CN116444514A - Preparation method of apigenin Sha Banyi esterified product - Google Patents
Preparation method of apigenin Sha Banyi esterified product Download PDFInfo
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- CN116444514A CN116444514A CN202210008948.6A CN202210008948A CN116444514A CN 116444514 A CN116444514 A CN 116444514A CN 202210008948 A CN202210008948 A CN 202210008948A CN 116444514 A CN116444514 A CN 116444514A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229940117893 apigenin Drugs 0.000 title claims abstract description 11
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 235000008714 apigenin Nutrition 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000004694 iodide salts Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910001619 alkaline earth metal iodide Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 6
- 229960003886 apixaban Drugs 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 2
- -1 ethyl [ (4-methoxyphenyl) hydrazino ] chloroacetate Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229910001511 metal iodide Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of an apigenin Sha Banyi esterified compound. The invention firstly reacts the compound of formula (1) with the compound of formula (2) in inorganic alkali, iodide and non-hydrophilic organic solvent, and then reacts with acid to obtain the apigenin Sha Banyi esterified compound. The preparation method obviously improves the yield, reduces the reaction time, has simple post-treatment and is very suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of an apigenin Sha Banyi esterified compound, belonging to the field of pharmaceutical chemicals.
Background
Apixaban is a novel factor Xa direct inhibitor and can be used for preventing and treating thrombus. Apixaban has the structural formula shown below:
the apixaban Sha Banyi esterified compound is a key intermediate for synthesizing apixaban, and the structure is shown as the following formula:
patent document WO2014108919 reports that 5, 6-dihydro-3- (4-morpholino) -1- [4- (2-oxo-1-piperidinyl) phenyl ] -2 (1H) -pyridone represented by formula (1) is reacted with ethyl [ (4-methoxyphenyl) hydrazino ] chloroacetate represented by formula (2) under the conditions of sodium carbonate, acetone, etc. to give an apine Sha Banyi ester, the synthetic route of which is shown below:
the repeated experiment process of the method reported by the patent finds that the process is unstable, the product yield is generally lower than 60%, the purity is lower than 97%, and the post-treatment is complex, so that the method is not beneficial to industrial mass production.
Patent document CN101967145 reports a method for preparing an apigenin Sha Banyi ester from formula (1) and formula (2) under the condition of organic base and metal iodide, and the synthetic route is as follows:
the repeated experiment process of the method reported by the patent generally requires more than 20 hours, and the product yield is generally lower than 80 percent, which is unfavorable for industrial mass production.
Disclosure of Invention
The invention aims to provide a preparation method of an apigenin Sha Banyi esterified compound with high yield, high purity and short reaction time.
The invention provides a preparation method of an apigenin Sha Banyi esterified compound, which has the following reaction formula:
1) Reacting a compound of formula (1) with a compound of formula (2) in an inorganic base, iodide and a non-hydrophilic organic solvent;
2) After the reaction of step 1), the reaction mixture was reacted with an acid to obtain an ester of apigenin Sha Banyi.
In the present invention, the inorganic base may be hydroxide, carbonate, bicarbonate, acetate of alkali metal and alkaline earth metal, preferably carbonate, and more preferably sodium carbonate.
In the present invention, the iodides may be organic iodides, alkali metal iodides and alkaline earth metal iodides, preferably tetrabutylammonium iodide and potassium iodide.
In the present invention, the non-hydrophilic organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, toluene, ethyl acetate, 2-methyltetrahydrofuran, and the like, and a mixed solvent thereof, preferably tetrahydrofuran and ethyl acetate.
In the present invention, the molar ratio of the iodide to the formula (1) is 0.05 to 2.0, preferably 0.1 to 1.0, and more preferably 0.1 to 0.5.
In the present invention, the molar ratio of the inorganic base to the formula (1) is 1.0 to 10.0, preferably 1.0 to 4.0, and more preferably 1.5 to 3.5.
In the present invention, the molar ratio of the compound represented by the formula (2) to the compound represented by the formula (1) is 1.0 to 2.0, preferably 1.05 to 1.4; the mass ratio of the non-hydrophilic organic solvent to the formula (1) is 3 to 30, preferably 8 to 15.
In the present invention, the reaction temperature is 50 to 110 ℃, preferably 60 to 100 ℃; the reaction time is 5 to 12 hours, preferably 5 to 10 hours.
In the present invention, the acid may be an inorganic acid or an organic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and more preferably hydrochloric acid.
In the present invention, the molar ratio of the acid to the compound of formula (1) is 2.0 to 12.0, preferably 3.0 to 6.0.
In the invention, the step 2) of acid adding reaction further comprises the following steps: cooling, filtering and drying; or distilling, pulping with water, and recrystallizing.
The invention provides a preparation method of apixaban Sha Banyi esterified compound, which remarkably improves the yield of apixaban esterified compound, and has the advantages of stable process, short reaction time, less impurities, simple post-treatment and suitability for industrial production.
Detailed Description
The technical scheme of the present invention and the technical effects thereof will be further described with reference to examples below to fully understand the objects, technical features and effects of the present invention.
Example 1:
at room temperature, 10g of formula (1), 10g of formula (2), 10g of sodium carbonate and 1g of potassium iodide are sequentially put into a four-port reaction bottle, 100g of ethyl acetate is added, then the reaction bottle is heated to 70-80 ℃ for reaction for 5 hours, the temperature is reduced to 0-10 ℃, 90mL of 2N diluted hydrochloric acid is dripped, the temperature is raised to 20-30 ℃ for stirring for 1 hour, the temperature is cooled to 0-10 ℃, the temperature is kept for stirring for 2 hours, filtration is carried out, and a filter cake is leached by a small amount of ethyl acetate and dried to obtain a target product, namely light yellow solid. Yield: 87.1% and 97.4% HPLC purity.
Example 2:
at room temperature, 10g of formula (1), 10g of formula (2), 10g of sodium carbonate and 2g of tetrabutylammonium iodide are sequentially put into a four-port reaction bottle, 100g of tetrahydrofuran is added, then the reaction bottle is heated to 70-80 ℃ for reaction for 8 hours, the temperature is reduced to 0-10 ℃, 90mL of 2N diluted hydrochloric acid is dripped, the temperature is raised to 20-30 ℃ for stirring for 1 hour, the temperature is cooled to 0-10 ℃, 20mL of water is added, the temperature is kept for stirring for 2 hours, the filtration is carried out, a filter cake is leached by a small amount of tetrahydrofuran, and the target product is obtained after drying, namely light yellow solid. Yield: 90.1% and 98.0% HPLC purity.
Example 3:
at room temperature, sequentially adding 10g of formula (1), 9g of formula (2), 10g of sodium carbonate and 1g of potassium iodide into a four-port reaction bottle, adding 100g of tetrahydrofuran, heating the reaction bottle to 60-70 ℃, reacting for 6 hours, cooling to 0-10 ℃, dropwise adding 90mL of 2N diluted hydrochloric acid, heating to 20-30 ℃, stirring for 1 hour, distilling to remove tetrahydrofuran, adding 100g of water, pulping, filtering, recrystallizing a filter cake with toluene, and drying to obtain a target product, namely a pale yellow solid. Yield: 86.2% and HPLC purity of 98.3%.
Example 4:
at room temperature, sequentially adding 10g of formula (1), 8.3g of formula (2), 5g of sodium carbonate and 1.5g of potassium iodide into a four-port reaction bottle, adding 100g of ethyl acetate, heating the reaction bottle to 80-90 ℃, reacting for 10 hours, cooling to 0-10 ℃, dropwise adding 90mL of 2N diluted hydrochloric acid, heating to 20-30 ℃, stirring for 1 hour, filtering, leaching a filter cake with a small amount of ethyl acetate, and drying to obtain a target product, namely light yellow solid. Yield: 86.8% and 97.6% HPLC purity.
Comparative example 1
10g of formula (1), 11g of formula (2) and 9g of sodium carbonate were added to a four-necked flask at room temperature, 50mL of acetone was added, the reaction was allowed to react at 50℃for 3 hours, cooled to 25℃and 50mL of diluted hydrochloric acid (15 mL of purified hydrochloric acid+35 mL of water) was added, followed by stirring for 2 hours, 30mL of water was added, and stirring was performed for 0.5 hour. Filtering and drying. The filter cake was recrystallized from 50mL of toluene, filtered, dried, 8g of product was obtained in 58.4% yield and 94.2% HPLC purity.
Claims (11)
1. A method for preparing an apigenin Sha Banyi esterified compound, which has the following reaction formula:
1) Reacting a compound of formula (1) with a compound of formula (2) in an inorganic base, iodide and a non-hydrophilic organic solvent;
2) After the reaction of step 1), the reaction mixture was reacted with an acid to obtain an ester of apigenin Sha Banyi.
2. The preparation method according to claim 1, characterized in that the inorganic base is an alkali metal and alkaline earth metal hydroxide, carbonate, bicarbonate, acetate, preferably carbonate, further preferably sodium carbonate.
3. The preparation method according to claim 1, wherein the iodide is selected from the group consisting of organic iodides, alkali metal iodides and alkaline earth metal iodides, preferably tetrabutylammonium iodide and potassium iodide.
4. The preparation method according to claim 1, wherein the non-hydrophilic organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, toluene, ethyl acetate, 2-methyltetrahydrofuran and mixed solvents thereof, preferably tetrahydrofuran and ethyl acetate.
5. The process according to claim 1, characterized in that the molar ratio of iodide to formula (1) is 0.05 to 2.0, preferably 0.1 to 1.0, more preferably 0.1 to 0.5.
6. The process according to claim 1, characterized in that the molar ratio of the inorganic base to formula (1) is 1.0 to 10.0, preferably 1.0 to 4.0, further preferably 1.5 to 3.5.
7. The production method according to claim 1, characterized in that the molar ratio of the compound represented by formula (2) to the compound represented by formula (1) is 1.0 to 2.0, preferably 1.05 to 1.4; the mass ratio of the non-hydrophilic organic solvent to the formula (1) is 3 to 30, preferably 8 to 15.
8. Preparation method according to claim 1, characterized in that the reaction temperature is 50-110 ℃, preferably 60-100 ℃; the reaction time is 5 to 12 hours, preferably 5 to 10 hours.
9. The preparation method according to claim 1, characterized in that the acid may be an inorganic or organic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, further preferably hydrochloric acid.
10. The process according to claim 1, characterized in that the molar ratio of acid to compound of formula (1) is 2.0 to 12.0, preferably 3.0 to 6.0.
11. The preparation method according to claim 1, wherein the acid addition reaction in the step 2) further comprises the following steps: cooling, filtering and drying; or distilling, pulping with water, and recrystallizing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210008948.6A CN116444514A (en) | 2022-01-05 | 2022-01-05 | Preparation method of apigenin Sha Banyi esterified product |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210008948.6A CN116444514A (en) | 2022-01-05 | 2022-01-05 | Preparation method of apigenin Sha Banyi esterified product |
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| CN116444514A true CN116444514A (en) | 2023-07-18 |
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| CN202210008948.6A Pending CN116444514A (en) | 2022-01-05 | 2022-01-05 | Preparation method of apigenin Sha Banyi esterified product |
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- 2022-01-05 CN CN202210008948.6A patent/CN116444514A/en active Pending
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