CN115073483A - Preparation method of enantiomer of irinotecan - Google Patents
Preparation method of enantiomer of irinotecan Download PDFInfo
- Publication number
- CN115073483A CN115073483A CN202210888605.3A CN202210888605A CN115073483A CN 115073483 A CN115073483 A CN 115073483A CN 202210888605 A CN202210888605 A CN 202210888605A CN 115073483 A CN115073483 A CN 115073483A
- Authority
- CN
- China
- Prior art keywords
- irinotecan
- enantiomer
- preparation
- esterification
- esterification product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of an enantiomer of irinotecan, and relates to the technical field of chemical pharmacy. The enantiomer of the irinotecan is an impurity which is difficult to separate from the irinotecan, and the synthesis of the enantiomer of the irinotecan can be realized by two steps of esterification and ammonolysis by taking the irinotecan as a raw material. The preparation method provided by the invention has the advantages of mild reaction conditions, strong operability and short production period; the enantiomer purity of the prepared irinotecan is as high as 99.6%, and the evaluation on the quality and safety of the irinotecan provides an important basis and can be well used for researching the impurity of the irinotecan.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of an enantiomer of irinotecan.
Background
Camptothecin antineoplastic drugs are natural quinoline alkaloids separated from plant camptothecin (Camptotheca acuminate), and are one of the most important anticancer lead compounds. It binds to topoisomerase I, inhibits tumor growth, leads to DNA damage and subsequent cell death and thus, since camptothecin was discovered, academic and pharmaceutical industries have been working on the development of various camptothecin derivatives that can be used in clinical therapy. The most successful of these products is irinotecan, a first-line drug for the treatment of advanced colorectal cancer, and is also effective in lung, breast and pancreatic cancers. Irinotecan is a compound of the S configuration containing only one quaternary carbon chiral center, and its enantiomer (i.e., the R configuration) is an impurity that is difficult to isolate. So far, there are very few reports on the synthesis of irinotecan enantiomer, and how to efficiently realize the synthesis of irinotecan enantiomer is directly related to the quality control and the medication safety of irinotecan, and is crucial to further research on the physiological activity, toxicity and purity characterization of the drug.
Disclosure of Invention
The invention aims to provide a preparation method of an enantiomer of irinotecan, and the yield of the enantiomer of the irinotecan obtained by the preparation method is high, the product quality is good, and the purity is higher than 99.0 percent; and the synthesis route is short, the operation is simple, the reaction condition is mild, and the potential application value is high.
The technical scheme adopted by the invention for realizing the purpose is as follows:
a process for preparing an enantiomer of irinotecan comprising:
firstly, irinotecan and benzoic acid derivatives are in contact reaction in an organic solvent medium to obtain an esterification product, wherein the chemical structure of the esterification product is shown as a formula I:
wherein R is selected from hydrogen, hydroxyl, cyano, amino, halogen, aryl, benzyl, nitro, trifluoromethyl and C 1-6 Alkyl or C 1-30 One of alkoxy groups;
then the enantiomer of irinotecan shown as a formula II is obtained by treating and purifying the product by an alcoholic solution of ammonia through esterification:
finally, the enantiomer of the irinotecan is treated by an alcoholic solution of hydrogen chloride to obtain the hydrochloride of the enantiomer of the irinotecan. The invention provides a method for synthesizing an enantiomer of irinotecan, which takes easily purchased chemical products as raw materials, has reasonable reaction route design, can quickly complete the synthesis of the enantiomer of the irinotecan, has short production period and higher economic benefit; meanwhile, the reaction condition is mild, and the operation is simple. The invention provides a new way for synthesizing an enantiomer of irinotecan, diphenyl phenol phosphite ester and azodicarboxylate are adopted to react firstly, then esterification reaction is promoted, and finally aminolysis is carried out to obtain a product with higher purity, so that an important basis and a reference sample can be provided for quality control and medication safety of the irinotecan drug, the product can be well used for impurity research of the irinotecan, and the product is vital to further research on physiological activity, toxicity and purity characterization of the drug; and has important application value in the aspect of drug declaration.
