CN118459338A - Preparation method of bevacizidine acid impurity - Google Patents
Preparation method of bevacizidine acid impurity Download PDFInfo
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- CN118459338A CN118459338A CN202410583896.4A CN202410583896A CN118459338A CN 118459338 A CN118459338 A CN 118459338A CN 202410583896 A CN202410583896 A CN 202410583896A CN 118459338 A CN118459338 A CN 118459338A
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- 239000012535 impurity Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002253 acid Substances 0.000 title abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000000126 substance Substances 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 238000006467 substitution reaction Methods 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 33
- 239000007788 liquid Substances 0.000 claims description 12
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 claims description 9
- 238000005917 acylation reaction Methods 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
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- 238000006243 chemical reaction Methods 0.000 abstract description 50
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 8
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- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
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- 238000012544 monitoring process Methods 0.000 description 6
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- 102000000853 LDL receptors Human genes 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- -1 2408132-01-2 Chemical compound 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000012512 characterization method Methods 0.000 description 2
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- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
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- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MKBBSFGKFMQPPC-UHFFFAOYSA-N 2-propyl-1h-imidazole Chemical compound CCCC1=NC=CN1 MKBBSFGKFMQPPC-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229950002974 bempedoic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 238000011112 process operation Methods 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical class [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of bevacizidine acid, and discloses a preparation method of bevacizidine acid impurities, which comprises the following steps: substitution reaction of bevacizidine with a substance having a structure represented by formula (1) in the presence of a first solvent; wherein R 1、R2、R3 is each independently selected from H, C-C5 alkyl. The method for preparing the bevacizidine acid impurity has the advantages of simplicity in operation, safety, environment friendliness, mild reaction conditions, high yield and the like, and can realize the large-scale production of the bevacizidine acid impurity, so that an impurity standard substance is provided for the development of bevacizidine acid medicines.
Description
Technical Field
The invention relates to the technical field of bevacizidine acid, in particular to a preparation method of bevacizidine acid impurities.
Background
Beeperide (Bempedoic Acid), also known as ETC-1002, is a Low Density Lipoprotein Receptor (LDLR) modulator. It can reduce synthesis of cholesterol by inhibiting cholesterol synthase HMG-CoA reductase, thereby reducing degradation of LDLR, increasing expression of LDLR, promoting removal of cholesterol, and reducing blood lipid level. ETC-1002 is commonly used to lower low density lipoprotein cholesterol (LDL-C) levels and control hyperlipidemia. The preparation can be used as a single therapeutic drug or can be combined with statin drugs (such as atorvastatin) to play a role in synergistically reducing blood fat.
In the process of drug development, the research of impurities is an important link, a certain amount of impurity standard substances are needed for establishing quality standards, and in order to obtain enough impurity standard substances, the development of an impurity directional synthesis method is an important task of drug development.
The chemical name of bevacizidine acid is 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid.
W02004067489 discloses a synthesis method of bevacizidine and analogues thereof: under the conditions of low temperature and no water and oxygen, ethyl isobutyrate and 1, 5-di-Australian pentane are subjected to condensation reaction under the action of organic metal alkali to obtain 7 carbon chain compounds; the intermediate and p-toluenesulfonyl methyl isonitrile are catalyzed by strong alkalinity and tetrabutylammonium iodide to prepare a p-toluenesulfonyl methyl isonitrile addition product; the adduct is subjected to ester hydrolysis and carbonyl reduction in sequence to finally obtain the target product bevacizidine.
The impurities of bepidic acid have various structures, and the common impurities are ACS No.: 2511500-14-2, 2127387-65-7, 738606-64-9, 2408132-01-2, 413624-71-2, and the like.
The synthesis route of the bevacizidine is longer, the byproducts of the intermediate are more, the process operation is complicated, the production cost is high, the three wastes are more, the impurities of the bevacizidine are more, and the bevacizidine is difficult to separate. Separating the bevacizidine impurities from the mother liquor is a very difficult task. In order to ensure that research and inspection work of related substances in the development of the bevacizumab medicament is smoothly advanced, a preparation method and process of the bevacizumab impurity, which are low in cost, high in yield, safe, environment-friendly, simple to operate and capable of being used for industrial production, are important tasks for research of technicians in the field.
Disclosure of Invention
The invention aims to overcome the technical problems in the prior art and provide a preparation method of the bevacizidine acid impurity.
In order to achieve the above object, the present invention provides a method for preparing a bevacizidine impurity having a structure represented by formula (3), the method comprising: substitution reaction of bevacizidine with a substance having a structure represented by formula (1) in the presence of a first solvent;
Wherein R 1、R2、R3 is each independently selected from H, C-C5 alkyl.
Through the technical scheme, the invention has the following beneficial effects:
The method for preparing the bevacizidine acid impurity has the advantages of simplicity in operation, safety, environment friendliness, mild reaction conditions, high yield and the like, and can realize the large-scale production of the bevacizidine acid impurity, so that an impurity standard substance is provided for the development of bevacizidine acid medicines.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The present invention provides a method for preparing bevacizidine impurities having a structure represented by formula (3), the method comprising: substitution reaction of bevacizidine with a substance having a structure represented by formula (1) in the presence of a first solvent;
Wherein R 1、R2、R3 is each independently selected from H, C-C5 alkyl.
In the present invention, the C1-C5 alkyl group may be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like.
According to the present invention, it is preferable that the substance having the structure represented by formula (1) is acetylimidazole, that is, R 1、R2、R3 in the structure represented by formula (1) is H.
According to the present invention, in order to further improve the yield of the reaction and the purity of the product, it is preferable that the mole ratio of the bepric acid to the substance having the structure represented by formula (1) is 1:0.7-1.5 (e.g., can be 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, and ranges consisting of any two of the foregoing).
According to the present invention, in order to further improve the yield of the reaction and the purity of the product, preferably, the conditions of the substitution reaction include: the temperature is 40-75 ℃ and the time is 1-24h. Further preferably, the substitution reaction conditions include, in combination, product yield, energy consumption and time consumption: the temperature is 65-75 ℃ and the time is 3-5h. Although the reduction of the reaction temperature can save energy consumption, the reaction time is prolonged, and therefore, the conditions for the substitution reaction are limited to the above-described further preferable range, and higher economic benefits can be obtained.
According to the present invention, the amount of the first solvent may be selected within a wide range as long as the raw materials can be sufficiently reacted in the solvent, and preferably, the amount of the first solvent is 700 to 2300mL per mole of bevacizidine.
According to the present invention, preferably, the first solvent is ethyl acetate and/or isopropyl acetate.
According to the present invention, preferably, the method further comprises: after the substitution reaction is finished, the reaction liquid obtained by the substitution reaction is extracted and purified.
The extraction mode in the invention can be an extraction mode commonly used in the field, and the extractant adopted in the extraction process is an inorganic acid aqueous solution (such as hydrochloric acid aqueous solution). The concentration of the inorganic acid is not particularly limited, and preferably the concentration of the inorganic acid is 3 to 10%.
According to the present invention, preferably, the inorganic acid is used in an amount of 1100 to 2200mL per mole of bevacizidine.
The purification means in the present invention may be purification means commonly used in the art, such as column chromatography purification and the like. The column chromatography purification can be carried out by adopting ethyl acetate and petroleum ether as eluent. The ratio of ethyl acetate to petroleum ether in the eluent can be selected within a wide range, preferably the volume ratio of ethyl acetate to petroleum ether is 1:4-6. More preferably, the packing in the chromatographic column used for the column chromatography purification is 200-300 mesh silica gel.
According to the present invention, the substance having the structure represented by formula (1) may be obtained by purchase or may be prepared by itself, and preferably, the preparation method of the substance having the structure represented by formula (1) includes: acylating acetic anhydride with a substance having a structure represented by formula (2) in the presence of an optional second solvent;
Wherein R 1、R2、R3 is as defined in claim 1.
According to the present invention, preferably, the conditions of the acylation reaction include: the temperature is 20-30 ℃ and the time is 6-8h.
According to the present invention, preferably, the molar ratio of the acetic anhydride to the substance having the structure represented by formula (2) is 1:0.5-1.1.
According to the present invention, preferably, the second solvent is ethyl acetate and/or isopropyl acetate.
According to the present invention, it is preferable that the second solvent is used in an amount of 700 to 2300mL per mole of acetic anhydride.
According to the present invention, preferably, the preparation method of the substance having the structure represented by formula (1) further comprises: after the acylation reaction is finished, the reaction liquid obtained by the acylation reaction is contacted with inorganic base, then liquid is obtained by solid-liquid separation, and then the liquid is concentrated.
According to the present invention, preferably, the inorganic base comprises an alkali metal carbonate and/or an alkali metal bicarbonate, more preferably potassium carbonate and/or sodium carbonate.
According to the present invention, it is preferable that the inorganic base is used in an amount of 0.5 to 1.5mol per mol of acetic anhydride.
According to the present invention, the concentration method is preferably not particularly limited as long as the solvent in the liquid can be removed.
According to a particularly preferred embodiment of the present invention, the synthetic route for the preparation of the bevacizidine impurity according to the present invention is as follows:
wherein EA represents ethyl acetate and BP represents bevacizidine.
According to a particularly preferred embodiment of the present invention, the process for preparing bevacizidine impurities having the structure represented by formula (3) according to the present invention comprises the steps of:
(1) Acetic anhydride, imidazole and ethyl acetate are sequentially added into a reaction bottle, the reaction is carried out under stirring and room temperature, TLC is used for monitoring the reaction progress in the reaction process, the reaction is finished after 7-7.5 hours, then potassium carbonate is added into the reaction bottle, stirring is carried out for 1-1.2 hours, filtration is carried out, filtrate is collected, and the filtrate is concentrated to obtain 1-acetylimidazole (white solid). Wherein, the dosage of imidazole is 0.1-0.15mol, the dosage of ethyl acetate is 160-165mL, and the dosage of potassium carbonate is 0.1-0.105mol relative to 0.1mol of acetic anhydride.
(2) Adding the 1-acetylimidazole obtained in the step (1) into a reaction bottle, adding bevacizidine and ethyl acetate, heating to 65-70 ℃ for reaction, monitoring the reaction progress by using TLC in the reaction process, wherein no raw materials remain, ending the reaction after 5-5.5h, adding dilute hydrochloric acid into the reaction bottle, extracting and separating liquid, concentrating the obtained organic phase, and using ethyl acetate: petroleum ether = 1:5-5.5, and purifying by column chromatography (200-300 mesh silica gel) as eluent to obtain the bevacizidine impurity (colorless oily substance) having the structure shown in formula (3). Wherein, the dosage of the bevacizidine acid is 0.1-0.12mol relative to 0.1mol of 1-acetylimidazole, the dosage of the ethyl acetate is 200-220mL, and the dosage of the dilute hydrochloric acid is 150-160mL.
The present invention will be described in detail by examples. In the following examples of the present invention,
Room temperature is about 20-30deg.C;
the concentration of the dilute hydrochloric acid is 5wt%;
the purity of the bevacizidine impurities was tested by high performance liquid chromatography HPLC.
Example 1
(1) 0.1Mol of acetic anhydride, 0.1mol of imidazole and 160mL of ethyl acetate are sequentially added into a reaction bottle, the reaction is carried out under stirring and at room temperature, TLC is used for monitoring the reaction progress degree in the reaction process, the reaction is finished after 7 hours, then 0.105mol of potassium carbonate is added into the reaction bottle, the stirring is carried out for 1 hour, the filtration is carried out, the filtrate is collected, and the filtrate is concentrated to obtain 1-acetylimidazole (white solid).
(2) Adding 0.1mol of 1-acetylimidazole obtained in the step (1) into a reaction bottle, adding 0.1mol of bevacizidine and 200mL of ethyl acetate, heating to 65 ℃ to perform a reaction, monitoring the reaction progress by using TLC in the reaction process, stopping the reaction after 5 hours, adding 150mL of dilute hydrochloric acid into the reaction bottle, extracting and separating liquid, concentrating the obtained organic phase, and using ethyl acetate: petroleum ether = 1:5, column chromatography (200-300 mesh silica gel) purification was performed as an eluent to obtain the bevacizidine impurity (colorless oil) having the structure represented by formula (3) in a yield of 84.5% and a purity of 99.2%.
Example 2
(1) 0.1Mol of acetic anhydride, 0.09mol of imidazole and 200mL of ethyl acetate are sequentially added into a reaction bottle, the reaction is carried out under stirring and at room temperature, TLC is used for monitoring the reaction progress during the reaction, the reaction is finished after 8 hours, then 0.105mol of potassium carbonate is added into the reaction bottle, the stirring is carried out for 1 hour, the filtration is carried out, the filtrate is collected, and the filtrate is concentrated to obtain 1-acetylimidazole (white solid).
(2) Adding 0.12mol of 1-acetylimidazole obtained in the step (1) into a reaction bottle, adding 0.1mol of bevacizidine and 200mL of ethyl acetate, heating to 75 ℃ to perform a reaction, monitoring the reaction progress by using TLC (thin layer chromatography) in the reaction process, finishing the reaction after 5 hours, adding 150mL of dilute hydrochloric acid into the reaction bottle, extracting and separating liquid, concentrating the obtained organic phase, and using ethyl acetate: petroleum ether = 1:6, column chromatography (200-300 mesh silica gel) purification was performed as an eluent to obtain the bevacizidine impurity (colorless oil) having the structure represented by formula (3) in a yield of 83.5% and a purity of 98.7%.
Example 3
The procedure of example 1 was followed except that in step (2), the reaction solvent ethyl acetate was replaced with an equal volume of isopropyl acetate. The yield of the bevacizidine impurity having the structure of formula (3) was 81.7% and the purity was 99.0%.
Example 4
The procedure of example 1 was followed, except that in step (2), the temperature of the reaction was 60 ℃. The yield of the bevacizidine impurity having the structure of formula (3) was 81.5% and the purity was 97.9%.
Example 5
The procedure of example 1 was followed, except that in step (2), the eluent "ethyl acetate: petroleum ether = 1:5 "replace with" ethyl acetate: petroleum ether = 1:7". The yield of the bevacizidine impurity having the structure of formula (3) was 80.5% and the purity was 96.8%.
Example 6
The procedure of example 1 was followed, except that in step (2), the eluent "ethyl acetate: petroleum ether = 1:5 "replace with" ethyl acetate: n-heptane=1: 6". The yield of the bevacizidine impurity having the structure of formula (3) was 81.1% and the purity was 98.6%. Meanwhile, after n-heptane is replaced by n-hexane, the yield and purity of the bevacizidine impurity are equivalent to those when n-heptane is used.
Example 7
The procedure of example 1 was followed, except that in step (1), imidazole was replaced with equimolar 2-propylimidazole. The yield of the bevacizidine impurity having the structure shown in formula (3) was 85.8% and the purity was 96.9%.
Comparative example 1
The bevacizidine impurity of the structure shown in formula (3) is prepared according to the following process:
(1) To the reaction flask was added acetic acid (2.00 g,33.30 mmol), N, N-Dimethylformamide (DMF) 50ml, CDI (N, N' -carbonyldiimidazole, 6.48g,39.97 mmol) was added and stirred at room temperature for 2 hours, bevacizidine (11.47 g,33.39 mmol) was added, the reaction was carried out at a temperature of 50℃overnight, and the concentration of the bevacizidine impurity having the structure represented by formula (3) was 38.56% and the other unknown impurity content was 54.39% by sampling and control.
(2) To the reaction flask was added water (100 ml), ethyl acetate (100 ml), stirred, separated, the aqueous phase was extracted with ethyl acetate (50 ml), the organic phases were combined and concentrated to a colorless oil, using ethyl acetate: petroleum ether = 1:6, purifying by column chromatography (200-300 mesh silica gel) as eluent, and separating to obtain single product, wherein the yield is 10.8% and the purity is 95.2%.
The inventors have further found that the unknown impurity has a polarity similar to that of the bevacizidine impurity having the structure represented by formula (3), separation is difficult, and that the formation of the unknown impurity is related to the presence of CDI.
Comparative example 2
The bevacizidine impurity of the structure shown in formula (3) is prepared according to the following process:
(1) To the reaction flask was added bevacizidine (5.0 g,14.51 mmol), methylene chloride (50 ml), triethylamine (1.76 g,17.42 mmol) was cooled to 0-10 ℃, acetyl chloride (1.2 g,15.24 mmol) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature for 5 hours, and the reaction was carried out with sampling and control (no bevacizidine impurity having the structure represented by formula (3)) as a waste liquid treatment.
Comparative example 3
In the preparation process of the bevacizidine acid, the bevacizidine acid impurity with the structure shown in the formula (3) is generated by transesterification reaction of the bevacizidine acid and ethyl acetate which is a solvent in the refining process, and the bevacizidine acid impurity with the structure shown in the formula (3) is prepared according to the following process:
(1) The reaction flask was charged with bevacizidine acid (5.0 g,14.51 mmol), ethyl acetate (50 ml), and the mixture was stirred and reacted at 60 to 70℃for 96 hours, and the concentration of the bevacizidine acid impurity in the structure represented by formula (3) was controlled by sampling (the content of the bevacizidine acid impurity was only 4%), and the reaction flask was treated as a waste liquid because the amount of the product formed was small.
Nuclear magnetic characterization ：1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),4.79–4.69(m,1H),1.98(s,3H),1.48–1.38(m,8H),1.26–1.14(m,12H),1.11–1.02(m,12H). of the colorless oil obtained in step (2) of example 1 can obtain colorless oil as bevacizidine impurity having the structure shown in formula (3) through nuclear magnetic analysis. The nuclear magnetic resonance spectrum characterization of the colorless oil obtained in step (2) of examples 2-7 is the same as that of example 1, and is not described here.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. A process for preparing a bevacizidine impurity having a structure represented by formula (3), which comprises: substitution reaction of bevacizidine with a substance having a structure represented by formula (1) in the presence of a first solvent;
Wherein each R 1、R2、R3 is independently selected from the group consisting of alkyl groups of H, C 1-C5.
2. The method according to claim 1, wherein the substance having a structure represented by formula (1) is acetylimidazole;
and/or the mole ratio of the bevacizidine to the substance with the structure shown in the formula (1) is 1:0.7-1.5.
3. The method of claim 1, wherein the substitution reaction conditions comprise: the temperature is 65-75 ℃ and the time is 3-5h.
4. The method of claim 1, wherein the first solvent is used in an amount of 700-2300mL per mole of bevacizidine;
And/or the first solvent is ethyl acetate and/or isopropyl acetate.
5. The method of claim 1, wherein the method further comprises: after the substitution reaction is finished, the reaction liquid obtained by the substitution reaction is extracted and purified.
6. The method according to claim 1, wherein the preparation method of the substance having the structure represented by formula (1) comprises: acylating acetic anhydride with a substance having a structure represented by formula (2) in the presence of an optional second solvent;
Wherein R 1、R2、R3 is as defined in claim 1.
7. The method of claim 6, wherein the acylation reaction conditions comprise: the temperature is 20-30 ℃ and the time is 6-8h.
8. The method according to claim 6, wherein the molar ratio of the acetic anhydride to the substance having the structure represented by formula (2) is 1:0.5-1.1.
9. The method of claim 6, wherein the second solvent is ethyl acetate and/or isopropyl acetate;
And/or the second solvent is used in an amount of 700 to 2300mL per mole of acetic anhydride.
10. The method according to claim 6, wherein the method for producing the substance having the structure represented by formula (1) further comprises: after the acylation reaction is finished, the reaction liquid obtained by the acylation reaction is contacted with inorganic base, then liquid is obtained by solid-liquid separation, and then the liquid is concentrated.
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