce the production cost of using the noble metal catalyst, but the post-treatment operation is complex, a large amount of solid wastes are generated in the industrial production, and the method is not beneficial to environmental protection.
WO2006064196 A1 discloses the preparation of compound I by the reaction of 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 the commercial production is difficult to realize. The route is as follows:
in WO 2005065266A 2, compound III is used for reacting with compound V to prepare compound I, and the method uses compound V with lower cost, but the reaction yield is only 34%, and the method is not suitable for commercial production.
Disclosure of Invention
The invention aims to solve the technical problems of few preparation methods, high cost and complicated post-treatment steps of the existing 3-chloro-4- (2-pyridylmethoxy) aniline. Therefore, the invention provides a preparation method of 3-chloro-4- (2-pyridylmethoxy) aniline. The method provided by the invention has the advantages of high yield, easy product separation, good product purity, low catalyst cost and better 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 which is conventional in the field of such reactions, and preferably, the solvent is C 1 -C 4 Alcohol or C 4 An epoxy compound, and more preferably, the solvent is ethanol.
In the reduction reaction, the catalyst is a catalyst which is conventional in the field of such reactions, preferably, the catalyst is ferric trichloride, and more preferably, the catalyst is ferric trichloride hexahydrate.
In the reduction reaction, the auxiliary is an auxiliary conventional in the art for such reactions, such as activated carbon.
In a certain scheme, the catalyst is ferric chloride 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 conventional in such reactions in the field, preferably, the mass-to-volume ratio is 20g/L to 300g/L, and more preferably, the mass-to-volume ratio is 100g/L or 250g/L.
The molar ratio of the compound II to the catalyst in the reduction reaction is a molar ratio conventional in such reactions in the art, preferably 2:1 to 100, more preferably 5:1 to 100; further preferably 10.
In the reduction reaction, the mass ratio of the catalyst to the promoter is a mass ratio conventional in such reactions in the art, preferably, the mass ratio is 0.01.
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 1.5 to 1.
In the reduction reaction, the reaction temperature is a reaction temperature conventional in such reactions in the art, preferably, the reaction temperature is a reflux temperature, the reflux temperature refers to a boiling point of the solvent ± 5 ℃, more preferably, the reaction temperature is 60-100 ℃, and further, when the solvent is ethanol, the reaction temperature is preferably 75 ℃ to 80 ℃.
In the reduction reaction, the reaction may be carried out in a protective gas, for example, in nitrogen.
In the reduction reaction, the progress of the reaction can be monitored by methods conventionally used in the art for monitoring such reactions (e.g., HPLC, LCMS), and the end point of the reaction is generally defined as the disappearance or no longer reaction of the compound II. 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 comprises the following post-treatment steps after the reaction is completed: after the reaction is finished, filtering the reaction solution (for example, cooling to 30-60 ℃ for filtering), and washing a filter cake containing the catalyst and the auxiliary agent (for example, washing the filter cake with ethanol); concentrating the filtrate, adding water for crystallization (for example, adding water at a temperature of 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 mechanically applied to the next reaction; preferably, the number of applications is 1 to 10, for example 10.
In the post-treatment step, the ratio of the volume of the concentrated solution obtained in the filtrate concentrating step to the mass of the compound II in the raw material is N mL/g, preferably, N is 3.5 to 4.5, and more preferably, N is 4.
In the post-treatment step, the amount of water added in the crystallization step is the amount of water used in the reaction conventional in the field, and the preferred ratio of the volume of the added water to the mass of the compound II in the raw material is M mL/g; where M = (N-1) × M, M may be 0 to 4,N as defined above, preferably 2 to 4, and more preferably 3.
In one embodiment, the reduction reaction preferably comprises the steps of: under the protection of nitrogen, mixing the compound II, the catalyst, the auxiliary agent and the solvent, and adding hydrazine hydrate at 75-80 ℃ for reduction reaction; and after the reaction is finished, filtering the reaction solution, washing a filter cake, concentrating the filtrate, adding water for crystallization, filtering, washing the filter cake, and drying to obtain the compound I.
In a certain scheme, the materials of the reduction reaction are the compound II, the ferric chloride hexahydrate, the activated carbon, the hydrazine hydrate and the solvent.
In one embodiment, the process for preparing compound I further comprises the steps of: carrying out substitution reaction on a compound VI and a compound V in a solvent under the action of alkali to obtain a compound II;
in the substitution reaction, the solvent is an aprotic solvent conventional in such reactions 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 acid 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 the mass-to-volume ratio conventional in such reactions in the art, preferably, the mass-to-volume ratio is 50-1000g/L, and 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 excluding lithium, and preferably, the base is potassium carbonate.
The molar ratio of the compound VI to the base in the substitution reaction is a molar ratio conventional in such reactions in the art, such as 1:1-1, preferably 1.
The molar ratio of the compound VI to the compound V in the substitution reaction is a molar ratio conventional in such reactions in the art, such as 1:1-1:2, preferably 1.1.
In the substitution reaction, the reaction temperature is a reaction temperature conventional in such reactions in the art, for example, 50 to 100 ℃, preferably 60 to 65 ℃.
In the substitution reaction, the reaction may be carried out in a protective gas, for example, in nitrogen.
The progress of the substitution reaction can be monitored by methods routinely used in the art for monitoring such reactions (e.g., HPLC, LCMS), and is generally determined by the disappearance or absence of the compound VI as the end point of the reaction. The reaction time is a reaction time conventional in the art for such reactions, for example 16 hours.
In the substitution reaction, the following post-treatment steps are preferably included after the reaction is completed: after the reaction is completed, the reaction solution is cooled (for example, 20 to 30 ℃ C.), water is added (for example, water is added at 0 to 60 ℃ C.), filtration is carried out (for example, filtration is carried out after stirring at 20 to 30 ℃ C. For 2 to 4 hours), the cake is washed (for example, with water), and the compound II is obtained by drying.
In the substitution reaction, in the post-treatment step, the volume ratio of the 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: under the protection of nitrogen, mixing the compound VI, the compound V and the potassium carbonate with the solvent, 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 of 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 to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method provided by the invention has the advantages of simple post-treatment operation and high reaction yield, 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 green and environment-friendly.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLES Synthesis of Compound II
120g (0.68mol, 1 equivalent) of Compound VI,82g (0.75mol, 1.1 equivalent) of Compound V,236g (1.71mol, 2.5 equivalents) of anhydrous potassium carbonate powder, and 600mL of DMF were added to a reaction vessel under nitrogen atmosphere, and the temperature was raised to 60-65 ℃ with stirring, followed by reaction 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 while controlling the temperature to not more than 60 ℃. After the dropwise addition, the temperature is controlled to be 20-30 ℃, the mixture is stirred for 2-4 hours and then filtered. 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%.
Examples Synthesis of two Compounds II
Under the protection of nitrogen, 150g of compound II,15.3g of ferric chloride hexahydrate, 76.5g of activated carbon and 1500mL of ethanol are added into a reaction kettle, and the temperature is raised to 75-80 ℃ under the stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 1 hour under the condition of heat preservation; after cooling to 30-60 ℃, the mixture is filtered, and the filter cake is rinsed by 300mL of ethanol. All filtrates are combined, decompressed and concentrated to about 4 times of the volume of the compound II (namely about 600 mL), and then 1350mL of water is added dropwise for crystallization under the temperature controlled at 50-60 ℃; cooling to 20-30 ℃, filtering, and rinsing the filter cake with 550mL of ethanol-water solution (volume ratio = 1:8); the filter cake was dried in vacuo to give 120g of a white solid with a yield of 90.2% and a purity of 100.0%.
EXAMPLES three catalysts recycle
Under the protection of nitrogen, 2g of compound II,0.20g of ferric chloride hexahydrate, 1.02g of activated carbon and 20mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 1 hour in a heat preservation way, and the reaction is completely shown by central control; after cooling to 30-60 ℃, the mixture is filtered and the filter cake is rinsed with 4mL of ethanol.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely controlled, the temperature is reduced to 30-60 ℃, then the filtration is carried out, and 4mL of ethanol is used for rinsing a filter cake.
Adding the activated carbon filter cake into a reaction bottle, adding 2g of the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 the compound II and 20mL of ethanol into the reaction bottle under the protection of nitrogen, and heating to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is kept for 1 hour, the reaction is completely shown by the central control, the temperature is reduced to 30-60 ℃, then 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 times of recovery and cyclic utilization experiments and can catalyze the complete conversion of materials.
Example four
Under the protection of nitrogen, 5g of compound II,0.051g of ferric chloride hexahydrate, 5.11g of activated carbon and 20mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under the stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 28 hours under the condition of heat preservation, and the reaction is completely shown by central control.
Under the protection of nitrogen, 5g of compound II,2.56g of ferric chloride hexahydrate, 5.11g of activated carbon and 20mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 1 hour under the condition of heat preservation, and the reaction is completely controlled by a middle control.
EXAMPLE five
Under the protection of nitrogen, 20g of compound II,2.0g of ferric chloride hexahydrate, 10.2g of activated carbon and 200mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 1 hour in a heat preservation way, and the reaction is completely shown by central control; cooling to 30-60 ℃, filtering, and rinsing the obtained filter cake containing the catalyst (ferric trichloride hexahydrate) and the auxiliary agent (activated carbon) by using 40mL of ethanol. Concentrating under reduced pressure to about 80mL, and dropping 180mL of water at 50-60 ℃ for crystallization; cooling to 20-30 ℃, filtering, and rinsing the filter cake with 70-80mL of 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 and 99.9% purity.
Under the protection of nitrogen, 20g of compound II, the activated carbon filter cake obtained by the reaction and 200mL of ethanol are added into a reaction bottle, and the temperature is raised to 75-80 ℃ under stirring. The temperature is controlled at 75-80 ℃, and 3 equivalents of hydrazine hydrate aqueous solution is slowly dropped. After the dropwise addition, the reaction is carried out for 1 hour in a heat preservation way, and the reaction is completely shown by central control; the temperature is reduced to 30-60 ℃, then the mixture is filtered, and 40mL of ethanol is used for rinsing the filter cake. Concentrating under reduced pressure to about 80mL, and dropping 180mL of water at 50-60 ℃ for crystallization; cooling to 20-30 ℃, filtering, and rinsing the filter cake with 70-80mL of ethanol-water solution (volume ratio = 1:8); the filter cake was dried under vacuum to give 17.3g of a white solid with a yield of 97.6% and a purity of 99.9%.
Claims (10)
1. A process for the preparation of compound I, characterized in that it 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;
2. the method of claim 1, wherein the method satisfies one or more of the following conditions:
(1) In the reduction reaction, the solvent is C 1 -C 4 Alcohol or C 4 An epoxy compound, preferably, the solvent is ethanol;
(2) In the reduction reaction, the catalyst is ferric trichloride, preferably ferric trichloride hexahydrate;
(3) In the reduction reaction, the auxiliary agent is activated carbon;
(4) In the reduction reaction, the mass-to-volume ratio of the compound II to the solvent is 20g/L to 300g/L, preferably, the mass-to-volume ratio is 100g/L or 250g/L;
(5) In the reduction reaction, the molar ratio of the compound II to the catalyst is 2:1 to 100, preferably 5:1 to 100; further preferably 10;
(6) In the reduction reaction, the mass ratio of the catalyst to the auxiliary is 0.01 to 0.5, preferably, the mass ratio is 0.05;
(7) In the reduction reaction, the molar ratio of the compound II to the hydrazine hydrate is 1.5 to 1;
(8) In the reduction reaction, the reaction temperature is a reflux temperature, wherein the reflux temperature refers to the boiling point of the solvent within +/-5 ℃, preferably, the reaction temperature is 60-100 ℃, and more preferably, when the solvent is ethanol, the reaction temperature is preferably 75-80 ℃;
(9) In the reduction reaction, the reaction is carried out in a protective gas, for example, in nitrogen.
3. The method of claim 1 or 2, wherein the 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 post-treatment step is included after the reaction is finished: 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 reduction reaction comprises the following steps: under the protection of nitrogen, mixing the compound II, the catalyst, the auxiliary agent and the solvent, and adding hydrazine hydrate at 75-80 ℃ for reduction reaction; after the reaction is finished, filtering the reaction solution, washing a filter cake, concentrating the filtrate, adding water for crystallization, filtering, washing the filter cake, and drying to obtain the compound I;
(4) The materials of the reduction reaction are the compound II, the ferric trichloride hexahydrate, the activated carbon, the hydrazine hydrate and the solvent.
4. The method of claim 3, wherein the method satisfies one or more of the following conditions:
(1) In the post-treatment step, the ratio of the volume of the concentrated solution obtained in the filtrate concentrating step to the mass of the compound II in the raw material is N mL/g, N is 3.5 to 4.5, and preferably, N is 4;
(2) In the post-treatment step, the obtained filter cake containing the catalyst and the auxiliary agent is mechanically applied to the next reaction; preferably, the number of applications is 1 to 10, for example 10.
5. The method according to claim 4, wherein in the post-treatment step, the ratio of the volume of the water added in the crystallization step to the mass of the compound II in the starting material is M mL/g; wherein M = (N-1) × M, M is 0 to 4, preferably 2 to 4, and more preferably 3; n is defined as stated in claim 4.
6. The method of claim 1, further comprising the steps of: carrying out substitution reaction on a compound VI and a compound V in a solvent under the action of alkali to obtain a compound II;
7. the method of claim 6, wherein the method satisfies one or more of the following conditions:
(1) In the substitution reaction, the solvent is an aprotic solvent;
(2) In the substitution reaction, the mass volume ratio of the compound VI to the solvent is 50-1000g/L;
(3) In the substitution reaction, the alkali is a salt of an 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 1:1-1;
(5) In the substitution reaction, the molar ratio of the compound VI to the compound V is 1:1-1:2;
(6) In the substitution reaction, the reaction temperature is 50-100 ℃;
(7) In the substitution reaction, the reaction is carried out in a protective gas.
8. The method of claim 7, wherein the method satisfies one or more of the following conditions:
(1) In the substitution reaction, the solvent is one or more of a nitrile solvent, a ketone solvent, a nitrogen-containing compound solvent and a sulfur-containing compound solvent; preferably, the solvent is N, N-dimethylformamide;
(2) In the substitution reaction, the mass-to-volume ratio of the compound VI to the solvent is 200g/L;
(3) In the substitution reaction, the alkali is hydroxide, phosphate or carbonate of alkali metal, the alkali metal does not include lithium, and preferably the alkali is potassium carbonate;
(4) In the substitution reaction, the molar ratio of the compound VI to the base is 1;
(5) In the substitution reaction, the molar ratio of the compound VI to the compound V is 1.1;
(6) In the substitution reaction, the reaction temperature is 60-65 ℃;
(7) In the substitution reaction, the reaction is carried out in nitrogen.
9. The method according to any one of claims 6 to 8, wherein the method satisfies one or more of the following conditions:
(1) In the substitution reaction, the post-treatment step is included after the reaction is finished: after the reaction is finished, cooling the reaction solution, adding water, filtering, washing a filter cake, and drying to obtain the compound II;
(2) The substitution reaction comprises the following steps: under the protection of nitrogen, mixing the compound VI, the compound V and the potassium carbonate with the solvent, and reacting at 60-65 ℃; after the reaction is finished, adding water, filtering, washing a filter cake, and drying to obtain the compound II;
(3) The materials of the reduction reaction are the compound VI, the compound V, the base and the solvent.
10. The method of claim 9, wherein in the post-treatment step, the ratio of the volume of the added water to the volume of the solvent is 1:1 to 10:1, preferably 2:1.
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