CN115701422B - Preparation method of KGP94 - Google Patents
Preparation method of KGP94 Download PDFInfo
- Publication number
- CN115701422B CN115701422B CN202110879143.4A CN202110879143A CN115701422B CN 115701422 B CN115701422 B CN 115701422B CN 202110879143 A CN202110879143 A CN 202110879143A CN 115701422 B CN115701422 B CN 115701422B
- Authority
- CN
- China
- Prior art keywords
- benzophenone
- bromo
- reaction
- formula
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- ZDBKSZKTCPOBFR-GHRIWEEISA-N [(z)-[(3-bromophenyl)-(3-hydroxyphenyl)methylidene]amino]thiourea Chemical compound C=1C=CC(Br)=CC=1C(=N/NC(=S)N)\C1=CC=CC(O)=C1 ZDBKSZKTCPOBFR-GHRIWEEISA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- YJQLWOJNDBFINH-UHFFFAOYSA-N (3-bromophenyl)-(3-methoxyphenyl)methanone Chemical compound COC1=CC=CC(C(=O)C=2C=C(Br)C=CC=2)=C1 YJQLWOJNDBFINH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 34
- -1 amide compound Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 20
- PBOOZQFGWNZNQE-UHFFFAOYSA-N 3-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Br)=C1 PBOOZQFGWNZNQE-UHFFFAOYSA-N 0.000 claims abstract description 12
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 claims abstract description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 40
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 34
- 238000006482 condensation reaction Methods 0.000 claims description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 19
- JWAONYKLAUBMBH-UHFFFAOYSA-N (3-bromophenyl)-(3-hydroxyphenyl)methanone Chemical compound OC1=CC=CC(C(=O)C=2C=C(Br)C=CC=2)=C1 JWAONYKLAUBMBH-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 16
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 15
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 238000009833 condensation Methods 0.000 abstract description 5
- 230000005494 condensation Effects 0.000 abstract description 5
- 230000017858 demethylation Effects 0.000 abstract description 5
- 150000001408 amides Chemical class 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical group O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000002274 desiccant Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000002902 bimodal effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VIDYVRMUWBNYCT-UHFFFAOYSA-N (benzhydrylideneamino)thiourea Chemical class C=1C=CC=CC=1C(=NNC(=S)N)C1=CC=CC=C1 VIDYVRMUWBNYCT-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005009 overhauser spectroscopy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001896 rotating frame Overhauser effect spectroscopy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of KGP94, which belongs to the technical field of organic synthesis. The invention starts from common 3-bromobenzoyl chloride, adopts Weinreb amide method to prepare amide compound with structure shown in formula 1, and then utilizes format reagent 3-methoxy phenyl magnesium bromide to couple with amide compound with structure shown in formula 1 to obtain 3-bromo-3' -methoxy-benzophenone. In the present invention, 3-bromo-3' -methoxy-benzophenone is used as an intermediate material and KGP94 is obtained by either a demethylation followed by condensation or a condensation followed by demethylation. The method provided by the invention has the advantages of short synthetic route and high total yield, and the results of examples show that the total yield of the method provided by the invention is 80% or 89%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of KGP94.
Background
KGP94 is a selective, highly active ((IC) 50 =131.4 μm), low toxicity ((GI) 50 =26.9 μm)), belonging to the class of substituted benzophenone thiosemicarbazone compounds. The treatment of KGP94 against metastatic cancers is currently under preclinical investigation and is of great interest.
At present, there are two main reported methods for synthesizing KGP94. The synthetic route for the first method is as follows:
the second method is improved based on the first method, and the synthetic route is as follows:
both reported methods use cross coupling reaction as a key step, and finally obtain the target product through oxidation, condensation and deprotection, but the defects of longer synthetic route and low total yield exist.
Disclosure of Invention
In view of the above, the present invention is directed to a process for preparing KGP94. The preparation method provided by the invention has the advantages of short synthetic route and high total yield.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of KGP94, which comprises the following steps:
(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1:
(2) Performing a coupling reaction on 3-methoxy phenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) 3-bromo-3' -methoxy-benzophenone to obtain KGP94;
the first route includes: carrying out a first condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain a compound with a structure shown in a formula 2:
carrying out a first demethylation reaction on a compound with a structure shown in a formula 2 and boron tribromide to obtain KGP94;
the second route includes: carrying out a second demethylation reaction on the 3-bromo-3 '-methoxy-benzophenone and boron tribromide to obtain 3-bromo-3' -hydroxy-benzophenone;
and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
Preferably, in the step (1), the molar ratio of the 3-bromobenzoyl chloride to the N, O-dimethylhydroxylamine hydrochloride to the potassium carbonate is 1:1.5:2.5.
