CN115521309A - Iruaoke impurity and preparation method thereof - Google Patents
Iruaoke impurity and preparation method thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 99
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 177
- -1 m-fluorobenzyl ether compound Chemical class 0.000 claims abstract description 48
- WLKUSVNHZXUEFO-UHFFFAOYSA-N 4-fluoro-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(F)=CC=C1[N+]([O-])=O WLKUSVNHZXUEFO-UHFFFAOYSA-N 0.000 claims abstract description 33
- PLEJCMKVJYUUBA-UHFFFAOYSA-N 2-fluoro-4-methoxy-1-nitrobenzene Chemical compound COC1=CC=C([N+]([O-])=O)C(F)=C1 PLEJCMKVJYUUBA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- OADNVNPVQYWJMK-UHFFFAOYSA-N undecane;hydrochloride Chemical compound Cl.CCCCCCCCCCC OADNVNPVQYWJMK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 71
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 238000001035 drying Methods 0.000 claims description 34
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 28
- 239000012295 chemical reaction liquid Substances 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 229940126062 Compound A Drugs 0.000 claims description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 17
- 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 description 16
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 16
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 7
- 238000010790 dilution Methods 0.000 claims description 6
- 239000012895 dilution Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 9
- 238000004458 analytical method Methods 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 3
- 231100000027 toxicology Toxicity 0.000 abstract description 3
- WZKCRJVJFMWNQT-UHFFFAOYSA-N 1-fluoro-3-[(3-fluorophenyl)methoxymethyl]benzene Chemical compound FC1=CC=CC(COCC=2C=C(F)C=CC=2)=C1 WZKCRJVJFMWNQT-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 6
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 241000287196 Asthenes Species 0.000 description 5
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- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 238000006053 organic reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 3
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 239000013558 reference substance Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides an ibruok impurity and a preparation method thereof. An ibruok impurity which is a spirocyclic aryl derivative; the structural general formula of the spiro aryl derivative is shown in the specification
Wherein X is
Y is H,
Any one of the above. The invention also provides a preparation method of the ibraok impurity, which comprises the following steps: by reacting an m-fluorobenzyl ether compound with a 3, 9-diazaspiro [5,5]]The undecane hydrochloride is prepared by reaction; the m-fluorobenzyl ether compoundComprising 5-fluoro-2-nitro-anisole and/or 3-fluoro-4-nitro-anisole. The Iruaoke impurity provided by the invention has very important significance for quality control of Iruaoke medicine and analysis and research in aspects of clinic, pharmacology, pharmacokinetics, toxicology and the like, and the provided preparation method has the advantages of stable reaction, good reproducibility, easily obtained raw materials, simple process, high yield, simple and safe operation and convenience for industrial expanded production.
Description
Technical Field
The invention belongs to the technical field of impurity standards of medicines and preparation thereof, and particularly relates to an ibraoke impurity and a preparation method thereof.
Background
Iruaoke (iruplinalkkib) is a novel ALK/ROS1 inhibitor independently developed by Qilu pharmaceutical Limited in Shandong, and has the code of WX-0593, can inhibit the ALK kinase activity of wild types of different fusion types and drug-resistant mutation of the ALK inhibitor, and can also effectively inhibit the activity of ROS1 kinase of different fusion types. The study shows that WX-0593 has antitumor activity in ALK positive or ROS1 positive NSCLC, the safety is acceptable, and the dosage scheme within 180mg has very good pharmacokinetic parameters and safety. In 7 months in 2021, qilu pharmacy filed the application of class 1 new drug [ Yiluoka tablet ] (code number: WX-0593) on the market and received the acceptance of the national food and drug administration (NMPA). The Qilu pharmaceutical application is applicable to the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with disease progression or crizotinib intolerant Anaplastic Lymphoma Kinase (ALK) positive after the patients have been treated by the perczotinib, and the product is expected to be marketed in China in the next half year, so that a new treatment selection is provided for the Chinese patients with advanced ALK positive non-small cell lung cancer.
The impurity standard substance has very important significance for the quality control of medicines and the analysis and research in the aspects of clinic, pharmacology, pharmacokinetics, toxicology and the like, and can provide a reference substance for comprehensively analyzing the medicines. Therefore, the method for preparing the standard substance of the Iruoecker impurity is of great significance.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide an ibruoka impurity and a preparation method thereof, and aims to solve the problems.
In order to realize the purpose, the invention adopts the following technical scheme:
an ibruok impurity which is a spirocyclic aryl derivative;
the structural general formula of the spirocyclic aryl derivative is shown in the specification
Wherein X is
Any one of, Y is H, -CH 3 And
any one of the above.
Optionally, the ibruok impurity comprises any one or more of the following structural formulas:
formula I:
formula II:
formula III:
formula IV:
formula V:
the invention also provides a preparation method of the ibruok impurity, which comprises the following steps: the intermediate is prepared by reacting an m-fluorobenzyl ether compound with 3, 9-diazaspiro [5,5] undecane hydrochloride;
the m-fluorobenzyl ether compound comprises 5-fluoro-2-nitro-anisole and/or 3-fluoro-4-nitro-anisole.
Optionally, the reaction comprises: mixing the m-fluorobenzyl ether compound, the 3, 9-diazaspiro [5,5] undecane hydrochloride, N-dimethylformamide and potassium carbonate solid for carrying out a first reaction, and then sequentially carrying out cooling, diluting, extracting, drying and purifying treatment on a reaction liquid of the first reaction to obtain an ibraok impurity;
preferably, the structural formula of the ibrouk impurity comprises:
preferably, the temperature of the first reaction is 40-80 ℃;
preferably, the time of the first reaction is 5 to 15 hours.
Optionally, when the structural formula of the Irouoks impurity is shown as
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is 1.
Optionally, when the structural formula of the ibraok impurity is shown as
When the m-fluoroanisole compound is 3-fluoro-4-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 3-fluoro-4-nitro-anisole is 1.
Optionally, when the structural formula of the ibraok impurity is shown as
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is 1.7-2.
Optionally, the reaction comprises: subjecting said 3, 9-diazaspiro [5,5]]Mixing undecane hydrochloride with potassium carbonate, N-dimethylformamide and methyl iodide, performing a second reaction, adding water for quenching, and sequentially washing, extracting, drying and purifying to obtain a compound A, wherein the structural formula of the compound A is shown in the specification
Mixing the compound A, the 5-fluoro-2-nitro-anisole, N-dimethylformamide and potassium carbonate for a third reaction, and sequentially performing cooling, dilution, extraction, drying and purification treatment to obtain a compound B, wherein the structural formula of the compound B is shown in the specification
Dissolving the compound B in tetrahydrofuran, carrying out fourth reaction with hydrazine hydrate under the condition of rhodium carbon as a catalyst, and then sequentially filtering, washing, extracting, drying and purifying to obtain the compound B with the structural formula shown in the specification
The eluok impurity of (a);
or,
mixing and dissolving the compound B with ammonium chloride solid, dichloromethane and methanol, adding zinc powder to carry out fifth reaction, and sequentially coolingDiluting, extracting, drying and purifying to obtain a compound C, wherein the structural formula of the compound C is shown in the specification
Dissolving the compound C in dichloromethane, carrying out a sixth reaction with an Oxone aqueous solution, and then diluting, extracting, drying, concentrating and purifying to obtain the compound C with the structural formula
The ibruok impurity of (a).
Optionally, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride, potassium carbonate and methyl iodide in the second reaction is 1;
preferably, the temperature of the second reaction is 0-50 ℃ and the time is 5-15h;
preferably, the molar mass ratio of compound a, potassium carbonate and 5-fluoro-2-nitro-anisole in the third reaction is 1;
preferably, the temperature of the third reaction is 25-80 ℃ and the time is 5-15h;
preferably, the molar mass ratio of the compound B, rhodium carbon and hydrazine hydrate in the fourth reaction is 1.
Preferably, the temperature of the fourth reaction is 25-80 ℃ and the time is 5-15h;
preferably, the molar mass ratio of the compound B to the zinc powder in the fifth reaction is 1;
preferably, the time of the fifth reaction is 5 to 15 hours.
Optionally, dissolving the compound B in tetrahydrofuran, and after adding a rhodium carbon catalyst, keeping the system temperature at 0 ℃, stirring for 30-60min, adding hydrazine hydrate into the system, stirring again for 1-2h, and then performing the fourth reaction, before performing the fourth reaction with hydrazine hydrate.
The invention has the beneficial effects that:
the Ereux impurity provided by the invention is an important impurity in an Ereux medicine, has very important significance for the quality control of the Ereux medicine and the analysis and research of clinical, pharmacological, pharmacokinetic, toxicological and other aspects of the Ereux medicine, and can provide a reference substance for the comprehensive analysis of the Ereux.
The invention creatively prepares the Iruaoke impurity by reacting the m-fluorobenzene methyl ether compound with 3, 9-diazaspiro [5,5] undecane hydrochloride, can prepare a plurality of Iruaoke impurities according to different m-fluorobenzene methyl ether compounds, and has the advantages of generally available reagents, mild reaction conditions, high reaction yield, low preparation cost, good reproducibility and contribution to popularization and use.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a HNMR image of the eluok impurity kw obtained in example 1;
FIG. 2 is a mass spectrum of the ibruok impurity kw obtained in example 1;
FIG. 3 is a liquid phase spectrum of the eluoks impurity kw obtained in example 1;
FIG. 4 is a HNMR image of Ilouox impurity 1 prepared in example 3;
FIG. 5 is a mass spectrum of Iruoks impurity 1 obtained in example 3;
FIG. 6 is a liquid phase spectrum of Iruoks impurity 1 obtained in example 3;
FIG. 7 is a HNMR image of the Ilouox impurity 2 prepared in example 5;
FIG. 8 is a mass spectrum of Iruoks impurity 2 obtained in example 5;
FIG. 9 is a HNMR image of Ilouoke impurity 3 prepared in example 7.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
First, the present invention is explained in its entirety, specifically as follows:
the invention provides an ibruok impurity which is a spiro aryl derivative;
the structural general formula of the spirocyclic aryl derivative is shown in the specification
Wherein X is
Y is H or-CH 3 And
any one of the above.
