CN111138398A - Synthesis process of 2- (2-amino-3-methoxyphenyl) chromone - Google Patents
Synthesis process of 2- (2-amino-3-methoxyphenyl) chromone Download PDFInfo
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- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 29
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000008569 process Effects 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- WBFBYTQEVJEJFI-UHFFFAOYSA-N 2-(3-methoxy-2-nitrophenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1[N+]([O-])=O WBFBYTQEVJEJFI-UHFFFAOYSA-N 0.000 claims abstract description 29
- PPIGNFWISZXSNS-UHFFFAOYSA-N 1-(2-hydroxyphenyl)-3-(3-methoxy-2-nitrophenyl)propane-1,3-dione Chemical compound COC1=CC=CC(C(=O)CC(=O)C=2C(=CC=CC=2)O)=C1[N+]([O-])=O PPIGNFWISZXSNS-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 20
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 claims abstract description 15
- YMOMYSDAOXOCID-UHFFFAOYSA-N 3-methoxy-2-nitrobenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1[N+]([O-])=O YMOMYSDAOXOCID-UHFFFAOYSA-N 0.000 claims abstract description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- -1 hexafluorophosphate Chemical compound 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000007832 Na2SO4 Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000010923 batch production Methods 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
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- 229910052739 hydrogen Inorganic materials 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
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- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention belongs to the technical field of polymer synthesis, and relates to a synthesis process of 2- (2-amino-3-methoxyphenyl) chromone, which comprises the following steps: 1) 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester as the first intermediate is synthesized by 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid; 2) synthesizing a second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione by using the first intermediate; 3) synthesizing by using the second intermediate to obtain a third intermediate 2- (2-nitro-3-methoxyphenyl) chromone; 4) and synthesizing the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone to obtain the 2- (2-amino-3-methoxyphenyl) chromone. The synthesis process has the advantages of simple operation, mild reaction conditions, easily obtained raw materials and industrial batch production.
Description
Technical Field
The invention belongs to the technical field of polymer synthesis, and relates to a synthesis process of 2- (2-amino-3-methoxyphenyl) chromone.
Background
2- (2-amino-3-methoxyphenyl) chromone (PD98059, 1) is a selective specific blocker participating in a Ras/Raf/ERK signaling pathway MEK1, can block the action of a downstream cell signaling protein ERK1/2, can inhibit the growth of various tumors, and particularly has better curative effect on patients with advanced melanoma by combining the 2- (2-amino-3-methoxyphenyl) chromone with sorafenib. In addition, the higher the concentration of PD98059 in breast cancer, liver cancer and gastric cancer cells, the stronger the inhibition effect on the cells. Therefore, PD98059 can play a role in effectively resisting cancers by inhibiting the activation of MAPK/ERK signaling pathway; however, by examining patents and literatures, we found that PD98059 is not only expensive but also has no direct literature reporting on its preparation method, which is not favorable for further development of PD98059 derivatives.
Disclosure of Invention
The invention provides a synthesis process of 2- (2-amino-3-methoxyphenyl) chromone, which has the advantages of simple operation, mild reaction condition, easily obtained raw materials and industrial batch production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthesis process of 2- (2-amino-3-methoxyphenyl) chromone comprises the following steps:
1) 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester as the first intermediate is synthesized by 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid for later use;
2) synthesizing a second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione by using the first intermediate obtained in the step 1) for later use;
3) synthesizing a third intermediate 2- (2-nitro-3-methoxyphenyl) chromone by using the second intermediate obtained in the step 2) for later use;
4) and synthesizing the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone to obtain the 2- (2-amino-3-methoxyphenyl) chromone.
Further, the synthesis of the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester in the step 1) comprises the following steps;
1.1) dissolving 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid in N, N-dimethylformamide, adding 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and stirring at room temperature to obtain a mixed solution;
1.2) addition of saturated NaHCO to step 1.1)3Extracting and drying the solution to obtain a crude product;
1.3) to obtain a first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester after chromatography and purification.
Further, in the step 1.1), the mass ratio of the 2-hydroxyacetophenone, the 3-methoxy-2-nitrobenzoic acid, the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine is 1:1: 1-2: 2.5-3.5;
in the step 1.1), the stirring speed is 120-150 r/min; stirring for 12-15 h;
in the step 1.2), the extracting agent is dichloromethane, and the drying agent is anhydrous Na2SO4。
Further, in the step 2), the synthesis step of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione is as follows:
2.1) adding the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester into pyridine, adding KOH, and stirring to obtain a reaction solution;
2.2) cooling the obtained reaction liquid to room temperature, adding acid liquor to adjust the pH of the reaction liquid to acidity, separating out a precipitate, washing with water, filtering, and drying a filter cake under reduced pressure to obtain a light yellow second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione solid.
Further, in the step 2.1), the mass ratio of the 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester to the pyridine to the KOH is 1: 20-30: 3.2-5.5;
in the step 2.1), the stirring temperature is 40-70 ℃, the stirring speed is 150-;
in the step 2.2), the acid solution is acetic acid, and the pH value of the reaction solution is 4.5-5.5; the drying temperature is 45-60 deg.C, and the drying time is 10-15 h.
Further, in the step 3), the synthesis of the third intermediate, namely 2- (2-nitro-3-methoxyphenyl) chromone, comprises the following steps:
3.1) adding the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione to acetic acid, then slowly adding concentrated H2SO4Heating and refluxing to react to obtain a reaction solution;
3.2) cooling the reaction liquid to room temperature, precipitating, filtering, washing, drying the filter cake under reduced pressure, and recrystallizing with ethanol to obtain a light yellow third intermediate 2- (2-nitro-3-methoxyphenyl) chromone solid.
Further, the mass ratio of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, acetic acid and concentrated sulfuric acid is 1: 80-100: 1-5;
in the step 3.1), the heating reflux time is 0.5-2 h;
in the step 3.2), the drying temperature is 45-60 ℃, and the drying time is 10-15 h.
Further, in the step 4), the synthesis of the 2- (2-amino-3-methoxyphenyl) chromone comprises the following steps:
4.1) adding the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone into ethanol, adding tin powder, heating to reflux, adding concentrated HCl, and continuing reflux reaction to obtain a reaction solution;
4.2) cooling the reaction liquid to room temperature, adding alkali liquor to adjust the pH of the reaction liquid to be alkaline, adding water, and extracting; the organic phases were combined and dried over anhydrous sodium sulfate; filtering, and removing the solvent under reduced pressure to obtain a crude product;
4.3) recrystallizing the crude product with ethanol to obtain yellow crystalline 2- (2-amino-3-methoxyphenyl) chromone solid.
Further, in the step 4.1), the mass ratio of the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone to the tin powder to the concentrated HCl is 1: 2-7: 3-9;
in the step 4.1), the heating reflux time is 0.5-2 h;
in the step 4.2), alkali liquor is NaOH and KOH; adjusting the pH value of the reaction liquid to 8.5-9.5; the extractant is ethyl acetate; the drying time is 24-30 h.
The invention has the beneficial effects that: the invention provides a synthesis method of 2- (2-amino-3-methoxyphenyl) chromone, which adopts 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid to synthesize under mild conditions to obtain the target compound 2- (2-amino-3-methoxyphenyl) chromone, and has mild reaction conditions, easily obtained raw materials and easy industrial synthesis.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 2- (2-amino-3-methoxyphenyl) chromone;
FIG. 2 is a nuclear magnetic carbon spectrum of 2- (2-amino-3-methoxyphenyl) chromone.
Detailed Description
The present invention will now be described in detail with reference to the accompanying drawings and examples.
The process route for synthesizing 2- (2-amino-3-methoxyphenyl) chromone comprises the following steps:
wherein: 1-2- (2-amino-3-methoxyphenyl) chromone; 2-hydroxyacetophenone; 3-methoxy-2-nitrobenzoic acid; 4-first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester; 5-the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione; 6-third intermediate 2- (2-nitro-3-methoxyphenyl) chromone.
Example 1
1) Synthesis of first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester
1.1) 69.0g (0.35mol) of 3-methoxy-2-nitrobenzoic acid and 47.6g (0.35mol) of 2-hydroxyacetophenone are dissolved in 0.7L (9.1mol) of DMF solution, 174.9g (0.46mol) of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate HATU and 135.7g (1.05mol) of diisopropylethylamine DIEA are added and stirred at room temperature and a speed of 150r/min for 12 hours;
1.2) after the reaction is complete, 25mL of saturated NaHCO is added3Solution, dichloromethane (3X 0.4L) extraction, anhydrous Na2SO4Drying, and evaporating to remove dichloromethane to obtain a crude product;
1.3) to obtain 119.7g of a first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester after column chromatography purification.