Preferably, the nucleophilic substitution reaction is carried out at a temperature of 0-30 ℃ for 5-7 hours.
Preferably, in the step (2), the molar ratio of the 3-methoxyphenylmagnesium bromide to the amide compound having a structure represented by formula 1 is 1.5 to 2.5:1.
preferably, the temperature of the coupling reaction is 0-30 ℃ and the time is 5-7 h.
Preferably, in the first route, the molar ratio of the 3-bromo-3' -methoxy-benzophenone to the thiosemicarbazide to the p-toluenesulfonic acid is 1 (3-3.5): 1;
the temperature of the first condensation reaction is 75-85 ℃ and the time is 20-24 h.
Preferably, in the first route, the molar ratio of the compound having the structure represented by formula 2 to boron tribromide is (0.8 to 1.2): 0.6;
the temperature of the first demethylation reaction is 0-30 ℃ and the time is 5-7 h.
Preferably, in the second route, the molar ratio of the 3-bromo-3' -methoxy-benzophenone to the boron tribromide is 1:0.3-0.5;
the temperature of the second demethylation reaction is 0-30 ℃ and the time is 5-7 h.
Preferably, in the second route, the molar ratio of the 3-bromo-3' -hydroxy-benzophenone to the thiosemicarbazide to the p-toluenesulfonic acid is 1 (3-4): 1-1.2;
the temperature of the second condensation reaction is 75-85 ℃ and the time is 18-24 h.
The invention provides a preparation method of KGP94, which comprises the following steps: (1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1: (2) Performing a coupling reaction on 3-methoxy phenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone; (3) 3-bromo-3' -methoxy-benzophenone to obtain KGP94; the first route includes: carrying out a first condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain a compound with a structure shown in a formula 2: carrying out a first demethylation reaction on a compound with a structure shown in a formula 2 and boron tribromide to obtain KGP94; the second route includes: carrying out a second demethylation reaction on the 3-bromo-3 '-methoxy-benzophenone and boron tribromide to obtain 3-bromo-3' -hydroxy-benzophenone; and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94. The invention starts from common 3-bromobenzoyl chloride, adopts Weinreb amide method to prepare amide compound with structure shown in formula 1, and then utilizes format reagent 3-methoxy phenyl magnesium bromide to couple with amide compound with structure shown in formula 1 to obtain 3-bromo-3' -methoxy-benzophenone. In the present invention, 3-bromo-3' -methoxy-benzophenone is used as an intermediate material and KGP94 is obtained by either a demethylation followed by condensation or a condensation followed by demethylation. The method provided by the invention has the advantages of short synthetic route and high total yield, and the results of examples show that the total yield of the method provided by the invention is 80% or 89%.
Drawings
FIG. 1 is a synthetic scheme for KGP94.
Detailed Description
The invention provides a preparation method of KGP94, which comprises the following steps:
(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1:
(2) Performing a coupling reaction on 3-methoxy phenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) 3-bromo-3' -methoxy-benzophenone to obtain KGP94;
the first route includes: carrying out a first condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain a compound with a structure shown in a formula 2:
carrying out a first demethylation reaction on a compound with a structure shown in a formula 2 and boron tribromide to obtain KGP94;
the second route includes: carrying out a second demethylation reaction on the 3-bromo-3 '-methoxy-benzophenone and boron tribromide to obtain 3-bromo-3' -hydroxy-benzophenone;
and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
In the present invention, all reactions are carried out under an inert atmosphere unless specifically stated otherwise.
In the invention, under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1. In the present invention, the solvent used in the nucleophilic substitution reaction is preferably chloroform and water, and the volume ratio of chloroform to water is preferably 1:1.
In the invention, the molar ratio of the 3-bromobenzoyl chloride to the N, O-dimethylhydroxylamine hydrochloride to the potassium carbonate is preferably 1 (1-2): (2-3), more preferably 1:1.5:2.5. In the present invention, the temperature of the nucleophilic substitution reaction is preferably 0 to 30 ℃, and the time is preferably 5 to 7 hours, more preferably 6 hours.
In the present invention, the nucleophilic substitution reaction is particularly preferably:
mixing potassium carbonate, N, O-dimethylhydroxylamine hydrochloride and a solvent, adding 3-bromobenzoyl chloride under stirring at 0 ℃, and heating to room temperature to perform nucleophilic substitution reaction. In the present invention, the reaction time of the nucleophilic substitution reaction is calculated from the temperature rise of 0 ℃.