In an alternative embodiment, the ibruoka impurity comprises any one or more of the following structural formulas:
formula I:
formula II:
formula III:
formula IV:
formula V:
the structural formula of the ibruok impurity provided by the invention is different due to different substituents X and Y on a spiro structure, and the following ibruok impurities are preferably selected in the invention:
when X and Y are both
When the structure formula of the ibraoke impurity is shown as formula I
When X is
And Y is-CH 3 The structural formula of the Irgaoke impurity is shown as a formula II
When X is
And when Y is H, the structural formula of the ibraok impurity is shown as formula III
When X is
And when Y is H, the structural formula of the ibraok impurity is shown as formula IV
When X is
And Y is-CH 3 The structural formula of the Irgaoke impurity is shown as a formula V
The invention also provides a preparation method of the ibruok impurity, which comprises the following steps: the intermediate fluorine benzyl ether compound is reacted with 3, 9-diazaspiro [5,5] undecane hydrochloride to prepare the intermediate fluorine benzyl ether compound;
the m-fluorobenzyl ether compound comprises 5-fluoro-2-nitro-anisole and/or 3-fluoro-4-nitro-anisole.
In an alternative embodiment, the reaction comprises: mixing the m-fluorobenzyl ether compound, the 3, 9-diazaspiro [5,5] undecane hydrochloride, N-dimethylformamide and potassium carbonate solid for carrying out a first reaction, and then sequentially carrying out cooling, diluting, extracting, drying and purifying treatment on a reaction liquid of the first reaction to obtain an ibraok impurity;
in a preferred embodiment, the structural formula of the ibruok impurity includes:
in a preferred embodiment, the temperature of the first reaction is 40 to 80 ℃;
alternatively, the temperature of the first reaction may be any value between 40 ℃, 50 ℃, 60 ℃, 70 ℃ and 80 ℃;
in a preferred embodiment, the time of the first reaction is 5 to 15 hours.
Alternatively, the time of the first reaction may be any value between 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, and 15h.
In an alternative embodiment, when the ibruok impurity has the formula
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
in a preferred embodiment, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is 1.
Alternatively, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole can be any value between 1.
In an alternative embodiment, when the formula of the ibruoka impurity is as follows
When the m-fluoroanisole compound is 3-fluoro-4-nitro-anisole;
in a preferred embodiment, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 3-fluoro-4-nitro-anisole is from 1.
Alternatively, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 3-fluoro-4-nitro-anisole may be any value between 1.7, 1, 0.8, 1.9, 1, 1.2, 1.4, 1.6, 1.
In an alternative embodiment, when the ibruok impurity has the formula
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
in a preferred embodiment, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is from 1.
Alternatively, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole can be any value between 1.
When the structural formula of the ibraok impurity is shown as
Then, the synthetic route is:
when the structural formula of the ibraok impurity is shown as
Then, the synthetic route is:
when the structural formula of the ibraok impurity is shown as
Then, the synthetic route is:
the target molecule is generated by nucleophilic substitution reaction of 5-fluoro-2-nitro-anisole or 3-fluoro-4-nitro-anisole and 3, 9-diazaspiro [5,5] undecane hydrochloride under the action of an alkaline reagent potassium carbonate, and the synthesis is simple and easy to implement and has a short route. By optimizing the reaction environment and conditions and controlling the position and the degree of nucleophilic substitution, a plurality of Iruaoke impurities can be prepared and the yield is improved.
In an alternative embodiment, the reaction comprises: reacting the 3, 9-diazaspiro [5,5]]Mixing undecane hydrochloride with potassium carbonate, N-dimethylformamide and methyl iodide, performing a second reaction, adding water for quenching, and sequentially washing, extracting, drying and purifying to obtain a compound A, wherein the structural formula of the compound A is shown in the specification
Mixing the compound A, the 5-fluoro-2-nitro-anisole, N-dimethylformamide and potassium carbonate for a third reaction, and sequentially performing cooling, dilution, extraction, drying and purification treatment to obtain a compound B, wherein the structural formula of the compound B is shown in the specification
Dissolving the compound B in tetrahydrofuran, carrying out a fourth reaction with hydrazine hydrate under the condition of rhodium carbon as a catalyst, and sequentially filtering, washing, extracting, drying and purifying to obtain the compound B with the structural formula shown in the specification
The ibruok impurity of (a);
or,
mixing and dissolving the compound B with ammonium chloride solid, dichloromethane and methanol, adding zinc powder to perform a fifth reaction, and sequentially performing cooling, dilution, extraction, drying and purification treatment to obtain a compound C, wherein the structural formula of the compound C is shown in the specification
Dissolving the compound C in dichloromethane, carrying out a sixth reaction with an Oxone aqueous solution, and then diluting, extracting, drying, concentrating and purifying to obtain a compound with a structural formula
Ibrut ofAn oke impurity.
When the structural formula of the ibraok impurity is shown as
Then, the synthetic route is:
when the structural formula of the Irgaoke impurity is shown as
Then, the synthesis route is as follows:
3, 9-diazaspiro [5,5] undecane hydrochloride is taken as a substrate, a compound B is generated by two steps of nucleophilic substitution reaction under the alkaline condition, and then the compound B is reduced by zinc powder and synthesized into the Iruaoke impurity by Oxone oxidation reaction.
In an alternative embodiment, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride, potassium carbonate, and methyl iodide in the second reaction is 1 to 5;
alternatively, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride, potassium carbonate and methyl iodide in the second reaction can be 1;
in a preferred embodiment, the temperature of the second reaction is 0-50 ℃ and the time is 5-15h;
optionally, the temperature of the second reaction may be any value between 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃ and 50 ℃, and the time may be any value between 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h and 15h;
in a preferred embodiment, the molar mass ratio of compound a, potassium carbonate and 5-fluoro-2-nitro-anisole in the third reaction is 1 to 5;
alternatively, the molar mass ratio of compound a, potassium carbonate and 5-fluoro-2-nitro-anisole in the third reaction may be any of 1;
in a preferred embodiment, the temperature of the third reaction is 25-80 ℃ and the time is 5-15h;
optionally, the temperature of the third reaction may be any value between 25 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ and 80 ℃, and the time may be any value between 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h and 15h;
in a preferred embodiment, the molar mass ratio of the compound B, rhodium carbon and hydrazine hydrate in the fourth reaction is 1.
Alternatively, the molar mass ratio of the compound B, rhodium carbon and hydrazine hydrate in the fourth reaction may be 1.
In a preferred embodiment, the temperature of the fourth reaction is 25-80 ℃ and the time is 5-15h;
optionally, the temperature of the fourth reaction may be any value between 25 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ and 80 ℃, and the time may be any value between 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h and 15h;
in a preferred embodiment, the molar mass ratio of the compound B to the zinc powder in the fifth reaction is 1;
alternatively, the molar mass ratio of the compound B to the zinc powder in the fifth reaction can be any value between 1;
in a preferred embodiment, the time of the fifth reaction is 5 to 15 hours.
Alternatively, the time of the fifth reaction may be any value between 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, and 15h.
In an alternative embodiment, before the compound B is dissolved in tetrahydrofuran and subjected to the fourth reaction with hydrazine hydrate under the condition of rhodium carbon as a catalyst, the method further comprises the steps of dissolving the compound B in tetrahydrofuran, adding rhodium carbon as a catalyst, keeping the temperature of the system at 0 ℃, stirring for 30-60min, adding hydrazine hydrate into the system, stirring again for 1-2h, and then performing the fourth reaction.
Optionally, dissolving the compound B in tetrahydrofuran, adding rhodium carbon as a catalyst, keeping the temperature of the system at 0 ℃, and stirring for any value between 30min, 40min, 50min and 60min, adding hydrazine hydrate into the system, stirring again for any value between 1h, 1.5h and 2h, and then performing the fourth reaction.
The method combines multiple factors such as experimental environment, experimental reagent preparation conditions and purity, experimental equipment parameters and precision to optimize reaction parameters, and experiments prove that the optimized reaction parameters well control the structures of intermediate compounds and products on the premise of ensuring reaction stability, and can improve the yield of the reaction and the purity of the products.
Example 1
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following steps:
s1: preparation of compound a:
5.00g of 3, 9-diazaspiro [5,5] with a concentration of 22.0mmol were added to the reaction flask]Undecane hydrochloride, 15.2g of potassium carbonate having a concentration of 110.0mmol and 100mL of a solvent of N, N-dimethylformamide were stirred at 50 ℃ for 30 minutes, after completion of the stirring, the reaction flask was placed in an ice bath, 3.75g of methyl iodide having a concentration of 26.4mmol was slowly dropped into the reaction flask, and the reaction was carried out at constant temperature for 8 hours. After completion of the reaction, the solid was filtered off, the organic reaction solution was washed three times with 150mL of saturated saline solution and extracted three times with 100mL of dichloromethane,then dried over anhydrous sodium sulfate, the organic layer was collected and spin dried and purified by silica gel column chromatography to give 3.08g of a white powdery solid compound A of the formula
The calculated yield was 83.2%.
S2: preparation of compound B:
1.72g of Compound A having a concentration of 8.39mmol, 2.15g of 5-fluoro-2-nitro-anisole having a concentration of 12.59mmol and 20mL of N, N-dimethylformamide were sequentially charged into a reaction flask, and then 3.47g of a solid potassium carbonate having a concentration of 25.17mmol was added to the reaction flask, and the reaction was stirred at 60 ℃ for 8 hours. After the reaction is finished, cooling the reaction liquid to room temperature, washing the reaction liquid for three times by using 50mL of saturated saline solution respectively, extracting the reaction liquid for three times by using 20mL of ethyl acetate respectively, drying the reaction liquid by using anhydrous sodium sulfate, collecting an organic layer, spin-drying the organic layer, and purifying the organic layer by using silica gel column chromatography to obtain 3.00g of yellow oily compound B, wherein the structural formula of the yellow oily compound B is shown in the specification
The calculated yield was 92%.
S3: preparing an ibruok impurity:
adding 1.20g of compound B with the concentration of 3.78mmol and 195mg of rhodium carbon with the concentration of 1.87mmol into a reaction bottle, adding 25mL of tetrahydrofuran solvent, placing the temperature of the reaction system at 0 ℃, stirring and reacting for 60 minutes, then slowly adding 1.2mL of hydrazine hydrate with the concentration of 22.68mmol into the reaction bottle, stirring for 2 hours, raising the temperature to 25 ℃, and stirring and reacting for 10 hours. After the reaction is finished, filtering the reaction liquid by using kieselguhr, washing the reaction liquid by using 30mL of saturated saline solution for three times respectively, extracting the reaction liquid by using 10mL of ethyl acetate for three times respectively, drying the reaction liquid by using anhydrous sodium sulfate, collecting an organic phase, spin-drying the organic phase, and purifying the organic phase by using a silica gel column chromatography to obtain 0.94g of green oily target compound Iruaoke impurity with a structural formula of
Named as ibraok impurity kw with a yield of 80%.
The HNMR spectrum of the ibrouoke impurity kw of the obtained product is shown in figure 1, the mass spectrum is shown in figure 2, and the liquid phase spectrum is shown in figure 3.
Example 2
Preparing an ibraoke impurity according to the preparation method provided by the invention:
s1: preparation of compound a:
to a reaction flask was added 100mg of 3, 9-diazaspiro [5,5] of 0.44mmol]Undecane hydrochloride, 310mg of potassium carbonate with a concentration of 2.24mmol and 2mL of N, N-dimethylformamide solvent were stirred at 50 ℃ for 30 minutes, after completion of the stirring, the reaction flask was placed in an ice bath, 172mg of iodomethane with a concentration of 26.4mmol was slowly dropped into the reaction flask, and a constant temperature reaction was carried out for 8 hours. Filtering to remove solid after reaction, washing organic reaction solution with 3mL saturated saline solution for three times, extracting with 1.5mL dichloromethane for three times, drying with anhydrous sodium sulfate, collecting organic layer, spin drying, and purifying by silica gel column chromatography to obtain 63mg white powdery solid compound A with structural formula
The calculated yield was 85%.
S2: preparation of compound B:
100mg of Compound A having a concentration of 0.59mmol, 132mg of 5-fluoro-2-nitro-anisole having a concentration of 0.77mmol, and 2mL of N, N-dimethylformamide were sequentially added to a reaction flask, and then 245mg of a solid potassium carbonate having a concentration of 1.77mmol was added to the reaction flask, and the reaction was stirred at 60 ℃ for 8 hours. After the reaction is finished, cooling the reaction liquid to room temperature, respectively washing the reaction liquid with 3mL of saturated saline solution for three times, respectively extracting the reaction liquid with 1.5mL of ethyl acetate for three times, drying the reaction liquid with anhydrous sodium sulfate, collecting an organic layer, spin-drying the organic layer, and purifying the organic layer by silica gel column chromatography to obtain 3.00g of yellow oily compound B, wherein the structural formula of the yellow oily compound B is
The calculated yield was 88%.
S3: preparing an ibruok impurity:
200mg of compound B with a concentration of 0.63mmol and 27mg of rhodium on carbon with a concentration of 0.26mmol were added to a reaction flask, andadding 5mL of tetrahydrofuran solvent, placing the temperature of the reaction system at 0 ℃, stirring and reacting for 30 minutes, then slowly adding 0.2mL of hydrazine hydrate with the concentration of 3.78mmol into a reaction bottle, stirring for 1 hour, then heating to 30 ℃, and stirring and reacting for 8 hours. After the reaction is finished, filtering the reaction liquid by using kieselguhr, washing the reaction liquid by using 5mL of saturated saline solution for three times respectively, extracting the reaction liquid by using 2mL of ethyl acetate for three times respectively, drying the reaction liquid by using anhydrous sodium sulfate, collecting an organic phase, spin-drying the organic phase, and purifying the organic phase by using a silica gel column chromatography to obtain 150mg of green oily target compound Iruaoke impurity with a structural formula of
I.e. the ibraok impurity kw, in a yield of 78%.
Example 3
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following specific steps:
100mg of 3, 9-diazaspiro [5,5] in a concentration of 0.44mmol were added to the reaction flask in succession]Undecane hydrochloride, 166mg of 5-fluoro-2-nitro-anisole having a concentration of 0.97mmol, and 2ml of N, N-dimethylformamide, then 304mg of potassium carbonate having a concentration of 2.20mmol was added to the reaction flask, and the reaction system was heated to 60 ℃ and stirred for reaction for 12 hours. After the reaction, the reaction solution was cooled to room temperature, washed with 2mL of saturated brine three times, extracted with 1mL of ethyl acetate three times, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 177mg of a dark solid compound of formula
The yield was 88% as iluooke impurity 1.
The HNMR spectrum of the prepared product, namely the Iruoecker impurity 1, is shown in a figure 4, the mass spectrum is shown in a figure 5, and the liquid phase spectrum is shown in a figure 6.
Example 4
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following specific steps:
2.00g of 3, 9-diazaspiro [5,5] in a concentration of 8.80mmol were added sequentially to the reaction flask]Undecane hydrochloride, 3,31g concentrated5-fluoro-2-nitro-anisole with a degree of 19.36mmol and 45ml of N, N-dimethylformamide, 6.08g of potassium carbonate with a concentration of 44.00mmol are subsequently added to the reaction flask, and the reaction system is heated to 60 ℃ and stirred for reaction for 8h. After the reaction, the reaction solution is cooled to room temperature, washed by 60mL of saturated saline solution for three times, extracted by 10mL of ethyl acetate for three times, dried by anhydrous sodium sulfate, collected, spun-dried, and purified by silica gel column chromatography to obtain 3.82g of dark solid compound with the structural formula shown in the specification
I.e., the eluok impurity 1, in 95% yield.
Example 5
The preparation method provided by the invention is used for preparing the Ilouak impurity and comprises the following steps:
s1: preparation of compound a:
100mg of 3, 9-diazaspiro [5,5] in a concentration of 0.44mmol were added to the reaction flask]Undecane hydrochloride, 310mg of potassium carbonate with a concentration of 2.24mmol and 2mL of N, N-dimethylformamide solvent were stirred at 50 ℃ for 30 minutes, after completion of the stirring, the reaction flask was placed in an ice bath, 172mg of iodomethane with a concentration of 26.4mmol was slowly dropped into the reaction flask, and a constant temperature reaction was carried out for 8 hours. After the reaction was completed, the solid was filtered off, the organic reaction solution was washed three times with 3mL of saturated brine, and extracted three times with 1.5mL of dichloromethane, and then dried with anhydrous sodium sulfate, the organic layer was collected and spin-dried, and purified by silica gel column chromatography to obtain 63mg of a white powdery solid compound A having the formula
The calculated yield was 85%.
S2: preparation of compound B:
100mg of compound A having a concentration of 0.59mmol, 132mg of 5-fluoro-2-nitro-anisole having a concentration of 0.77mmol and 2mL of N, N-dimethylformamide were added in this order to a reaction flask, followed by 245mg of a solid potassium carbonate having a concentration of 1.77mmol was added to the reaction flask, and the reaction was stirred at 60 ℃ for 8 hours. After the reaction is finished, the reaction solution is cooled to room temperature and respectively cooledWashing with 3mL saturated saline solution for three times, extracting with 1.5mL ethyl acetate for three times, drying with anhydrous sodium sulfate, collecting organic layer, spin drying, and purifying with silica gel column chromatography to obtain 3.00g yellow oily compound B with structural formula
The calculated yield was 88%.
S3: preparation of compound C:
100mg of compound B having a concentration of 0.31mmol, 166mg of ammonium chloride having a concentration of 3.10mmol as a solid, and 0.2mL of methylene chloride and 1.5mL of methanol were added in this order to dissolve them, and then 203mg of 3.10mmol zinc powder was added to the reaction flask, and the reaction was stirred for 15 hours. Cooling the reaction solution to room temperature after the reaction is finished, filtering the reaction solution, collecting the filtrate, concentrating the filtrate, and purifying by column chromatography to obtain 74mg of green solid compound with the structural formula
The calculated yield was 82% as compound C.
S4: preparing an ibruok impurity:
100mg of compound C from S3, 0.35mmol, was dissolved in 1.5mL of dichloromethane, 258mg of 0.42mmol of Oxone in water was slowly added dropwise to the reaction flask at room temperature, and the reaction was stirred for 8h. After the reaction was completed, the reaction mixture was washed three times with 3mL of saturated brine, extracted three times with 1mL of dichloromethane, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 45mg of a dark compound having the formula
The yield was 42% as iluooke impurity 2.
The HNMR pattern of the Iruoks impurity 2 of the obtained product is shown in figure 7, and the mass spectrum thereof is shown in figure 8.
Example 6
Preparing an ibraoke impurity according to the preparation method provided by the invention:
s1: preparation of compound a:
5.00g of 3, 9-diazaspiro [5,5] with a concentration of 22.0mmol were added to the reaction flask]Undecane hydrochloride, 15.2g of potassium carbonate having a concentration of 110.0mmol and 100mL of a solvent of N, N-dimethylformamide were stirred at 50 ℃ for 30 minutes, after completion of the stirring, the reaction flask was placed in an ice bath, 3.75g of methyl iodide having a concentration of 26.4mmol was slowly dropped into the reaction flask, and the reaction was carried out at constant temperature for 8 hours. Filtering to remove solid after reaction, washing organic reaction solution with 150mL saturated saline solution for three times, extracting with 100mL dichloromethane for three times, drying with anhydrous sodium sulfate, collecting organic layer, spin drying, and purifying by silica gel column chromatography to obtain 3.08g white powdery solid compound A with structural formula as
The calculated yield was 83.2%.
S2: preparation of compound B:
1.72g of Compound A having a concentration of 8.39mmol, 2.15g of 5-fluoro-2-nitro-anisole having a concentration of 12.59mmol and 20mL of N, N-dimethylformamide were sequentially charged into a reaction flask, and then 3.47g of a solid potassium carbonate having a concentration of 25.17mmol was added to the reaction flask, and the reaction was stirred at 60 ℃ for 8 hours. After the reaction is finished, cooling the reaction liquid to room temperature, washing the reaction liquid for three times by using 50mL of saturated saline solution respectively, extracting the reaction liquid for three times by using 20mL of ethyl acetate respectively, drying the reaction liquid by using anhydrous sodium sulfate, collecting an organic layer, spin-drying the organic layer, and purifying the organic layer by using silica gel column chromatography to obtain 3.00g of yellow oily compound B, wherein the structural formula of the yellow oily compound B is shown in the specification
The calculated yield was 92%.
S3: preparation of compound C:
6.61g of compound B having a concentration of 20.72mmol, 13.18g of ammonium chloride solid having a concentration of 248.64mmol, 7mL of methylene chloride and 70mL of methanol were added in this order to dissolve the compound, and 18.86g of 290.08mmol zinc powder was added to the stirred system to react for 10 hours. Cooling the reaction solution to room temperature after the reaction, filtering the reaction solution, collecting the filtrate, concentrating, and purifying by column chromatography to obtain 5.4g of green solid compound with the structural formulaIs composed of
I.e. compound C, in a calculated yield of 90%.
S4: preparing an ibruok impurity:
1g of compound C from S3 with a concentration of 3.46mmol was weighed out and dissolved in 30mL of dichloromethane, 2.13g of an aqueous solution of Oxone with a concentration of 3.46mmol was slowly added dropwise to the reaction flask at room temperature, and the reaction was stirred for 8 hours. After the reaction was completed, the reaction mixture was washed three times with 30mL of saturated brine and extracted three times with 10mL of dichloromethane, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 0.37g of a dark compound of formula
I.e., the eluok impurity 2, in 35% yield.
Example 7
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following specific steps:
100mg of 3, 9-diazaspiro [5,5] with a concentration of 0.44mmol were added to the reaction flask in succession]Undecane hydrochloride, 75mg of 3-fluoro-4-nitro-anisole having a concentration of 0.44mmol, and 2ml of N, N-dimethylformamide, followed by adding 182mg of potassium carbonate having a concentration of 1.32mmol to a reaction bottle, and heating the reaction system to 60 ℃ and stirring the reaction for 5 hours. After the reaction, the reaction solution was cooled to room temperature, washed with 2mL of saturated brine for three times, extracted with 1mL of ethyl acetate for three times, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 105mg of a dark solid compound of formula
The yield was 78% as iluooke impurity 3.
The HNMR image of the resulting product, ibraoke impurity 3, is shown in FIG. 9.
Example 8
The preparation method provided by the invention is used for preparing the Ilouak impurity and comprises the following steps:
2.00g of 3, 9-diazaspiro [5,5] in a concentration of 8.80mmol were added sequentially to the reaction flask]Undecane hydrochloride, 1.81g of 3-fluoro-4-nitro-anisole having a concentration of 10.56mmol and 45ml of N, N-dimethylformamide, 4.84g of potassium carbonate having a concentration of 35.00mmol was then added to the reaction flask, and the reaction system was heated to 60 ℃ and stirred for reaction for 15 hours. After the reaction, the reaction solution was cooled to room temperature, washed three times with 60mL of saturated brine, extracted three times with 10mL of ethyl acetate, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 2.33g of a dark solid compound having the formula
I.e., ibraok impurity 3, in 87% yield.
Example 9
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following specific steps:
100mg of 3, 9-diazaspiro [5,5] in a concentration of 0.44mmol were added to the reaction flask in succession]Undecane hydrochloride, 90mg of 5-fluoro-2-nitro-anisole having a concentration of 0.53mmol, and 2ml of N, N-dimethylformamide, followed by adding 182mg of potassium carbonate having a concentration of 1.32mmol to a reaction bottle, and heating the reaction system to 60 ℃ and stirring the reaction for 9 hours. After the reaction is finished, the reaction solution is cooled to room temperature, washed by 2mL of saturated saline solution for three times respectively, extracted by 1mL of ethyl acetate for three times respectively, dried by anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 111mg of dark solid compound with the structural formula as shown in the specification
The yield was 83% as ibruok impurity 4.
Example 10
The preparation method provided by the invention is used for preparing the ibraoke impurity and comprises the following specific steps:
2.00g of 3, 9-diazaspiro [5,5] with a concentration of 8.80mmol were added to the reaction flask in succession]Undecane hydrochloride, 1.81g of 5-fluoro-2-nitro-anisole in a concentration of 10.6mmol and 45ml ofN, N-dimethylformamide, 4.84g of potassium carbonate with a concentration of 35.00mmol was then added to the reaction flask, and the reaction was warmed to 60 ℃ and stirred for reaction for 11 hours. After the reaction, the reaction solution was cooled to room temperature, washed three times with 60mL of saturated brine, extracted three times with 15mL of ethyl acetate, dried over anhydrous sodium sulfate, collected and spin-dried, and purified by silica gel column chromatography to obtain 2.31g of a dark solid compound having the formula
I.e. the ibraok impurity 4, in 86% yield.
From the examples 1 to 10, it can be seen that the preparation method provided by the invention for preparing the ibruoka impurity has the advantages of generally available reagents, strong reaction stability, good reproducibility, high yield, low cost, mild required conditions, simple and convenient purification, high production condition safety, small environmental hazard and suitability for large-scale industrial production.
It should be noted that the technical features of the above embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the above embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the scope of the present description should be considered. The above examples only express several embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, which falls within the scope of protection of the present application. Therefore, the protection scope of the present patent application shall be subject to the appended claims.
Claims (10)
1. An ibruoka impurity, characterized in that the ibruoka impurity is a spirocyclic aryl derivative;
the structural general formula of the spirocyclic aryl derivative is shown in the specification
Wherein X is
Y is H or-CH 3 And
any one of the above.
2. The ibruok impurity according to claim 1, characterized in that it comprises any one or more of the following structural formulae:
formula I:
formula II:
formula III:
formula IV:
formula V:
3. a process for the preparation of the ibruok impurity as claimed in claim 1 or 2, characterized in that it comprises: the intermediate fluorine benzyl ether compound is reacted with 3, 9-diazaspiro [5,5] undecane hydrochloride to prepare the intermediate fluorine benzyl ether compound;
the m-fluorobenzyl ether compound comprises 5-fluoro-2-nitro-anisole and/or 3-fluoro-4-nitro-anisole.
4. The method of claim 3, wherein the reacting comprises: mixing the m-fluorobenzyl ether compound, the 3, 9-diazaspiro [5,5] undecane hydrochloride, N-dimethylformamide and potassium carbonate solid to carry out a first reaction, and then sequentially carrying out cooling, dilution, extraction, drying and purification on reaction liquid of the first reaction to obtain an ibruok impurity;
preferably, the structural formula of the ibruok impurity includes:
preferably, the temperature of the first reaction is 40-80 ℃;
preferably, the time of the first reaction is 5 to 15 hours.
5. The method as claimed in claim 4, wherein the structural formula of the ibruoka impurity is
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is 1.
6. The method as claimed in claim 4, wherein the structural formula of the ibruoka impurity is
When the m-fluoroanisole compound is 3-fluoro-4-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 3-fluoro-4-nitro-anisole is 1.
7. The method according to claim 4, wherein when the structure of the ibruok impurity is shown as
When the m-fluorobenzyl ether compound is 5-fluoro-2-nitro-anisole;
preferably, the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride to the 5-fluoro-2-nitro-anisole is 1.
8. The method of claim 3, wherein the reacting comprises: reacting the 3, 9-diazaspiro [5,5]]Mixing undecane hydrochloride with potassium carbonate, N-dimethylformamide and methyl iodide, carrying out a second reaction, adding water for quenching, and sequentially washing, extracting, drying and purifying to obtain a compound A, wherein the structural formula of the compound A is
Mixing the compound A, the 5-fluoro-2-nitro-anisole, N-dimethylformamide and potassium carbonate for a third reaction, and then sequentially carrying out cooling, dilution, extraction, drying and purification treatment to obtain a compound B, wherein the structural formula of the compound B is shown in the specification
Dissolving the compound B in tetrahydrofuran, carrying out fourth reaction with hydrazine hydrate under the condition of rhodium carbon as a catalyst, and then sequentially filtering, washing, extracting, drying and purifying to obtain the compound B with the structural formula shown in the specification
The eluok impurity of (a);
or,
mixing and dissolving the compound B with ammonium chloride solid, dichloromethane and methanol, adding zinc powder to perform a fifth reaction, and sequentially performing cooling, dilution, extraction, drying and purification treatment to obtain a compound C, wherein the structural formula of the compound C is shown in the specification
Dissolving the compound C in dichloromethane, carrying out a sixth reaction with an Oxone aqueous solution, and then diluting, extracting, drying, concentrating and purifying to obtain a compound with a structural formula
Of the compound of formula (i).
9. The production method according to claim 8, wherein the molar mass ratio of the 3, 9-diazaspiro [5,5] undecane hydrochloride, potassium carbonate, and methyl iodide in the second reaction is 1;
preferably, the temperature of the second reaction is 0-50 ℃ and the time is 5-15h;
preferably, the molar mass ratio of compound a, potassium carbonate and 5-fluoro-2-nitro-anisole in the third reaction is 1;
preferably, the temperature of the third reaction is 25-80 ℃ and the time is 5-15h;
preferably, the molar mass ratio of the compound B, rhodium carbon and hydrazine hydrate in the fourth reaction is 1.
Preferably, the temperature of the fourth reaction is 25-80 ℃ and the time is 5-15h;
preferably, the molar mass ratio of the compound B to the zinc powder in the fifth reaction is 1;
preferably, the time of the fifth reaction is 5 to 15 hours.
10. The preparation method according to any one of claims 8 or 9, wherein the compound B is dissolved in tetrahydrofuran, and before the fourth reaction with hydrazine hydrate is carried out under the condition of rhodium carbon as a catalyst, the method further comprises the steps of dissolving the compound B in tetrahydrofuran, adding rhodium carbon as a catalyst, maintaining the temperature of the system at 0 ℃, stirring for 30-60min, adding hydrazine hydrate into the system, stirring again for 1-2h, and then carrying out the fourth reaction.
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