In this example, the purity of 3-methoxy-2-nitrobenzoic acid was 98% and was purchased from Beijing YinuoKai science and technology Co., Ltd; the purity of the 2-hydroxyacetophenone is 98%, which is purchased from Beijing YinuoKa science and technology Co., Ltd; the yield of the first intermediate, 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester, was 90.4%.
2) Synthesis of second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione
2.1) adding 88.3g (0.28mol) of the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester to 0.6L of pyridine, then adding 67.3g (1.2mol) of KOH solution, and stirring for reaction at 50 ℃ for 0.5 h; obtaining a reaction solution;
2.2) cooling the reaction solution to room temperature, adding 5% acetic acid solution to adjust the pH value to 5, precipitating and precipitating, washing with water, filtering, drying the filter cake at 50 ℃ under reduced pressure for 12h to obtain light yellow 68.7g of a second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione solid.
In this example, the yield of the second intermediate, 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, was 77.8%.
3) Synthesis of third intermediate 2- (2-nitro-3-methoxyphenyl) chromone
3.1) 66.2g (0.21mol) of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione are taken, added to 1.1L of acetic acid and then 19.2mL (0.36mol) of concentrated H are slowly added2SO4Heating and refluxing for reaction for 1 h;
3.2) cooling the reaction liquid to room temperature, precipitating, filtering, washing, drying the filter cake at 50 ℃ under reduced pressure for 12h, and recrystallizing with ethanol to obtain light yellow 41.3g of a third intermediate 2- (2-nitro-3-methoxyphenyl) chromone solid.
In this example, the yield of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, was 66.2%.
4) Synthesis of 2- (2-amino-3-methoxyphenyl) chromone
1.1) 39.6g (0.13mol) of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, were added to 1.1L of ethanol; then adding 77.2g (0.65mol) of tin powder, heating to reflux, adding 65mL (0.78mol) of concentrated HCl, and continuing reflux reaction for 1h to obtain a reaction solution;
4.2) the reaction mixture was cooled to room temperature, and 5% NaOH solution was added to adjust pH to 9, 800mL of water was added, followed by extraction with (900mL × 3) ethyl acetate; the organic phases are combined and dried for 24h by anhydrous sodium sulfate; filtering, and removing the solvent under reduced pressure to obtain a crude product;
4.3) the crude product obtained is recrystallized from ethanol to yield 28.2g of yellow crystalline 2- (2-amino-3-methoxyphenyl) chromone solid.
In this example, the yield of 2- (2-amino-3-methoxyphenyl) chromone was 81.2%.
Example 2
1) Synthesis of first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester
1.1) 78.86g (0.4mol) of 3-methoxy-2-nitrobenzoic acid and 54.4g (0.4mol) of 2-hydroxyacetophenone are dissolved in 0.77L (10mol) of DMF solution, 228.13g (0.6mol) of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate HATU and 142.48g (1mol) of N, N-diisopropylethylamine DIEA are added and stirred at room temperature and 120r/min for 15 h;
1.2) after the reaction is complete, 30mL of saturated NaHCO are added3Solution, dichloromethane (3X 0.5L) extraction, anhydrous Na2SO4Drying, and evaporating to remove dichloromethane to obtain a crude product;
1.3) through column chromatography to obtain 138.01g of a first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester.
In this example, the purity of 3-methoxy-2-nitrobenzoic acid was 98% and was purchased from Beijing YinuoKai science and technology Co., Ltd; the purity of the 2-hydroxyacetophenone is 98%, which is purchased from Beijing YinuoKa science and technology Co., Ltd; the yield of the first intermediate, 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester, was 91.2%.
2) Synthesis of second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione
2.1) 94.6g (0.3mol) of the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester were added to 0.48L of pyridine, and 53.84g (0.96mol) of KOH solution were added, followed by stirring at 70 ℃ for 25 min; obtaining a reaction solution;
2.2) the reaction solution was cooled to room temperature, 5% acetic acid solution was added to adjust pH to 5.5, and a precipitate was precipitated, washed with water, filtered, and the filter cake was dried at 60 ℃ under reduced pressure for 10 hours to obtain 72.19g of a pale yellow solid of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione.
In this example, the yield of the second intermediate, 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, was 76.3%.
3) Synthesis of third intermediate 2- (2-nitro-3-methoxyphenyl) chromone
3.1) 75.65g (0.24mol) of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione were taken, added to 1.11L of acetic acid and then 12.8mL (0.24mol) of concentrated H were slowly added2SO4Heating and refluxing for reaction for 0.5 h;
3.2) cooling the reaction liquid to room temperature, precipitating, filtering, washing, drying the filter cake at 45 ℃ under reduced pressure for 15h, and recrystallizing with ethanol to obtain 47.6g of light yellow third intermediate 2- (2-nitro-3-methoxyphenyl) chromone solid.
In this example, the yield of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, was 66.8%.
4) Synthesis of 2- (2-amino-3-methoxyphenyl) chromone
1.1) 60.9g (0.2mol) of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, was added to 1L of ethanol; then adding 47.5g (0.4mol) of tin powder, heating to reflux, adding 50mL (0.6mol) of concentrated HCl, and continuing reflux reaction for 2h to obtain a reaction solution;
4.2) the reaction mixture was cooled to room temperature, and 5% KOH solution was added to adjust the pH to 9.5, 800mL of water was added thereto, followed by extraction with ethyl acetate (900mL × 3); the organic phases are combined and dried for 30h by anhydrous sodium sulfate; filtering, and removing the solvent under reduced pressure to obtain a crude product;
4.3) the crude product obtained is recrystallized from ethanol to yield 43.59g of yellow crystalline 2- (2-amino-3-methoxyphenyl) chromone solid.
In this example, the yield of 2- (2-amino-3-methoxyphenyl) chromone was 81.6%.
Example 3
1) Synthesis of first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester
1.1) 88.7g (0.45mol) of 3-methoxy-2-nitrobenzoic acid and 61.2g (0.45mol) of 2-hydroxyacetophenone are dissolved in 0.7L (9.1mol) of DMF solution, then 342.2g (0.9mol) of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate HATU and 203.93g (1.578mol) of N, N-diisopropylethylamine DIEA are added and stirred at room temperature and at a rate of 120r/min for 15 hours;
1.2) after the reaction is complete, 40mL of saturated NaHCO is added3Solution, dichloromethane (3X 0.4L) extraction, anhydrous Na2SO4Drying, and evaporating to remove dichloromethane to obtain a crude product;
1.3) through column chromatography to obtain 152.71g of a first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester.
In this example, the purity of 3-methoxy-2-nitrobenzoic acid was 98% and was purchased from Beijing YinuoKai science and technology Co., Ltd; the purity of the 2-hydroxyacetophenone is 98%, which is purchased from Beijing YinuoKa science and technology Co., Ltd; the yield of the first intermediate, 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester, was 89.7%.
2) Synthesis of second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione
2.1) 78.84g (0.25mol) of the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester was added to 0.6L of pyridine, and 77.11g (1.375mol) of KOH solution was added, followed by stirring at 50 ℃ for 0.5 h; obtaining a reaction solution;
2.2) the reaction solution was cooled to room temperature, 5% acetic acid solution was added to adjust pH 4.5, and a precipitate was precipitated, washed with water, filtered, and the filter cake was dried at 45 ℃ under reduced pressure for 15 hours to obtain 61.81g of a pale yellow solid of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione.
In this example, the yield of the second intermediate, 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, was 78.4%.
3) Synthesis of third intermediate 2- (2-nitro-3-methoxyphenyl) chromone
3.1) 94.6g (0.3mol) of the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione are taken, added to 1.7L of acetic acid and 80mL (1.5mol) of concentrated H are then slowly added2SO4Heating and refluxing for reaction for 2 h;
3.2) cooling the reaction liquid to room temperature, precipitating, filtering, washing, drying the filter cake at 60 ℃ under reduced pressure for 10h, and recrystallizing with ethanol to obtain 59.27g of a third intermediate 2- (2-nitro-3-methoxyphenyl) chromone solid in light yellow.
In this example, the yield of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, was 66.5%.
4) Synthesis of 2- (2-amino-3-methoxyphenyl) chromone
1.1) 54.8g (0.18mol) of the third intermediate, 2- (2-nitro-3-methoxyphenyl) chromone, was added to 1.3L of ethanol; adding 149.65g (0.65mol) of tin powder, heating to reflux, adding 135mL (1.62mol) of concentrated HCl, and continuing to reflux for 0.5h to obtain a reaction solution;
4.2) the reaction mixture was cooled to room temperature, and 5% NaOH solution was added to adjust pH to 8.5, 800mL of water was added, followed by extraction with ethyl acetate (900mL × 3); the organic phases are combined and dried for 28h by anhydrous sodium sulfate; filtering, and removing the solvent under reduced pressure to obtain a crude product;
4.3) the crude product obtained is recrystallized from ethanol to yield 39.09g of yellow crystalline 2- (2-amino-3-methoxyphenyl) chromone solid.
In this example, the yield of 2- (2-amino-3-methoxyphenyl) chromone was 81.3%.
In order to verify and analyze the molecular structures of the synthesized first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester, the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone and the target product 2- (2-amino-3-methoxyphenyl) chromone, the nuclear magnetic spectrum of the 2- (2-amino-3-methoxyphenyl) chromone is analyzed.
Experimental groups: 2- (2-amino-3-methoxyphenyl) chromone prepared in example 1
The test process comprises the following steps: the 2- (2-amino-3-methoxyphenyl) chromone in the test group was analyzed by a nuclear magnetic resonance spectrometer to obtain a nuclear magnetic hydrogen spectrum and a nuclear magnetic carbon spectrum, and the results are shown in fig. 1 and fig. 2.
As a result, fig. 1 and 2 show that:
1) the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester,
1H NMR(400MHz,CDCl3):7.78-7.86(m,2H),7.52-7.61(m,2H),7.36-7.42(m,1H),7.31(t,J＝8.0Hz,1H),7.23(t,J＝8.4Hz,1H),2.53(s,3H),3.95(s,3H)；
2) a second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione,
1H NMR(400MHz,CDCl3):7.71-7.63(m,1H),7.42-7.57(m,2H),7.30-7.35(m,1H),7.21(t,J＝8.0Hz,1H),7.00-7.11(m,1H),6.86-6.95(m,1H),6.62(s,1H),3.97(s,3H)；
3) the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone,
1H NMR(400MHz,CDCl3):8.20(d,J＝8.0Hz,1H),7.65-7.80(m,1H),7.51-7.59(m,1H),7.41-7.47(m,2H),7.21-7.32(m,2H),6.60(s,1H),3.87(s,3H)；
4) compound 2- (2-amino-3-methoxyphenyl) chromone:
1H NMR(400MHz,DMSO-d6)δ:8.02-8.08(m,1H),7.80-7.84(m,1H),7.67-7.71(m,1H),7.52(t,J＝7.6Hz,1H),7.08(d,J＝7.6Hz,1H),6.99(d,J＝8.0Hz,1H),6.70(t,J＝8.0Hz,1H),6.57(s,1H),5.32(s,2H),3.86(s,3H)；13C NMR(100MHz,DMSO-d6)δ:177.42,165.10,156.51,147.46,137.23,134.40,125.76,125.11,123.86,121.57,119.08,116.51,115.87,112.81,110.34,56.32。
as can be seen from the comparison result of the hydrogen spectrum and the carbon spectrum, the preparation method can obtain the 2- (2-amino-3-methoxyphenyl) chromone compound, has mild reaction conditions in the preparation process, easily obtained raw materials and can meet the requirement of industrialization.
In order to verify the solubility test of the prepared 2- (2-amino-3-methoxyphenyl) chromone compound.
The solubility of the 2- (2-amino-3-methoxyphenyl) chromone compound prepared in example 2 was observed by placing it in methanol, Dimethylsulfoxide (DMSO), and water, respectively, and from the observation results, it was found that the 2- (2-amino-3-methoxyphenyl) chromone compound prepared in the present invention was dissolved in methanol and Dimethylsulfoxide (DMSO) and was not dissolved in water.
Claims (9)
1. A synthesis process of 2- (2-amino-3-methoxyphenyl) chromone is characterized by comprising the following steps:
1) 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester as the first intermediate is synthesized by 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid for later use;
2) synthesizing a second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione by using the first intermediate obtained in the step 1) for later use;
3) synthesizing a third intermediate 2- (2-nitro-3-methoxyphenyl) chromone by using the second intermediate obtained in the step 2) for later use;
4) and synthesizing the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone to obtain the 2- (2-amino-3-methoxyphenyl) chromone.
2. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 1, wherein the synthesis of the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester in the step 1) comprises the following steps;
1.1) dissolving 2-hydroxyacetophenone and 3-methoxy-2-nitrobenzoic acid in N, N-dimethylformamide, adding 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and stirring at room temperature to obtain a mixed solution;
1.2) addition of saturated NaHCO to step 1.1)3Extracting and drying the solution to obtain a crude product;
1.3) to obtain a first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester after chromatography and purification.
3. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 2, wherein in the step 1.1), the mass ratio of 2-hydroxyacetophenone, 3-methoxy-2-nitrobenzoic acid, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate and N, N-diisopropylethylamine is 1:1: 1-2: 2.5-3.5;
in the step 1.1), the stirring speed is 120-150 r/min; stirring for 12-15 h;
in the step 1.2), the extracting agent is dichloromethane, and the drying agent is anhydrous Na2SO4。
4. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 1, wherein in the step 2), the step for synthesizing the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione is:
2.1) adding the first intermediate 2-nitro-3-methoxybenzoic acid-2- (acetyl) phenyl ester into pyridine, adding KOH, and stirring to obtain a reaction solution;
2.2) cooling the obtained reaction liquid to room temperature, adding acid liquor to adjust the pH of the reaction liquid to acidity, separating out a precipitate, washing with water, filtering, and drying a filter cake under reduced pressure to obtain a light yellow second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione solid.
5. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 4, wherein in the step 2.1), the mass ratio of 2- (acetyl) phenyl 2-nitro-3-methoxybenzoate to pyridine to KOH is 1: 20-30: 3.2-5.5;
in the step 2.1), the stirring temperature is 40-70 ℃, the stirring speed is 150-;
in the step 2.2), the acid solution is acetic acid, and the pH value of the reaction solution is 4.5-5.5; the drying temperature is 45-60 deg.C, and the drying time is 10-15 h.
6. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 1, wherein in the step 3), the step for synthesizing the third intermediate, namely, 2- (2-nitro-3-methoxyphenyl) chromone, comprises the following steps:
3.1) adding the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione to acetic acid, then slowly adding concentrated H2SO4Heating ofCarrying out reflux reaction to obtain a reaction solution;
3.2) cooling the reaction liquid to room temperature, precipitating, filtering, washing, drying the filter cake under reduced pressure, and recrystallizing with ethanol to obtain a light yellow third intermediate 2- (2-nitro-3-methoxyphenyl) chromone solid.
7. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 6, wherein in the step 3.1), the second intermediate 1- (2-nitro-3-methoxyphenyl) -3- (2-hydroxyphenyl) -1, 3-propanedione, acetic acid and concentrated H2SO4The mass ratio of (A) to (B) is 1: 80-100: 1-5;
in the step 3.1), the heating reflux time is 0.5-2 h;
in the step 3.2), the drying temperature is 45-60 ℃, and the drying time is 10-15 h.
8. The process for synthesizing 2- (2-amino-3-methoxyphenyl) chromone according to claim 1, wherein in the step 4), the step of synthesizing 2- (2-amino-3-methoxyphenyl) chromone comprises the following steps:
4.1) adding the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone into ethanol, adding tin powder, heating to reflux, adding concentrated HCl, and continuing reflux reaction to obtain a reaction solution;
4.2) cooling the reaction liquid to room temperature, adding alkali liquor to adjust the pH of the reaction liquid to be alkaline, adding water, and extracting; the organic phases were combined and dried over anhydrous sodium sulfate; filtering, and removing the solvent under reduced pressure to obtain a crude product;
4.3) recrystallizing the crude product with ethanol to obtain yellow crystalline 2- (2-amino-3-methoxyphenyl) chromone solid.
9. The synthesis process of 2- (2-amino-3-methoxyphenyl) chromone according to claim 8, wherein in the step 4.1), the mass ratio of the third intermediate 2- (2-nitro-3-methoxyphenyl) chromone to the tin powder to the concentrated HCl is 1: 2-7: 3-9;
in the step 4.1), the heating reflux time is 0.5-2 h;
in the step 4.2), alkali liquor is NaOH and KOH; adjusting the pH value of the reaction liquid to 8.5-9.5; the extractant is ethyl acetate; the drying time is 24-30 h.
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| WO1997045412A1 (en) * | 1996-05-30 | 1997-12-04 | Merck & Co., Inc. | A method of treating cancer |
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| WO1997045412A1 (en) * | 1996-05-30 | 1997-12-04 | Merck & Co., Inc. | A method of treating cancer |
| CN101400659A (en) * | 2006-03-14 | 2009-04-01 | 参天制药株式会社 | Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity |
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