After the nucleophilic substitution reaction is completed, the present invention preferably performs a post-treatment on the resulting nucleophilic substitution reaction solution, the post-treatment preferably comprising the steps of:
diluting nucleophilic substitution reaction liquid with chloroform and water, and separating to obtain a first organic phase;
extracting the aqueous phase with chloroform to obtain a second organic phase, and combining the first organic phase and the second organic phase to obtain a combined organic phase;
the combined organic phases are sequentially subjected to alkali washing and drying to obtain an amide compound having a structure shown in formula 1.
In the invention, the alkali liquor used for alkali washing is preferably NaOH solution with the concentration of 6M; in the present invention, the drying agent used for drying is preferably anhydrous Na 2 SO 4 . After the drying, the solvent in the solid is preferably evaporated in vacuo.
After the amide compound with the structure shown in the formula 1 is obtained, 3-methoxy phenyl magnesium bromide and the amide compound with the structure shown in the formula 1 are subjected to coupling reaction to obtain 3-bromo-3' -methoxy-benzophenone. In the present invention, the organic solvent used in the coupling reaction is preferably one or more of tetrahydrofuran, toluene, diethylene glycol, 2-methacrolein and cyclopentyl methyl ether. In the present invention, the molar ratio of the 3-methoxyphenylmagnesium bromide to the amide compound having the structure represented by formula 1 is preferably 1.5 to 2.5:1, more preferably 2:1, and the temperature of the coupling reaction is preferably 0 to 30 ℃, and the time is preferably 5 to 7 hours, more preferably 6 hours.
In the present invention, the coupling reaction is particularly preferably:
3-methoxy phenyl magnesium bromide, amide compound with the structure shown in formula 1 and organic solvent are mixed, and the temperature is raised from 0 ℃ to room temperature for coupling reaction. In the present invention, the reaction time of the coupling reaction is calculated from the time of heating up to 0 ℃.
After the coupling reaction is completed, the present invention preferably performs a post-treatment on the resulting coupling reaction solution, and in the present invention, the post-treatment preferably includes the steps of:
quenching, extracting with organic solvent, washing and drying the coupling reaction liquid in sequence to obtain the 3-bromo-3' -methoxy-benzophenone pure product.
The quenching is preferably carried out using ice water. In the present invention, the organic solvent used for the extraction is preferably ethyl acetate. In the present invention, after the extraction, the aqueous phase is preferably re-extracted with ethyl acetate and the organic phases are combined. In the present invention, the washing detergent is preferably brine. In the present invention, the drying agent used for drying is preferably anhydrous Na 2 SO 4 。
After the 3-bromo-3 '-methoxy-benzophenone is obtained, in a first route, the 3-bromo-3' -methoxy-benzophenone, thiosemicarbazide and p-toluenesulfonic acid undergo a first condensation reaction to obtain a compound with a structure shown in a formula 2.
In the present invention, the molar ratio of 3-bromo-3' -methoxy-benzophenone to thiosemicarbazide to p-toluenesulfonic acid is preferably 1:3.5:1. In the present invention, the organic solvent used in the first condensation reaction is preferably one or more of absolute ethanol, methanol and tetrahydrofuran. In the present invention, the temperature of the first condensation reaction is preferably 75 to 85 ℃, more preferably 80 ℃, and the time is preferably 20 to 24 hours, more preferably 22 hours.
After the first condensation reaction, the present invention preferably performs a post-treatment of the obtained first condensation reaction liquid, the post-treatment preferably comprising the steps of:
evaporating the organic solvent in the first condensation reaction liquid, diluting the residual residue with water, and sequentially extracting, washing, drying, concentrating and performing column chromatography to obtain a pure compound with a structure shown in a formula 2.
In the present invention, the organic solvent used for the extraction is preferably ethyl acetate. In the present invention, after the extraction, the present invention preferably re-extracts the aqueous phase with ethyl acetateThe organic phases are combined. In the present invention, the washing detergent is preferably NaHCO 3 Solution, the drying agent used for drying is preferably anhydrous Na 2 SO 4 . The concentration method is not particularly limited, and concentration methods well known to those skilled in the art can be used.
In the present invention, the mobile phase used for the column chromatography is preferably petroleum ether: ethyl acetate, the petroleum ether: the volume ratio of the ethyl acetate is preferably 20:3.5 to 5.0.
After the compound with the structure shown in the formula 2 is obtained, the compound with the structure shown in the formula 2 and boron tribromide undergo a first demethylation reaction to obtain KGP94. In the present invention, the organic solvent used in the first demethylation reaction is preferably methylene chloride and/or chloroform. In the present invention, the molar ratio of the compound having the structure represented by formula 2 to boron tribromide is preferably 0.8 to 1.2:0.6, more preferably 1:0.6. In the present invention, the temperature of the first demethylation reaction is preferably 0 to 30 ℃, and the time is preferably 5 to 7 hours, more preferably 6 hours.
In the present invention, the first demethylation reaction is specifically preferably:
mixing a compound with a structure shown in a formula 2 and an organic solvent at 0 ℃, adding boron tribromide, and heating to room temperature to perform a first demethylation reaction. In the present invention, the reaction time of the first demethylation reaction is calculated from the time of the temperature rise of 0 ℃.
After the first demethylation reaction, the present invention preferably performs a post-treatment of the resulting first demethylation reaction solution, the post-treatment preferably comprising the steps of:
and quenching, extracting with an organic solvent, washing, drying, concentrating and performing column chromatography on the first demethylation reaction liquid in sequence to obtain a pure 3-bromo-3' -methoxy-benzophenone product.
The quenching is preferably carried out using ice water. In the present invention, the organic solvent used for the extraction is preferably methylene chloride. After the extraction, the aqueous phase obtained is preferably re-extracted with methylene chloride and the organic phases are combined. In the present inventionIn which the washing detergent is preferably NaHCO 3 Solution and brine solution, the drying agent used for drying is preferably anhydrous Na 2 SO 4 . The concentration method is not particularly limited, and concentration methods well known to those skilled in the art can be used.
In the invention, the mobile phase used for the column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 20:5-6.
After the 3-bromo-3 ' -methoxy-benzophenone is obtained, in a second route, carrying out a second demethylation reaction on the 3-bromo-3 ' -methoxy-benzophenone and boron tribromide to obtain 3-bromo-3 ' -hydroxy-benzophenone;
and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
In the present invention, the organic solvent used for the second demethylation is preferably methylene chloride and/or chloroform. In the present invention, the molar ratio of 3-bromo-3' -methoxy-benzophenone to boron tribromide is preferably 1:0.3 to 0.5, more preferably 1:0.4. In the present invention, the temperature of the second demethylation reaction is preferably 0 to 30 ℃, and the time is preferably 5 to 7 hours, more preferably 6 hours.
In the present invention, the second demethylation reaction is specifically preferably:
3-bromo-3' -methoxy-benzophenone and an organic solvent are mixed at 0 ℃, boron tribromide is added, and the temperature is raised to room temperature to perform a first demethylation reaction. In the present invention, the reaction time of the second demethylation reaction is calculated from the time of the temperature rise of 0 ℃.
After the second demethylation reaction, the obtained second demethylation reaction solution is preferably subjected to a post-treatment, and the post-treatment mode is preferably the same as that of the first demethylation reaction solution, and is not described herein.
After the 3-bromo-3 '-hydroxy-benzophenone is obtained, the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid undergo a second condensation reaction to obtain KGP94. In the present invention, the organic solvent used in the second condensation reaction is preferably absolute ethanol. In the present invention, the molar ratio of the 3-bromo-3' -hydroxy-benzophenone to the thiosemicarbazide to the p-toluenesulfonic acid is preferably 1 (3 to 4): (1 to 1.2), more preferably 1:3.5:1. In the present invention, the temperature of the second condensation reaction is preferably 75 to 85 ℃, more preferably 80 ℃, and the time is preferably 18 to 24 hours, more preferably 20 hours.
In the present invention, after the second condensation reaction, the obtained second condensation reaction solution is preferably subjected to a post-treatment, and the post-treatment mode is preferably the same as that of the first condensation reaction solution, and will not be described herein.
In the present invention, the synthetic route diagram of the KGP94 is shown in fig. 1.
The following examples are presented to illustrate the preparation of KGP94 according to the invention in detail, but they should not be construed as limiting the scope of the invention.
In the examples below, all reactions were carried out under an inert atmosphere, except as specified.
The nuclear magnetic resonance hydrogen spectrum (1H-NMR) was determined at 400MHz with a ruker Avance 400 spectrometer and the nuclear magnetic resonance carbon spectrum (13C-NMR) was determined at 100 MHz. Residual acetone (δ2.05;206.6, 29.9), chloroform (δ7.24; 77.2) and dimethylsulfoxide (δ2.50; 39.5) as solvent peak internal references for hydrogen and carbon spectra, tetramethylsilane (TMS) as internal standard, peak shape representation: s (unimodal), d (bimodal), t (trimodal), q (tetramodal), dd (diplex peak), ddd (triplex duplex peak), m (bimodal), brs (broad unimodal). The coupling constant is expressed as J (unit: hz) and the chemical shift is expressed as delta (unit: ppm). High resolution mass spectra were detected by Agilent 6540q-TOF (electrospray ionization, ESI-TOF) mass spectrometer. Column chromatography uses 200-300 mesh silica gel. Thin layer chromatography was performed using HSGF254 silica gel plates, ultraviolet light (254 nm) or potassium permanganate.
Example 1
(1) Preparation of amide Compound having Structure represented by formula 1
N, O-dimethylhydroxylamine hydrochloride (2.053 g,21.051mmol,1.5eq., 98%) and potassium carbonate (4.849 g,35.086mmol,2.5eq., 99%) were dissolved in a mixed solvent of chloroform (15.0 mL) and water (15.0 mL)3-bromobenzoyl chloride 3 (3.080 g,14.034mmol,1.0eq., 97%) was added dropwise with stirring at 0deg.C, after 10 minutes the temperature was gradually raised to room temperature and the reaction was continued with stirring. After 6 hours the reaction was diluted with chloroform and water, the organic phase was separated, the aqueous phase was further extracted with chloroform, the organic phases were combined, washed with 6M NaOH solution, the organic phase was separated, and the aqueous phase was taken up in anhydrous Na 2 SO 4 And (5) drying. After the solvent was evaporated in vacuo, weinreb amide compound (3.392 g, yield 99%) having the structure shown in formula 1 was obtained as colorless liquid.
1 H-NMR(400MHz,CDCl 3 )δ7.74(s,1H,Ar-H),7.54-7.49(m,2H,2xAr-H),7.20(t,J＝7.8Hz,1H,Ar-H),3.47(s,3H,OCH 3 ),3.27(s,3H,NCH 3 )； 13 C-NMR(100MHz,CDCl 3 )δ168.1(C＝O),135.9(C),133.5(CH),131.2(CH),129.6(CH),126.7(CH),122.0(C),61.2(OCH 3 ),33.5(NCH 3 )；HRMS(ESI)calcd.for C 9 H 10 BrNO 2 [M+H] + 243.9968,found 243.9969.
The reaction process is shown as a formula A:
(2) Preparation of 3-bromo-3' -methoxy-benzophenone
3-Methoxyphenylmagnesium bromide (1.0M, 28mL,27.793mmol,2.0eq.,98% tetrahydrofuran solution) was added to a dry tetrahydrofuran solution in which an amide compound having the structure shown in formula 1 (3.3992 g,13.896mmol,1.0 eq.) was dissolved by stirring and degassing under argon atmosphere at 0℃and stirred at 0℃for 30 minutes, and then gradually warmed to room temperature to continue the stirring reaction. After 4 hours quenching with ice water, extraction with ethyl acetate, separation of the organic phase, further extraction of the aqueous phase with ethyl acetate, combining the organic phases, washing with brine, anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate, gradient 20:0.5 to 20:1.5) to give the pale yellow product as 3-bromo-3' -methoxy-benzophenone (3.860 g, yield 95%).
1 H-NMR(400MHz,CDCl 3 )δ7.85(s,1H,Ar-H),7.64-7.62(dd,J＝6.2,1.5Hz,2H,2xAr-H),7.33-7.22(m,4H,4xAr-H),7.08-7.06(dd,J＝6.0,1.8Hz,1H,Ar-H),3.78(s,3H,OCH 3 )； 13 C-NMR(100MHz,CDCl 3 )δ194.9(C＝O),159.6(C),139.5(C),138.1(C),135.2(CH),132.7(CH),129.8(CH),129.4(CH),128.5(CH),122.8(C),122.5(CH),119.3(CH),114.2(CH),55.5(OCH 3 )；HRMS(ESI)calcd.for C 14 H 11 BrO 2 [M+H] + 291.0015,found 291.0017.
The reaction process is shown as a formula B:
(3) Preparation of Compounds having the Structure shown in formula 2
3-bromo-3' -methoxy-benzophenone (1.000 g, 3.284 mmol,1.0 eq.) thiosemicarbazide (1.095 g,12.021mmol,3.5eq., 99%) and p-toluenesulfonic acid monohydrate (0.653, 3.284 mmol,1.0eq., 98%) were dissolved in absolute ethanol (45 mL) and heated to reflux for 22 hours at 80 ℃. After the reaction was completed, ethanol was evaporated in vacuo. The residue was then diluted with water, extracted with ethyl acetate, the organic phase separated, the aqueous phase further extracted with ethyl acetate, the organic phases combined with NaHCO 3 Washing with solution, anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate, gradient, 20:3.5 to 20:5.0) to give a white crystalline product (1.239 g, 99% yield).
1 H-NMR(400MHz,(CD 3 ) 2 CO)δ8.57(brs,1H,NH),8.23(brs,1H,NH),7.97(s,1H,Ar-H),7.78(brs,1H,NH),7.63-7.56(3H,m,Ar-H),7.31(t,J＝7.9Hz,1H,Ar-H),7.19(dd,J＝8.4,1.9Hz,1H,Ar-H),6.96-6.94(m,2H,Ar-H)3.88(s,3H,OCH 3 )； 13 C-NMR(100MHz,(CD 3 ) 2 CO)δ180.4(C＝S),161.7(C),148.3(C＝N),139.8(C),133.3(CH),133.1(C),132.2(CH),131.1(CH),130.5(CH),127.6(CH),123.1(C),121.0(CH),116.7(CH),114.5(CH),55.9(OCH 3 )；HRMS(ESI)calcd.for C 15 H 14 BrN 3 OS[M+H] + 364.0114,found 364.0119.
The reaction process is shown as a formula C:
(4) Preparation of KGP94
The compound having the structure shown in formula 2 (0.500 g,1.372mmol,1.0 eq.) was dissolved in anhydrous dichloromethane (15 mL) and cooled to 0 ℃, then boron tribromide (1.0 m,0.8mL,0.6eq.,99.9% dichloromethane solution) was added dropwise, gradually returning to room temperature and stirring was continued. After 6 hours the reaction was quenched with ice water, the organic phase was separated by extraction with dichloromethane, the aqueous phase was further extracted with dichloromethane, the organic phases were combined and the aqueous phase was extracted with NaHCO 3 Washing with solution and brine solution, anhydrous Na 2 SO 4 Drying, concentration, column chromatography (petroleum ether: ethyl acetate, gradient 20:5.0 to 20:6.0) gave the product as a white solid, KGP94 (0.461 g, 96% yield), E: z=4.5:1.
1 H-NMR(400MHz,DMSO-d 6 )δ9.98(s,1H,OH),8.68(brs,1H,NH),8.55(brs,1H,NH),8.42(brs,1H,NH),8.05(s,1H,Ar-H),7.57(ddd,J＝7.7,1.95,1.0Hz,1H,Ar-H),7.78-7.44(m,2H,2x Ar-H),7.31(t,J＝7.9Hz,1H,Ar-H),7.02(dd,J＝6.5,1.7Hz,1H,Ar-H),6.73-6.71(m,1H,Ar-H),6.66-6.65(m,1H,Ar-H). 13 C-NMR(100MHz,DMSO-d 6 ,)δ177.8(C＝S),158.5(C),147.3(C＝N),138.5(C),132.3(CH),131.6(C),131.3(CH),130.4(CH),129.3(CH),126.9(CH),122.1(C),118.3(CH),117.2(CH),114.5(CH)；HRMS(ESI)calcd.for C 14 H 12 BrN 3 OS[M+H]+349.9957,found 349.9964.
The reaction process is shown as a formula D:
the imine (c=n) double bond of KGP94 is predominantly in the E configuration in solution, which is determined by the combined rotey (turning-Frame Overhauser Spectroscopy), HMBC (Heteronuclear Multiple Bond Correlation) and COSY (Correlation Spectroscopy) spectra. In the ROESY spectrum, NH (δ8.42) is significantly correlated with C-H (δ6.73) and C-H (δ6.66); in the HMB profile, NH (δ8.42) strongly correlated with c=s (177.8) (2J (strong)), weakly correlated with c=n (147.3) (3J (weak)); in the COSY spectrum, two protons of NHaHb (δ 8.68,8.55) can be found separately. The E and Z forms of KGP94 and its analog compound 2 are rapidly interconvertible and cannot be isolated alone, E: the ratio of Z is determined by integrating the characteristic signals of the two isomeric protons in the 1H-NMR spectrum of the purified mixture.
Example 2
An amide compound having a structure shown in formula 1 and 3-bromo-3' -methoxy-benzophenone were prepared in the same manner as in example 1.
(1) Preparation of 3-bromo-3' -hydroxy-benzophenone
3-bromo-3' -methoxy-benzophenone (2.860 g,9.823mmol,1.0 eq.) was dissolved in anhydrous dichloromethane (40 mL) solution, boron tribromide (1.0 m,4.2mL,0.4eq.,99.9% dichloromethane solution) was added at 0 ℃ and after stirring at room temperature for 6 hours, the mixture was slowly transferred to ice water, then extracted with dichloromethane, the organic phase was separated, the aqueous phase was further extracted with dichloromethane, the organic phases were combined, and the aqueous phase was extracted with NaHCO 3 Washing with solution and brine solution, anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate, gradient 20:2.0 to 20:4.0) to give the product as a white solid, 3-bromo-3' -hydroxy-benzophenone (2.391 g, 88% yield).
1 H-NMR(400MHz,CDCl 3 )δ7.84(brs,1H,Ar-H),7.61(dd,J＝6.7,1.1Hz,2H,2x Ar-H),7.26(t,J＝7.9Hz,3H,3x Ar-H),7.20(d,J＝7.7Hz,1H,Ar-H),7.05(dd,J＝7.9,1.7Hz,1H,Ar-H),6.43(brs,1H,OH), 13 C-NMR(100MHz,CDCl 3 )δ194.7(C＝O),155.1(C),138.1(C),137.0(C),134.5(CH),131.8(CH),128.8(CH),128.7(CH),127.6(CH),121.8(CH),121.5(C),119.5(CH),115.4(CH)；HRMS(ESI)calcd.for C 13 H 9 BrO 2 [M+H] + 276.9859,found 276.9860.
The reaction process is shown as a formula E:
(2) Preparation of KGP94
3-bromo-3' -hydroxy-benzophenone (2.3991 g, 8.6278 mmol,1.0 eq.) thiosemicarbazide (2.751 g,30.198mmol,3.5eq., 99%) and p-toluene sulphonic acid monohydrate (1.6411 g, 8.6278 mmol,1.0eq., 98%) were dissolved in absolute ethanol (60.0 mL) and after sonication for 10 minutes, the reaction was refluxed under argon at 80 ℃ for 20 hours. After completion of the reaction, the ethanol was removed under reduced pressure, the residue was extracted with ethyl acetate, and the aqueous phase was further extracted, the organic phases were combined, and the aqueous phase was extracted with NaHCO 3 Washing with solution, anhydrous Na 2 SO 4 Dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate, gradient, 20:4.0 to 20:6.0) to give the product as a white solid (2.930 g, 97% yield), E: z=4.5:1.
1 H-NMR(400MHz,(CD 3 ) 2 CO)δ8.93(brs,1H,OH),8.61(brs,1H,NH),8.24(brs,1H,NH),7.97(s,1H,Ar-H),7.78(brs,1H,NH),7.58-7.50(3H,m,Ar-H),7.31(t,J＝7.7Hz,1H,Ar-H),7.10(d,J＝7.5Hz,1H,Ar-H),6.85-6.83(m,2H,Ar-H)； 13 C-NMR(100MHz,(CD 3 ) 2 CO)δ180.4(C＝S),159.5(C),148.5(C＝N),139.9(C),133.3(CH),133.1(C),132.3(CH),131.1(CH),130.6(CH),127.7(CH),123.1(C),120.0(CH),118.3(CH),115.8(CH)；HRMS(ESI)calcd.for C 14 H 12 BrN 3 OS[M+H] + 349.9957,found 349.9963.
The reaction process is shown in formula F:
the foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. A process for the preparation of KGP94 comprising the steps of:
(1) Under the catalysis of potassium carbonate, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride undergo nucleophilic substitution reaction to obtain an amide compound with a structure shown in a formula 1:
(2) Performing a coupling reaction on 3-methoxy phenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) 3-bromo-3' -methoxy-benzophenone to obtain KGP94;
the first route includes: carrying out a first condensation reaction with thiosemicarbazide and p-toluenesulfonic acid to obtain a compound with a structure shown in a formula 2:
carrying out a first demethylation reaction on a compound with a structure shown in a formula 2 and boron tribromide to obtain KGP94;
the second route includes: carrying out a second demethylation reaction on the 3-bromo-3 '-methoxy-benzophenone and boron tribromide to obtain 3-bromo-3' -hydroxy-benzophenone;
and carrying out a second condensation reaction on the 3-bromo-3' -hydroxy-benzophenone and thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
2. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the 3-bromobenzoyl chloride to the N, O-dimethylhydroxylamine hydrochloride to the potassium carbonate is 1 (1-2): 2-3.
3. The method according to claim 1, wherein the nucleophilic substitution reaction is carried out at a temperature of 0 to 30 ℃ for a time of 5 to 7 hours.
4. The method according to claim 1, wherein in the step (2), the molar ratio of the 3-methoxyphenylmagnesium bromide to the amide compound having the structure represented by formula 1 is 1.5 to 2.5:1.
5. the preparation method according to claim 1, wherein the coupling reaction is carried out at a temperature of 0 to 30 ℃ for a time of 5 to 7 hours.
6. The preparation method according to claim 1, wherein in the first route, the molar ratio of 3-bromo-3' -methoxy-benzophenone to thiosemicarbazide to p-toluenesulfonic acid is 1 (3-3.5): 1;
the temperature of the first condensation reaction is 75-85 ℃ and the time is 20-24 h.
7. The method according to claim 1, wherein in the first route, the molar ratio of the compound having the structure represented by formula 2 to boron tribromide is (0.8 to 1.2): 0.6;
the temperature of the first demethylation reaction is 0-30 ℃ and the time is 5-7 h.
8. The method of claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -methoxy-benzophenone to boron tribromide is 1:0.3-0.5;
the temperature of the second demethylation reaction is 0-30 ℃ and the time is 5-7 h.
9. The preparation method according to claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -hydroxy-benzophenone to thiosemicarbazide to p-toluenesulfonic acid is 1 (3-4): 1-1.2;
the temperature of the second condensation reaction is 75-85 ℃ and the time is 18-24 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110879143.4A CN115701422B (en) | 2021-08-02 | 2021-08-02 | Preparation method of KGP94 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110879143.4A CN115701422B (en) | 2021-08-02 | 2021-08-02 | Preparation method of KGP94 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115701422A CN115701422A (en) | 2023-02-10 |
| CN115701422B true CN115701422B (en) | 2024-02-09 |
Family
ID=85142336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110879143.4A Active CN115701422B (en) | 2021-08-02 | 2021-08-02 | Preparation method of KGP94 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115701422B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003294750A1 (en) * | 2002-12-13 | 2004-07-09 | Basf Aktiengesellschaft | Method for the production of benzophenones |
| WO2017030983A1 (en) * | 2015-08-14 | 2017-02-23 | Mateon Therapeutics, Inc. | Compositions and methods for inhibition of cathepsins |
-
2021
- 2021-08-02 CN CN202110879143.4A patent/CN115701422B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003294750A1 (en) * | 2002-12-13 | 2004-07-09 | Basf Aktiengesellschaft | Method for the production of benzophenones |
| WO2017030983A1 (en) * | 2015-08-14 | 2017-02-23 | Mateon Therapeutics, Inc. | Compositions and methods for inhibition of cathepsins |
Non-Patent Citations (2)
| Title |
|---|
| Gan, Yonghong等. Nonsteroidal Benzophenone-Containing Analogs of Cholestero.2006,第71卷(第16期),P5864-5869. * |
| Synthesis of bromo-methoxyl benzophenone imidazole compounds and their protective activities against hydrogen peroxide induced injury in EA. hy 926 cells;Song, Ting等;Yingyong Huaxue;第34卷(第7期);P783-788 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115701422A (en) | 2023-02-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106632214A (en) | Synthetic method for cannabinol compound | |
| CN116063223A (en) | 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound and synthesis method thereof | |
| CN116283899A (en) | 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound and synthesis method thereof | |
| CN115701422B (en) | Preparation method of KGP94 | |
| Hu et al. | Synthesis of Asymmetric Triarylbenzenes by Using SOCl2‐C2H5OH Reagent | |
| CN115073479B (en) | Extended porphyrin constructed by naphthadipyrrole with near infrared absorption property, preparation method and application thereof | |
| Salama et al. | An efficient synthesis of O-methyl protected emodin aldehyde and emodin nitrile | |
| Hajipour et al. | Silicasulfuric acid/NaNO 2 as a new reagent for deprotection of S, S-acetals under solvent-free conditions | |
| de la Torre et al. | An efficient cyclization of lapachol to new benzo [h] chromene hybrid compounds: a stepwise vs. one-pot esterification-click (CuAAC) study | |
| CN109251174B (en) | 3-trinitromethylpyrazole compounds | |
| Nakatsuji et al. | Ethynologs of triphenylmethane dyes. Part 6. A simple and convenient synthesis of aryl-substituted push-pull butadienes from 1, 1-diaryl-2-propyn-1-ols. | |
| JP2009132623A (en) | Method for producing 2,3-dicyanonaphthalene derivative | |
| EP0007403A1 (en) | 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacenes and their synthesis | |
| CN109879830A (en) | A kind of oxaza heptane derivative and preparation method thereof containing exocyclic double bond | |
| Sasaki et al. | Synthesis of metal furoylacetonates and their SE reactions. I. Heteroaromaticity | |
| CN112574133B (en) | Synthesis method of 1, 3-diaryl substituted tetrazolone inner salt | |
| Ohwada et al. | Acyliminium cyclization of several chiral N-alkenylsuccinimide derivatives. | |
| CN112939920B (en) | Preparation method of dracorhodin A or dracorhodin B | |
| SUEYOSHI et al. | Preparation and properties of novel trisubstituted N-nitrosoureas which decompose to afford triazenes and nitro compounds under mild conditions | |
| JP2013047193A (en) | Resveratrol and method for producing derivative thereof | |
| Lin et al. | Substituent Effect on the Tautomerization of 1‐Arylazonaphthalen‐2‐ols by Mass Spectrometric Analysis | |
| Misra et al. | DFT studies on the mechanism of base-catalyzed hydrocyanation of alpha, beta-unsaturated ketones | |
| CN110770230A (en) | Production of trimethylbenzene derivatives | |
| Yuan et al. | Direct and highly stereoselective synthesis of quinolizidine iminosugars promoted by l-proline-Et 3 N | |
| Sierakowski | A convenient synthesis of two dibenzofurans |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |