CN115701422A - Preparation method of KGP94 - Google Patents
Preparation method of KGP94 Download PDFInfo
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- CN115701422A CN115701422A CN202110879143.4A CN202110879143A CN115701422A CN 115701422 A CN115701422 A CN 115701422A CN 202110879143 A CN202110879143 A CN 202110879143A CN 115701422 A CN115701422 A CN 115701422A
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- benzophenone
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- kgp94
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- 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 19
- 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
- -1 amide compound Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 16
- PBOOZQFGWNZNQE-UHFFFAOYSA-N 3-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Br)=C1 PBOOZQFGWNZNQE-UHFFFAOYSA-N 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
- 238000010520 demethylation reaction Methods 0.000 claims description 30
- 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
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001335 demethylating effect Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000007818 Grignard reagent Substances 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 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 20
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000001035 drying Methods 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 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
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 238000007865 diluting Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-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
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical group O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 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
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 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
- 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
- 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
- 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
Images
Classifications
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of KGP94, belonging to the technical field of organic synthesis. The invention starts from common 3-bromobenzoyl chloride, adopts a Weinreb amide method to prepare an amide compound with a structure shown in a formula 1, and then utilizes a Grignard reagent 3-methoxyphenyl magnesium bromide to couple with the amide compound with the structure shown in the formula 1 to obtain the 3-bromo-3' -methoxy-benzophenone. In the invention, 3-bromo-3' -methoxy-benzophenone is used as an intermediate raw material, and KGP94 is obtained by firstly demethylating and then condensing or firstly condensing and then demethylating. The method provided by the invention has the advantages of short synthetic route and high total yield, and the example results 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 reactive ((IC) 50 =131.4 μ M), low toxicity ((GI) 50 =26.9 μ M)) belonging to substituted benzophenone thiosemicarbazones. KGP94 is currently under preclinical investigation and of great interest for the treatment of metastatic cancer.
At present, there are two main methods for synthesizing KGP94 reported. The synthetic route of the first method is as follows:
the second method is an improvement on the first method, and the synthetic route is as follows:
the two reported methods both use cross coupling reaction as a key step, and finally obtain a target product through oxidation, condensation and deprotection, but both have the defects of longer synthetic route and low total yield.
Disclosure of Invention
Accordingly, 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) Carrying out nucleophilic substitution reaction on 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride under the catalysis of potassium carbonate to obtain an amide compound with a structure shown in a formula 1:
(2) Carrying out coupling reaction on 3-methoxyphenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) Carrying out a first route or a second route on the 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 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: performing 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, 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 and the potassium carbonate is 1.
Preferably, the temperature of the nucleophilic substitution reaction is 0-30 ℃ and the time is 5-7 h.
Preferably, in the step (2), the molar ratio of the 3-methoxyphenyl magnesium bromide to the amide compound having the 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 and the p-toluenesulfonic acid is 1 (3-3.5) to 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 with the structure shown in the formula 2 to the boron tribromide is (0.8-1.2): 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;
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 and the p-toluenesulfonic acid is 1 (3-4) to 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) Carrying out nucleophilic substitution reaction on 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride under the catalysis of potassium carbonate to obtain an amide compound with a structure shown in a formula 1: (2) Carrying out coupling reaction on 3-methoxyphenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone; (3) Carrying out a first route or a second route on the 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 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: performing 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, thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94. The method is characterized in that an amide compound with a structure shown in a formula 1 is prepared by a Weinreb amide method from common 3-bromobenzoyl chloride, and then a Grignard reagent 3-methoxyphenyl magnesium bromide is coupled with the amide compound with the structure shown in the formula 1 to obtain the 3-bromo-3' -methoxy-benzophenone. In the invention, 3-bromo-3' -methoxy-benzophenone is used as an intermediate raw material, and KGP94 is obtained by firstly demethylating and then condensing or firstly condensing and then demethylating. The method provided by the invention has the advantages of short synthetic route and high total yield, and the example results show that the total yield of the method provided by the invention is 80% or 89%.
Drawings
FIG. 1 is a scheme showing the synthesis scheme of KGP94.
Detailed Description
The invention provides a preparation method of KGP94, which comprises the following steps:
(1) Carrying out nucleophilic substitution reaction on 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride under the catalysis of potassium carbonate to obtain an amide compound with a structure shown in a formula 1:
(2) Carrying out coupling reaction on 3-methoxyphenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) Carrying out a first route or a second route on the 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 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: performing 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, thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
In the present invention, all reactions are carried out under an inert atmosphere except for the specific description.
In the invention, 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride are subjected to nucleophilic substitution reaction under the catalysis of potassium carbonate to obtain the amide compound with the structure shown in the 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) to (2-3), more preferably 1.5. 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 at the temperature of 0 ℃ under stirring, heating to room temperature, and carrying out nucleophilic substitution reaction. In the present invention, the reaction time of the nucleophilic substitution reaction is calculated from the time of temperature rise at 0 ℃.
After the nucleophilic substitution reaction is completed, the present invention preferably performs a post-treatment on the obtained nucleophilic substitution reaction solution, and the post-treatment preferably includes the following steps:
diluting the 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;
and sequentially performing alkali washing and drying on the combined organic phase to obtain the amide compound with the structure shown in the 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 said drying, the present invention preferably evaporates the solvent in the solid in vacuo.
After the amide compound with the structure shown in the formula 1 is obtained, 3-methoxyphenyl magnesium bromide and the amide compound with the structure shown in the formula 1 are subjected to coupling reaction to obtain the 3-bromo-3' -methoxy-benzophenone. In the invention, the organic solvent used in the coupling reaction is preferably one or more of tetrahydrofuran, toluene, diethylene glycol, 2-methylacrolein and cyclopentyl methyl ether. In the present invention, the molar ratio of the 3-methoxyphenyl magnesium bromide to the amide compound having the structure represented by formula 1 is preferably 1.5 to 2.5, 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:
mixing 3-methoxyphenyl magnesium bromide, amide compound with the structure shown in formula 1 and organic solvent, heating from 0 ℃ to room temperature, and carrying out coupling reaction. In the present invention, the reaction time of the coupling reaction is calculated from the time of raising the temperature to 0 ℃.
After the coupling reaction is completed, the present invention preferably performs post-treatment on the obtained coupling reaction solution, and in the present invention, the post-treatment preferably includes the following steps:
and sequentially quenching, extracting with an organic solvent, washing and drying the coupling reaction solution to obtain a pure product of the 3-bromo-3' -methoxy-benzophenone.
The present invention preferably uses ice water for the quenching. 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 are subjected to a first condensation reaction to obtain a compound with a structure shown in formula 2.
In the present invention, the molar ratio of 3-bromo-3' -methoxy-benzophenone to thiosemicarbazide, p-toluenesulfonic acid is preferably 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 on the obtained first condensation reaction liquid, and the post-treatment preferably includes the steps of:
evaporating the organic solvent in the first condensation reaction liquid, diluting the residual residue with water, and sequentially performing extraction, washing, drying, concentration and column chromatography to obtain a pure compound product with a structure shown in 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 acetate and combines the organic phases. In the present invention, the washing detergent is preferably NaHCO 3 The drying agent used for drying is preferably anhydrous Na 2 SO 4 . The present invention does not require any particular means for concentration, and may employ any means for concentration known to those skilled in the art.
In the present invention, the mobile phase used for the column chromatography is preferably petroleum ether: ethyl acetate, said petroleum ether: the volume ratio of 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 are subjected to a first demethylation reaction to obtain KGP94. In the present invention, the organic solvent used in the first demethylation reaction is preferably dichloromethane 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, and more preferably 1. 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 particularly preferably:
mixing a compound with a structure shown in formula 2 and an organic solvent at 0 ℃, adding boron tribromide, heating to room temperature, and carrying out a first demethylation reaction. In the present invention, the reaction time of the first demethylation reaction is calculated from the time of temperature rise at 0 ℃.
After the first demethylation reaction, the present invention preferably performs a post-treatment on the obtained first demethylation reaction solution, and the post-treatment preferably comprises the following steps:
and sequentially quenching, extracting with an organic solvent, washing, drying, concentrating and carrying out column chromatography on the first demethylation reaction liquid to obtain a pure product of the 3-bromo-3' -methoxy-benzophenone.
The present invention preferably uses ice water for the quenching. In the present invention, the organic solvent used for the extraction is preferably dichloromethane. After said extraction, the present invention preferably re-extracts the resulting aqueous phase using dichloromethane and combines the organic phases. In the present invention, the washing detergent is preferably NaHCO 3 Solution and saline solution, the drying agent used for drying is preferably anhydrous Na 2 SO 4 . The present invention does not require any particular means for concentration, and may employ any means for concentration known to those skilled in the art.
In the invention, the mobile phase used for column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 20 to 6.
After the 3-bromo-3 ' -methoxy-benzophenone is obtained, in a second route, performing 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, thiosemicarbazide and p-toluenesulfonic acid to obtain KGP94.
In the present invention, the organic solvent used for the second demethylation is preferably dichloromethane and/or chloroform. In the present invention, the molar ratio of the 3-bromo-3' -methoxy-benzophenone to the boron tribromide is preferably 1. 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 particularly preferably:
mixing 3-bromo-3' -methoxy-benzophenone and an organic solvent at 0 ℃, adding boron tribromide, heating to room temperature, and carrying out a first demethylation reaction. In the present invention, the reaction time of the second demethylation reaction is calculated from the time of heating at 0 ℃.
After the second demethylation reaction, the obtained second demethylation reaction liquid is preferably subjected to post-treatment in the same way as the first demethylation reaction liquid, and details are not repeated.
After the 3-bromo-3 '-hydroxy-benzophenone is obtained, the 3-bromo-3' -hydroxy-benzophenone, thiosemicarbazide and p-toluenesulfonic acid are subjected to 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 and p-toluenesulfonic acid is preferably 1 (3-4): (1 to 1.2), more preferably 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 liquid is preferably subjected to a post-treatment in the same manner as the post-treatment of the first condensation reaction liquid, and details thereof are not repeated herein.
In the present invention, the synthesis route of KGP94 is shown in fig. 1.
The following examples are provided to illustrate the preparation of KGP94 according to the invention in more detail, but they should not be construed as limiting the scope of the invention.
In the following examples, all reactions were carried out under an inert atmosphere, except where otherwise specified.
Hydrogen nuclear magnetic resonance (1H-NMR) spectrum was measured at 400MHz on a ruker Avance 400 spectrometer, and carbon nuclear magnetic resonance (13C-NMR) spectrum was measured at 100 MHz. Residual acetone (δ 2.05, 206.6, 29.9), chloroform (δ 7.24, 77.2) and dimethylsulfoxide (δ 2.50, 39.5) as internal references for the solvent peaks of the hydrogen spectrum, the carbon spectrum, tetramethylsilane (TMS) as internal standard, the peak shapes are expressed: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (triplet), m (doublet), brs (broad singlet). The coupling constant is expressed in J (unit: hz) and the chemical shift is expressed in delta (unit: ppm). The high resolution mass spectrum is detected by an Agilent 6540q-TOF (electrospray ionization, ESI-TOF) mass spectrometer. The column chromatography uses 200-300 mesh silica gel. Thin layer chromatography is carried out by using HSGF254 silica gel plate, ultraviolet light (254 nm) or potassium permanganate.
Example 1
(1) Preparation of amide Compound having the Structure shown in formula 1
N, O-dimethylhydroxylamine hydrochloride (2.053g, 21.051mmol,1.5eq, 98%) and potassium carbonate (4.849g, 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 (3.0800g, 14.034mmol, 1.eq, 97%) was added dropwise with stirring at 0 ℃, and 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, anhydrous Na was used 2 SO 4 And (5) drying. The solvent was evaporated in vacuo to afford the Weinreb amide compound of formula 1 (3.392 g, 99% yield) as a 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 formula A:
(2) Preparation of 3-bromo-3' -methoxy-benzophenone
3-methoxyphenyl magnesium bromide under the protection of argon at the temperature of 0 DEG C(1.0M, 28mL,27.793mmol,2.0eq, 98% tetrahydrofuran solution) was added to a dried tetrahydrofuran solution which was degassed with stirring and in which an amide compound having a structure represented by formula 1 (3.392g, 13.896mmol, 1.0eq) was dissolved, and after stirring at 0 ℃ for 30 minutes, the temperature was gradually raised to room temperature and the reaction was continued with stirring. Quenching reaction with ice water after 4 hours, extracting with ethyl acetate, separating organic phase, further extracting aqueous phase with ethyl acetate, combining organic phase, washing with brine, anhydrous Na 2 SO 4 Drying, concentration and column chromatography (petroleum ether: ethyl acetate, gradient 20, 0.5 to 20: 1.5) gave the product as 3-bromo-3' -methoxy-benzophenone (3.860 g, 95% yield) in a pale yellow color.
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 formula B:
(3) Preparation of Compound having the Structure shown in formula 2
3-bromo-3' -methoxy-benzophenone (1.000g, 3.434mmol, 1.0eq.), thiosemicarbazide (1.095g, 12.021mmol,3.5eq., 99%) and p-toluenesulfonic acid monohydrate (0.653, 3.434mmol,1.0eq., 98%) were dissolved in absolute ethanol (45 mL) and heated under reflux at 80 ℃ for 22 hours. After completion of the reaction, ethanol was evaporated in vacuo. Then diluting the residue with water, extracting with ethyl acetate, separating the organic phase, further extracting the aqueous phase with ethyl acetate, combining the organic phases, naHCO 3 Washing with anhydrous Na 2 SO 4 Drying, concentrating, and performing column chromatography (petroleum ether: ethyl acetate)Ester, gradient, petroleum ether: ethyl acetate, gradient, 20, 3.5 to 20) to afford the product as white crystals (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 formula C:
(4) Preparation of KGP94
The compound having the structure represented by formula 2 (0.500g, 1.372mmol, 1.0eq.) was dissolved in anhydrous dichloromethane (15 mL) and cooled to 0 ℃, and then boron tribromide (1.0m, 0.8ml,0.6eq, 99.9% dichloromethane solution) was added dropwise, gradually returned to room temperature, and the reaction was continued with stirring. Quenching the reaction solution with ice water after 6 hours, extracting with dichloromethane to separate the organic phase, further extracting the aqueous phase with dichloromethane, combining the organic phases, and reacting with NaHCO 3 Washing with saline solution, anhydrous Na 2 SO 4 Drying, concentration and column chromatography (petroleum ether: ethyl acetate, gradient 20, 5.0 to 20, 6.0) afforded the product as a white solid, KGP94 (0.461 g, 96% yield), E: Z = 4.5.
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 formula D:
the imine (C = N) double Bond of KGP94 is predominantly in the E configuration in solution, which is determined by a combination of the ROESY (Rotating-Frame Overhauser Spectroscopy), HMBC (heterocyclic Multiple Bond Correlation) and COSY (Correlation Spectroscopy) spectra. In the ROESY spectrum, NH (delta 8.42) is significantly correlated with C-H (delta 6.73) and C-H (delta 6.66); in the HMB spectrum, NH (δ 8.42) is strongly correlated with C = S (177.8) (2J (strong)), and 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 respectively. The E configuration and Z configuration of compound 2, KGP94 and its analogs, are rapidly interconvertible and cannot be isolated alone, E: the proportion of Z is determined by integrating the signals characteristic 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 (2.860g, 9.823mmol, 1.0eq.) was dissolved in anhydrous dichloromethane (40 mL), boron tribromide (1.0M, 4.2mL,0.4eq, 99.9% dichloromethane solution) was added at 0 ℃, after stirring at room temperature for 6 hours, the mixture was slowly transferred to ice water, followed by extraction with dichloromethane, separation of the organic phase, further extraction of the aqueous phase with dichloromethane, combination of the organic phases, and use of NaHCO for further extraction of the aqueous phase with dichloromethane 3 Washing with saline solution, anhydrous Na 2 SO 4 Drying, concentrating, and performing column chromatography (petroleum ether: ethyl acetate, terra)Degree 20, 2.0 to 20.0) to yield the product as a white solid, i.e., 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.
Reaction process as shown in formula E:
(2) Preparation of KGP94
3-bromo-3' -hydroxy-benzophenone (2.391g, 8.628mmol, 1.0eq.), thiosemicarbazide (2.751g, 30.198mmol,3.5eq., 99%) and p-toluenesulfonic acid monohydrate (1.64111g, 8.628mmol,1.0eq., 98%) were dissolved in absolute ethanol (60.0 mL), and after sonication for 10 minutes, the reaction was refluxed for 20 hours at 80 ℃ under argon protection. After completion of the reaction, 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 washed with NaHCO 3 Washing with anhydrous Na 2 SO 4 Drying, concentration, column chromatography (petroleum ether: ethyl acetate, gradient, 20, 4.0 to 20, 6.0) afforded the product as a white solid (2.930 g, 97% yield), E: Z = 4.5.
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 as formula F:
the foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (9)
1. A preparation method of KGP94 comprises the following steps:
(1) Carrying out nucleophilic substitution reaction on 3-bromobenzoyl chloride and N, O-dimethylhydroxylamine hydrochloride under the catalysis of potassium carbonate to obtain an amide compound with a structure shown in a formula 1:
(2) Carrying out coupling reaction on 3-methoxyphenyl magnesium bromide and an amide compound with a structure shown in a formula 1 to obtain 3-bromo-3' -methoxy-benzophenone;
(3) Carrying out a first route or a second route on the 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 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: performing 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, 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) to (2-3).
3. The preparation method according to claim 1, wherein the temperature of the nucleophilic substitution reaction is 0-30 ℃ and the time is 5-7 h.
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 process according to claim 1, wherein the temperature of the coupling reaction is between 0 and 30 ℃ and the time is between 5 and 7 hours.
6. The preparation method according to claim 1, wherein in the first route, the molar ratio of the 3-bromo-3' -methoxy-benzophenone to the thiosemicarbazide and 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.
7. The production method according to claim 1, characterized in that, 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 process according to claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -methoxy-benzophenone to boron tribromide is from 1;
the temperature of the second demethylation reaction is 0-30 ℃, and the time is 5-7 h.
9. The method according to claim 1, wherein in the second route, the molar ratio of 3-bromo-3' -hydroxy-benzophenone to thiosemicarbazide and p-toluenesulfonic acid is 1 (3-4) to (1-1.2);
the temperature of the second condensation reaction is 75-85 ℃, and the time is 18-24 h.
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| AU2003294750A1 (en) * | 2002-12-13 | 2004-07-09 | Basf Aktiengesellschaft | Method for the production of benzophenones |
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| 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 |
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| Title |
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| GAN, YONGHONG等: "Nonsteroidal Benzophenone-Containing Analogs of Cholestero", vol. 71, no. 16, pages 5864 - 5869 * |
| SONG, TING等: "Synthesis of bromo-methoxyl benzophenone imidazole compounds and their protective activities against hydrogen peroxide induced injury in EA. hy 926 cells", YINGYONG HUAXUE, vol. 34, no. 7, pages 783 - 788 * |
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