In one embodiment of the present invention, the chemical structure of the benzoic acid derivative is represented by formula III:
In one embodiment of the invention, the organic solvent comprises a halogenated hydrocarbon solution.
Specifically, the method for preparing an enantiomer of irinotecan comprises the following steps:
1) preparation of esterification product of enantiomer of irinotecan:
using halogenated hydrocarbon as a solvent, firstly reacting diphenyl phenol phosphite with azodicarbonic acid ester, then slowly dripping halogenated hydrocarbon solution of irinotecan and benzoic acid derivatives into the reaction solution, and after the reaction is finished, carrying out column chromatography purification to obtain an esterification product with reversed configuration;
2) preparation of the enantiomer of irinotecan:
adding an alcohol solvent into the esterification product obtained in the step 1) for dissolving, then slowly dripping an ammonia alcohol solution, and after the reaction is finished, carrying out column chromatography purification to obtain an enantiomer with inverted irinotecan configuration;
3) preparation of hydrochloride salt of enantiomer of irinotecan:
adding the enantiomer of the irinotecan obtained in the step 2) into an alcohol solvent for dissolving, then slowly dropwise adding an alcoholic solution of hydrogen chloride, and after the reaction is finished, recrystallizing to obtain the hydrochloride of the enantiomer of the irinotecan.
In one embodiment of the present invention, the preparation route of the esterification product in step 1) is as follows:
wherein R is selected from hydrogen, hydroxyl, cyano, amino, halogen, aryl, benzyl, nitro, trifluoromethyl and C 1-6 Alkyl or C 1-30 One of the alkoxy groups.
In one embodiment of the invention, the route for the preparation of the enantiomer of irinotecan in step 2) is as follows:
wherein R is selected from hydrogen, hydroxyl, cyano, amino, halogen, aryl, benzyl, nitro, trifluoromethyl and C 1-6 Alkyl or C 1-30 One of the alkoxy groups.
In one embodiment of the present invention, in step 1), the concentration of the halogenated hydrocarbon solution of irinotecan and a benzoic acid derivative is 0.3 to 1.5 mol/L, and the dropping time is 10 to 60 min.
In one embodiment of the invention, in step 1), the benzoic acid derivative is selected from the following compounds:
preferably, the benzoic acid derivative is o-nitrobenzoic acid. The invention carries out experimental synthesis tests on the multiple benzoic acid derivatives, and proves that the o-nitrobenzoic acid is an indispensable raw material for efficiently realizing the inversion of irinotecan configuration, has higher reaction activity, can efficiently promote the configuration transformation of the compound, obviously improves the enantiomeric yield of the synthesized irinotecan, and further improves the HPLC purity to 99.6%.
In one embodiment of the invention, in step 1), the halogenated hydrocarbon solution is one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride.
In one embodiment of the invention, in step 1), the molar ratio of diphenyl phenol phosphite, azodicarboxylate, irinotecan and benzoic acid derivative is 2-6:2-6:1: 1-4.
In one embodiment of the invention, the azodicarboxylate in step 1) is one or more of dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and dibenzyl azodicarboxylate.
In one embodiment of the invention, in the step 1), the step 2) and the step 3), the reaction process is carried out under the protection of nitrogen or argon and under the condition of keeping out of the light, and the reaction temperature is 15-60 ℃.
In one embodiment of the invention, in the step 2), the concentration of the ammonia alcohol solution is 3-10 mol/L, and the dropping time is 10-50 min.
In one embodiment of the present invention, in the step 2), the alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol and tert-butanol.
In one embodiment of the invention, in step 2), the molar ratio of esterification product to alcoholic solution of ammonia is 1: 50-150.
In one embodiment of the invention, in step 3), the concentration of the alcoholic solution of hydrogen chloride is 2-8 mol/L.
In one embodiment of the present invention, in the step 3), the alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol and tert-butanol.
In one embodiment of the invention, in step 3), the molar ratio of the enantiomer of irinotecan to the alcoholic solution of hydrogen chloride is 1: 2-10.
In one embodiment of the present invention, the recrystallization in step 3) is conducted by adding the hydrochloric acid solution of the enantiomer of irinotecan obtained by concentration to a low-polarity solvent to obtain a crystalline hydrochloric acid of the enantiomer of irinotecan.
In one embodiment of the invention, the low polarity solvent is one or more of an alkane, an ether.
Compared with the prior art, the invention has the following beneficial effects:
the invention develops a method for quickly and efficiently synthesizing an enantiomer of irinotecan, and the method has the advantages of easily available raw materials, reasonable design, mild reaction conditions, simple operation, easy regulation and control, short production period and high economic benefit. The o-nitrobenzoic acid is used as an esterification reaction raw material, the configuration inversion of irinotecan can be efficiently realized, the yield of an esterification product is obviously increased, the enantiomeric purity of the prepared irinotecan is up to 99.6%, an important basis and a control sample can be provided for the quality and safety evaluation of the irinotecan drug, the o-nitrobenzoic acid can be well used for the impurity research of the irinotecan, and has important application value in the aspect of drug application.
Therefore, the invention provides a preparation method of an enantiomer of irinotecan, and the yield of the enantiomer of the irinotecan obtained by the preparation method is high, the product quality is good, and the purity is higher than 99.0 percent; and the synthesis route is short, the operation is simple, the reaction condition is mild, and the potential application value is high.
Detailed Description
The technical solutions of the present invention are described in further detail below with reference to specific embodiments, but it should be understood that these examples are only for illustrating the disclosure of the present invention to assist understanding, and do not limit the scope of the present invention, and the scope of the present invention is not limited to the following examples.
The present invention is not particularly limited with respect to the sources of the raw materials in the following examples, and they may be prepared by a preparation method known to those skilled in the art or commercially available.
In the present invention, unless otherwise indicated, abbreviations have the meaning shown in table 1:
TABLE 1 meanings of abbreviations
Example 1:
preparation of an enantiomer of irinotecan:
1) the preparation of the esterification product of the enantiomer of irinotecan comprises the steps of:
a250 mL round-bottom three-necked flask wrapped with tinfoil (protected from light) was charged with the starting diphenyl phenol phosphite (PhOPPh) 2 ) (16.0 mmol, 4.45 g, 4.0 eq), followed by addition of 30 mL of anhydrous dichloromethane, addition of a tee, replacement of nitrogen three times, and dissolution with stirring at room temperature. Diethyl azodicarboxylate (DEAD) (16.0 mmol, 2.79 g, 4.0 eq) was then weighed out with a syringe, dissolved by adding 10 mL of anhydrous dichloromethane, and the solution of diethyl azodicarboxylate in dichloromethane was slowly added dropwise to the reaction solution in the three-necked flask, and the solution gradually changed from colorless to orange-red. Reacting for 20min, and obtaining a reaction solution A by finding that both raw materials are completely consumed through TLC (thin-layer chromatography) spot plates and the solution is gradually changed into light yellow from orange red;
weighing an o-nitrobenzoic acid (8.0 mmol, 1.34 g and 2.0 eq) and irinotecan (4.0 mmol, 2.34 g and 1.0 eq) into a clean sample bottle, adding 20mL of anhydrous dichloromethane into the sample bottle for dissolving and diluting, then transferring a dichloromethane solution mixed by the o-nitrobenzoic acid and the irinotecan into a 20mL syringe, slowly dripping a dichloromethane solution of the o-nitrobenzoic acid and the irinotecan into the reaction liquid A by using an injection pump, and setting the dripping speed to be 0.67 mL/min and the dripping time to be 30 min; after the dropwise addition, the mixture was stirred at room temperature overnight, the solution gradually changed from light yellow to bright yellow, and the reaction was monitored by TLC plates and was completed. The organic solvent was evaporated off under reduced pressure to give the crude product of esterification, which was first eluted through a column with pure ethyl acetate (to remove Ph) 2 P = OOPh), followed by column chromatography with an eluent mixture of methanol and dichloromethane (v/v, 5: 1) to finally obtain the esterification product with an inverted configuration, in a yield of 70%, as a yellow solid; 1 H NMR (500 MHz, CDCl 3 ) δ 8.39-8.37 (m, 2 H), 8.09 (dt, J = 7.3, 0.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1 H), 7.47-7.41 (m, 2 H), 7.30-7.26 (m, 2 H), 5.40 (dd, J = 3.3, 1.1 Hz, 2 H), 5.28 (s, 2 H), 4.10-4.04 (m, 2 H), 3.41 (q, J = 7.5 Hz, 2 H), 3.06-3.00 (m, 2 H), 2.41-2.36 (m, 5 H), 2.30-2.22 (m, 1 H), 2.06-1.98 (m, 1H), 1.84-1.78 (m, 2 H), 1.59-1.55 (m, 4 H), 1.44-1.38 (m, 2 H), 1.28-1.20 (m, 5 H), 1.01 (t, J= 8.4 Hz, 3 H)；
2) the preparation of the enantiomer of irinotecan comprises the following steps:
the esterification product of irinotecan inverted in configuration (0.68 mmol, 500.0 mg, 1.0 eq) was weighed into a 50 mL ported vial coated with tinfoil (to protect from light) at room temperature, followed by addition of 10 mL of methanol, followed by replacement of nitrogen three times and dissolution with stirring at room temperature. Subsequently, a methanol solution of ammonia (7.0 mol/L) (68.0 mmol, 9.7 mL, 100.0 eq) was weighed out by syringe and slowly dropped into the reaction solution in the sealed tube for 30min, and the solution gradually changed from yellow to orange-red. Reacting for 12 h, carrying out rotary evaporation on the organic solvent under reduced pressure to obtain a crude product with an inverted configuration of irinotecan, and then passing through a column by using an eluent mixed by methanol and dichloromethane (v/v, 4.5: 1) to finally obtain an enantiomer of irinotecan, wherein the enantiomer is bright yellow solid and the HPLC purity is 99.6%; 1 H NMR (400 MHz, DMSO) δ 8.12 (t, J = 10.3 Hz, 1 H), 7.94 (d, J = 9.4 Hz, 1 H), 7.64 (d, J = 9.4 Hz, 1 H), 7.30 (d, J = 11.6 Hz, 1 H), 6.51 (s, 1 H), 5.42 (d, J = 10.9 Hz, 2 H), 5.28 (d, J = 10.6 Hz, 2 H), 4.26 (s, 1 H), 4.07 (s, 1 H), 3.18-2.90 (m, 4 H), 2.50 (s, 5 H), 1.91-1.80 (m, 4 H), 1.51-1.39 (m, 8 H), 1.30 (q, J = 9.4 Hz, 3 H), 0.89 (t, J = 7.1 Hz, 3 H)；
3) the preparation of the hydrochloride salt of the enantiomer of irinotecan comprises the steps of:
the inverted enantiomer of irinotecan (0.85 mmol, 500.0 mg, 1.0 eq) was weighed into a 50 mL ported vial coated with tinfoil (to protect from light) at room temperature, followed by addition of 10 mL of methanol, followed by displacement of nitrogen three times and dissolution with stirring at room temperature. Then, a methanol solution (4.0 mol/L) of hydrogen chloride (4.3 mmol, 1.1 mL, 5.0 eq) was weighed out by a syringe and slowly dropped into the reaction solution in the sealed tube. Stirring for 3 h, finding the reaction mass to be somewhat sticky, then addingAfter 5 mL of diethyl ether, the reaction mixture was found to be quickly cloudy, and stirring was continued. The organic solvent is removed by rotary evaporation under reduced pressure, then 10 mL of ether is added to ensure that the hydrochloric acid salt is more obviously separated out, the solvent is dried in a rotary manner, and the equivalent amount of hydrochloride of the enantiomer of the irinotecan is finally obtained by pumping with an oil pump, wherein the purity of HPLC is 99.5 percent; HRMS (ESI) calcd. for C 33 H 39 N 4 O 6 [M+H]+: 587.2864, found: 587.2864。
In the steps 1), 2) and 3), the reaction process is carried out under the protection of nitrogen and in the dark, and the reaction temperature is (20 +/-2) DEG C.
Example 2:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
1) preparation of esterification product of enantiomer of irinotecan: the molar ratio of diphenyl phenol phosphite, azodicarboxylate, irinotecan and benzoic acid derivative is 3:3:1: 2.5; wherein the azodicarboxylate is diethyl azodicarboxylate;
2) preparation of the enantiomer of irinotecan: the concentration of the alcohol solution of ammonia is 8 mol/L; the alcohol solvent is tert-butyl alcohol; the molar ratio of the esterification product to the alcoholic solution of ammonia is 1: 120 of a solvent;
3) preparation of hydrochloride salt of enantiomer of irinotecan: the concentration of the alcoholic solution of hydrogen chloride is 6.5 mol/L; the alcohol solvent is tert-butyl alcohol; the molar ratio of the enantiomer of irinotecan to the alcoholic solution of hydrogen chloride is 1: 8.
example 3:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
1) preparation of esterification product of enantiomer of irinotecan: the molar ratio of diphenyl phenol phosphite, azodicarboxylate, irinotecan and benzoic acid derivative is 2:2:1: 2; wherein the azodicarboxylate is di-tert-butyl azodicarboxylate;
2) preparation of the enantiomer of irinotecan: the concentration of the alcohol solution of ammonia is 4 mol/L; the alcohol solvent is isopropanol; the molar ratio of the esterification product to the alcoholic solution of ammonia is 1: 80;
3) preparation of hydrochloride salt of enantiomer of irinotecan: the concentration of the alcoholic solution of hydrogen chloride is 4 mol/L; the alcohol solvent is isopropanol; the molar ratio of the enantiomer of irinotecan to the alcoholic solution of hydrogen chloride is 1: 4.
example 4:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
in the preparation of the esterification product of the enantiomer of irinotecan, o-methylbenzoic acid is adopted to replace o-nitrobenzoic acid.
Example 5:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan adopts o-methoxybenzoic acid to replace o-nitrobenzoic acid.
Example 6:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
in the preparation of the esterification product of the enantiomer of irinotecan, o-phenylbenzoic acid is used to replace o-nitrobenzoic acid.
Example 7:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
salicylic acid is used instead of o-nitrobenzoic acid in the preparation of the esterification product of the enantiomer of irinotecan.
Example 8:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses o-fluorobenzoic acid instead of o-nitrobenzoic acid.
Example 9:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with 2-benzylbenzoic acid.
Example 10:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with o-ethylbenzoic acid.
Example 11:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan adopts m-cyanobenzoic acid to replace o-nitrobenzoic acid.
Example 12:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by substituting m-bromobenzoic acid for o-nitrobenzoic acid.
Example 13:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
m-fluorobenzoic acid is adopted to replace o-nitrobenzoic acid in the preparation of an esterification product of an enantiomer of irinotecan.
Example 14:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses m-methylbenzoic acid instead of o-nitrobenzoic acid.
Example 15:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses 3-trifluoromethylbenzoic acid instead of o-nitrobenzoic acid.
Example 16:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with m-nitrobenzoic acid.
Example 17:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses 3-ethylbenzoic acid instead of o-nitrobenzoic acid.
Example 18:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses 3-chlorobenzoic acid instead of o-nitrobenzoic acid.
Example 19:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan uses p-fluorobenzoic acid instead of o-nitrobenzoic acid.
Example 20:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with p-nitrobenzoic acid.
Example 21:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with p-phenylbenzoic acid.
Example 22:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by using p-tert-butyl benzoic acid instead of o-nitrobenzoic acid.
Example 23:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the esterification product of the enantiomer of irinotecan is prepared by replacing o-nitrobenzoic acid with p-ethylbenzoic acid.
Example 24:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
in the preparation of the esterification product of the enantiomer of irinotecan, p-ethoxybenzoic acid is adopted to replace o-nitrobenzoic acid.
Example 25:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
the preparation of the esterification product of the enantiomer of irinotecan adopts p-methoxybenzoic acid to replace o-nitrobenzoic acid.
Example 26:
a difference from example 1 in the preparation of an enantiomer of irinotecan:
bis (2,2, 2-trichloroethyl) azodicarboxylate was used in place of 1/2 molar amount of diethyl azodicarboxylate in the preparation of the esterification product of the enantiomer of irinotecan. The method also adds a certain amount of bis (2,2, 2-trichloroethyl) azodicarboxylate in the esterification reaction process, so that the yield of the product prepared by the esterification reaction can be further enhanced, and the reason is that the bis (2,2, 2-trichloroethyl) azodicarboxylate has higher reaction activity, can play a certain synergistic enhancement role with diethyl azodicarboxylate, can be better combined with diphenyl phenol phosphite to enhance the catalytic activity of the product, further better promotes the esterification reaction, and further improves the yield of the esterification product.
Test example 1:
results of yield test
The esterification products prepared in step 1) of examples 1 to 26 were subjected to yield calculation, and the results are shown in table 2:
TABLE 2 esterification product yield values
| Sample (I) | Yield/%) | Sample (I) | Yield/%) |
| Example 1 | 70 | Example 14 | 25 |
| Example 2 | 71 | Example 15 | 30 |
| Example 3 | 69 | Example 16 | 55 |
| Example 4 | 35 | Example 17 | 28 |
| Example 5 | 20 | Example 18 | 36 |
| Example 6 | 33 | Example 19 | 28 |
| Example 7 | 10 | Example 20 | 58 |
| Example 8 | 40 | Example 21 | 37 |
| Example 9 | 25 | Example 22 | 42 |
| Example 10 | 37 | Example 23 | 36 |
| Example 11 | 30 | Example 24 | 25 |
| Example 12 | 32 | Example 25 | 22 |
| Example 13 | 32 | Example 26 | 76 |
Determination of purity
Purity measurement of the enantiomer of irinotecan prepared in step 2) of examples 1 to 26 showed the following results in table 3:
table 3 enantiomeric purity test results for irinotecan
| Sample (I) | Purity/%) | Sample (I) | Purity/%) |
| Example 1 | 99.6 | Example 14 | 94.3 |
| Example 2 | 99.5 | Example 15 | 95.4 |
| Example 3 | 99.6 | Example 16 | 93.0 |
| Example 4 | 96.4 | Example 17 | 92.9 |
| Example 5 | 95.8 | Example 18 | 96.1 |
| Example 6 | 97.1 | Example 19 | 96.7 |
| Example 7 | 94.8 | Example 20 | 97.9 |
| Example 8 | 98.0 | Example 21 | 91.0 |
| Example 9 | 96.5 | Example 22 | 94.8 |
| Example 10 | 97.6 | Example 23 | 92.6 |
| Example 11 | 92.3 | Example 24 | 93.3 |
| Example 12 | 93.8 | Example 25 | 94.2 |
| Example 13 | 92.6 | Example 26 | 99.8 |
As can be seen from the data in tables 2 and 3, the esterification reaction of irinotecan with benzoic acid derivatives provided by the present invention resulted in a certain yield of esterification product, which was then subjected to ester aminolysis, and the irinotecan enantiomer was successfully prepared. And the yield of the esterification product prepared in the embodiment 1 is obviously higher than that of the esterification products prepared in the embodiments 4 to 25, and the purity of the obtained irinotecan enantiomer is higher, which shows that the esterification reaction of irinotecan by using o-nitrobenzoic acid has better preparation effect, higher esterification reaction degree and more thorough configuration turnover, and the prepared irinotecan enantiomer product has better quality and obviously improved purity which can reach 99.6%.
In addition, the yield of the esterification product prepared in example 26 of the present invention is significantly higher than that of example 1, which indicates that the addition of a certain amount of bis (2,2, 2-trichloroethyl) azodicarboxylate in the esterification reaction process can further enhance the yield of the esterification reaction, and the reason may be that the addition of bis (2,2, 2-trichloroethyl) azodicarboxylate can perform a certain synergistic enhancement with diethyl azodicarboxylate, and better combine with diphenyl phenol phosphite to enhance the product catalytic activity, further better promote the esterification reaction, and further enhance the yield of the esterification reaction product; and has a certain positive effect on improving the purity of the prepared irinotecan enantiomer.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (9)
1. A process for preparing an enantiomer of irinotecan comprising:
firstly, irinotecan and benzoic acid derivatives are in contact reaction in an organic solvent medium to obtain an esterification product, wherein the chemical structure of the esterification product is shown as a formula I:
wherein R is selected from hydrogen, hydroxyl, cyano, amino, halogen, aryl, benzyl, nitro, trifluoromethyl and C 1-6 Alkyl or C 1-30 One of alkoxy groups;
then the enantiomer of irinotecan shown as a formula II is obtained by treating and purifying the product by an alcoholic solution of ammonia through esterification:
finally, the enantiomer of the irinotecan is treated by an alcoholic solution of hydrogen chloride to obtain the hydrochloride of the enantiomer of the irinotecan.
2. A process for preparing an enantiomer of irinotecan of claim 1 wherein the benzoic acid derivative has the chemical structure shown in formula III:
wherein R is selected from hydrogen, hydroxyl, cyano, amino, halogen, aryl, benzyl, nitro, trifluoromethyl and C 1-6 Alkyl or C 1-30 One of the alkoxy groups.
3. A method of preparing an enantiomer of irinotecan of claim 1 wherein the organic solvent comprises a halogenated hydrocarbon solution.
4. A method of preparing an enantiomer of irinotecan according to claim 3 wherein the halogenated hydrocarbon solution is one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride.
5. The method for producing an enantiomer of irinotecan of claim 1 wherein the molar ratio of irinotecan to the benzoic acid derivative is 1: 1-4.
6. The method of preparing an enantiomer of irinotecan of claim 1 wherein the concentration of the alcoholic solution of ammonia is 3 to 10 mol/L.
7. A process for the preparation of an enantiomer of irinotecan as claimed in claim 1 characterized in that the molar ratio of the esterification product to alcoholic solution of ammonia is 1: 50-150.
8. A method of preparing an enantiomer of irinotecan as claimed in claim 1 wherein the concentration of the alcoholic solution of hydrogen chloride is 2-8 mol/L.
9. The method for preparing an enantiomer of irinotecan of claim 1 wherein the molar ratio of the enantiomer of irinotecan to the alcoholic solution of hydrogen chloride is 1: 2-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210888605.3A CN115073483B (en) | 2022-07-27 | 2022-07-27 | Preparation method of enantiomer of irinotecan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210888605.3A CN115073483B (en) | 2022-07-27 | 2022-07-27 | Preparation method of enantiomer of irinotecan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115073483A true CN115073483A (en) | 2022-09-20 |
| CN115073483B CN115073483B (en) | 2022-10-25 |
Family
ID=83243150
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210888605.3A Active CN115073483B (en) | 2022-07-27 | 2022-07-27 | Preparation method of enantiomer of irinotecan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115073483B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6111107A (en) * | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
| US20020049324A1 (en) * | 1999-08-03 | 2002-04-25 | Zhisong Cao | Aromatic esters of camptothecins and methods to treat cancers |
| US20030216421A1 (en) * | 2002-05-06 | 2003-11-20 | Zhisong Cao | Cascade esters of camptothecins and methods of treating cancer using these compounds |
| CN1673226A (en) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | Carboxylate medicine precursors of hydroxycamptothecine and its derivative and thei prepn and application |
| US20070161668A1 (en) * | 2003-12-23 | 2007-07-12 | American Bioscience, Inc. | Di-ester prodrugs of camptothecin, process for their preparation and their therapeutical applications |
| CN102532151A (en) * | 2012-03-02 | 2012-07-04 | 南京工业大学 | 7-ethyl-20(S)-O-substituted benzoyl camptothecin compounds with anticancer activity |
| CN105636963A (en) * | 2013-12-03 | 2016-06-01 | 赛比亚斯药业股份公司 | Method for the synthesis of irinotecan |
-
2022
- 2022-07-27 CN CN202210888605.3A patent/CN115073483B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6111107A (en) * | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
| US20020049324A1 (en) * | 1999-08-03 | 2002-04-25 | Zhisong Cao | Aromatic esters of camptothecins and methods to treat cancers |
| US20030216421A1 (en) * | 2002-05-06 | 2003-11-20 | Zhisong Cao | Cascade esters of camptothecins and methods of treating cancer using these compounds |
| US20070161668A1 (en) * | 2003-12-23 | 2007-07-12 | American Bioscience, Inc. | Di-ester prodrugs of camptothecin, process for their preparation and their therapeutical applications |
| CN1673226A (en) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | Carboxylate medicine precursors of hydroxycamptothecine and its derivative and thei prepn and application |
| CN102532151A (en) * | 2012-03-02 | 2012-07-04 | 南京工业大学 | 7-ethyl-20(S)-O-substituted benzoyl camptothecin compounds with anticancer activity |
| CN105636963A (en) * | 2013-12-03 | 2016-06-01 | 赛比亚斯药业股份公司 | Method for the synthesis of irinotecan |
Non-Patent Citations (3)
| Title |
|---|
| VITTHAL DHAKANE ET AL.: "A Validated Chiral LC Method for the Enantiomeric Separation of Irinotecan Hydrochloride on Immobilized Cellulose Based Stationary Phase", 《INT. J. PHARM. SCI. REV. RES.》 * |
| ZAHEER-UL-HAQ ET AL.: "Benchmarking docking and scoring protocol for the identification of potential acetylcholinesterase inhibitors", 《JOURNAL OF MOLECULAR GRAPHICS AND MODELLING》 * |
| 吴晓静 等: "抗炎药物喜树碱的衍生化修饰", 《安徽医药》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115073483B (en) | 2022-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2188043C (en) | 7,11 disubstituted camptothecin derivatives, formulations containing such derivatives and their use | |
| CN108524482B (en) | Use of 2- (substituted phenylamino) benzoic acid FTO inhibitors for treating leukemia | |
| ES2903416T3 (en) | Preparation method of a tyrosine kinase inhibitor and a derivative thereof | |
| WO2013086804A1 (en) | 4-pyridyl porphyrin bridged crisscross quad-nuclear platinum complex, and preparation method and anti-tumor activity thereof | |
| Antoszczak et al. | Synthesis and antiproliferative activity of new bioconjugates of Salinomycin with amino acid esters | |
| WO2002028871A1 (en) | Platinum complexes as antitumor agents | |
| CN108329324B (en) | Six ring spiral shell sulfonylindoline compounds of one kind and preparation method thereof | |
| IL175369A (en) | Topotecan monohydrochloride pentahydrate products, processes for making them, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for therapy | |
| US8349863B2 (en) | Crystalline polymorphic form of a camptothecin analogue | |
| CN115073483B (en) | Preparation method of enantiomer of irinotecan | |
| CN107286220B (en) | 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof | |
| CN106317033B (en) | Silybin 23-substituted derivative and preparation method and application of injection thereof | |
| CN106995449A (en) | Podophyllotoxin vitamin A acid heterocomplex synthetic method and applied to prevention, treatment tumour medicine | |
| CN113024557B (en) | Penamine A alkaloid structure simplified substance and application thereof | |
| CN112500412B (en) | Penamine A alkaloid structure simplification compound and application thereof | |
| CN109476649B (en) | Five-membered heterocyclic compound and preparation method, pharmaceutical composition and application thereof | |
| CA2888015C (en) | 2',5'-dideoxy-5-fluorouridine derivatives having cytotoxic activity, a process for the manufacture thereof and application thereof | |
| CN109705187B (en) | Tripterine derivative and preparation method and application thereof | |
| AU2005318227B2 (en) | Stereoselective process and crystalline forms of a camptothecin | |
| CN110218230B (en) | Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application | |
| CN102351870B (en) | Method for preparing benzacridine derivative and application of benzacridine derivative as anti-cancer medicine | |
| CN111393416B (en) | Preparation method and application of pyrazole compound containing 1-methylpyridine-3- (4-chlorphenyl) pyrazole unit | |
| EP4137494A1 (en) | Crystal form of thiofuran pyridazine compound, preparation method therefor and application thereof | |
| TWI795706B (en) | Polycyclic compounds as kinase inhibitors | |
| CN111606815B (en) | Preparation method of phenylephrine hydrochloride impurity standard |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |