CN117567526A - Method for preparing beta-configuration gemcitabine hydrochloride intermediate - Google Patents
Method for preparing beta-configuration gemcitabine hydrochloride intermediate Download PDFInfo
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- CN117567526A CN117567526A CN202311572695.6A CN202311572695A CN117567526A CN 117567526 A CN117567526 A CN 117567526A CN 202311572695 A CN202311572695 A CN 202311572695A CN 117567526 A CN117567526 A CN 117567526A
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- gemcitabine hydrochloride
- configuration
- hydrochloride intermediate
- catalyst
- beta
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 54
- 229960005144 gemcitabine hydrochloride Drugs 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims abstract description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 239000012065 filter cake Substances 0.000 claims abstract description 3
- 238000001556 precipitation Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims abstract description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 20
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 11
- 229940104302 cytosine Drugs 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000006386 neutralization reaction Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- 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
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for preparing beta-configuration gemcitabine hydrochloride intermediate, which comprises the steps of filtering a catalyst, slowly adding tetrahydrofuran into a reaction solution, and stirring for 2 hours at a temperature ranging from 25 ℃ to 30 ℃; crystallization, filtration, washing of the resulting filter cake with tetrahydrofuran and drying, to form β -configuration gemcitabine hydrochloride intermediate II. At the same time Amberlyst-15 catalyst underwent a series of post-treatment steps including washing with 0.1HCl, neutralization with 0.1N NaOH solution to induce precipitation of solids, and crystallization at reduced temperature (0-10 ℃). According to the invention, by introducing Amberlyst-15 catalyst, the generation of an undesirable alpha-configuration gemcitabine hydrochloride intermediate II' is effectively inhibited, and the conversion rate is enhanced, so that the beta-configuration gemcitabine hydrochloride intermediate II is obtained, and the beta-configuration gemcitabine hydrochloride intermediate II has higher purity and yield, and is very suitable for industrial-scale production due to the simplicity of the preparation method, the simplicity of the operation steps and the post-treatment process.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for preparing beta-configuration gemcitabine hydrochloride intermediate.
Background
Gemcitabine hydrochloride, approved by the FDA in 1996 as an anticancer drug, specifically acts on S-phase cells at the DNA synthesis stage, and is particularly excellent in the treatment of pancreatic cancer. The current literature uses mainly hydroxy-protected D-erythro-2',2' -difluoro-1-carbonyl ribose (gemcitabine hydrochloride intermediate I) and silanized cytosine to produce β -1- (2 ' -deoxy-2 ',2' -difluoro-3 ',5' -di-benzoyl-D-ribofuranoside) -4-aminopyrimidin-2-one (gemcitabine hydrochloride intermediate II), which is a key intermediate in the synthesis of gemcitabine hydrochloride. However, existing methods, including l.w. hertel and t.s.chou methods, have certain limitations in large-scale industrial production due to problems of selectivity, chiral purity, and overall yield. The structure of the key intermediate (gemcitabine hydrochloride intermediate II) during the preparation of gemcitabine hydrochloride is shown below:
beta-1- (2 ' -deoxy-2 ',2' -difluoro-3 ',5' -dibenzoyl-D-ribofuranoside) -4-aminopyrimidin-2-one;
in the existing process for preparing gemcitabine hydrochloride intermediate II, poor reaction selectivity is a significant problem, leading to the formation of a large number of undesirable alpha configuration byproducts; this is detrimental to the yield and purity of the final product, complicating the subsequent post-treatment steps; for example, as described in the preparation method of gemcitabine hydrochloride of chinese patent No. CN201210040408.2, the method involves reacting cytosine, hexamethyldisilazane and ammonium sulfate to obtain a reaction solution. Subsequent steps include ethyl acetate dilution, hydrochloric acid treatment, pulping and pH adjustment, which then need to be performed to isolate the target product. However, these post-treatment steps are complex, resulting in a high ratio of alpha to beta configuration of the product (1:13), and a large amount of alpha configuration byproducts are present.
To solve these challenges, the present invention was introduced as a solution to improve the synthesis efficiency and purity of gemcitabine hydrochloride intermediate II, and a method for preparing the beta-form gemcitabine hydrochloride intermediate was provided.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a method for preparing a beta-configuration gemcitabine hydrochloride intermediate so as to solve the problems of the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions: a method for preparing gemcitabine hydrochloride intermediate with beta configuration, which comprises the following specific steps:
s1: placing gemcitabine hydrochloride intermediate I and silanized cytosine in a solvent;
s2: then Amberlyst15 catalyst is added, evenly stirred and reacted for 3 to 5 hours at the temperature of 150 to 160 ℃;
s3: after the reaction, amberlyst15 catalyst was isolated by filtration followed by slow addition of tetrahydrofuran and crystallization induced by stirring at 25-30 ℃ for 2 hours;
s4: then filtering, washing with tetrahydrofuran to obtain a filter cake, and drying to obtain a beta-configuration gemcitabine hydrochloride intermediate II;
s5: and finally, recycling Amberlyst-15 catalyst.
As a preferable technical scheme of the invention, the mass ratio of the solvent to the gemcitabine hydrochloride intermediate I is 5-8:1.
as a preferred embodiment of the present invention, the molar ratio between the gemcitabine hydrochloride intermediate I and the silylated cytosine is 1:5-10.
As a preferable embodiment of the present invention, the solvent is any one of Sulfolane, toulene and Xylene.
As a preferable technical scheme of the invention, the Amberlyst-15 catalyst in the step S5 is recovered and treated as follows:
s51: washing with HCl, neutralizing with NaOH solution to induce solid precipitation;
s52: crystallizing at 0-10deg.C;
s53: the catalyst was filtered and dried to give the alpha-configuration gemcitabine hydrochloride intermediate II and ready for reuse.
The beneficial effects of the invention are as follows: the present invention minimizes the production of undesirable alpha configuration byproducts and thus increases yield and purity by increasing the selectivity of the reaction by reacting hydroxy-protected D-erythro-2',2' -difluoro-1-carbonyl ribose (gemcitabine hydrochloride intermediate I) with silylated cytosine in the presence of Amberlyst-15 catalyst; the catalyst Amberlyst-15 is adopted to inhibit the bad formation of the alpha-configuration gemcitabine hydrochloride intermediate II and selectively adsorb any undesirable substances, so that the yield and purity of the beta-configuration gemcitabine hydrochloride intermediate II, which is a required product, are remarkably increased.
The invention effectively inhibits the generation of the undesirable alpha-configuration gemcitabine hydrochloride intermediate II' and enhances the conversion rate by introducing Amberlyst-15 catalyst, thereby obtaining the beta-configuration gemcitabine hydrochloride intermediate II which has higher purity and higher yield, and can be realized by a relatively simple post-treatment method, so that the simplicity of the preparation method, the operation steps and the simplicity of the post-treatment process make the preparation method very suitable for industrial-scale production.
Drawings
FIG. 1 is a flow chart of the preparation method of the present invention.
Detailed Description
The following detailed description of the preferred embodiments of the invention is provided with reference to the accompanying drawings so that the advantages and features of the invention will be more readily understood by those skilled in the art, and thus the scope of the invention will be more clearly defined.
Example 1: as in fig. 1: the invention provides a technical scheme that: a method for preparing gemcitabine hydrochloride intermediate with beta configuration, which comprises the following specific steps: in 700 g sulfolane, 100 g (0.22M) of gemcitabine hydrochloride intermediate I and 280 g (1.1 mol) of silanized cytosine were reacted at 150℃for 3 hours with the addition of 20 g Amberlyst15 catalyst; after the reaction, the catalyst was separated by filtration followed by slow addition of 700 g of Tetrahydrofuran (THF), stirring at 25 to 30 ℃ for 2 hours to induce crystallization, followed by filtration, washing with tetrahydrofuran and drying to give gemcitabine hydrochloride intermediate II in the β configuration; the Amberlyst-15 catalyst is treated and is convenient to reuse; the purity of the gemcitabine hydrochloride intermediate II obtained in this example was 99.3% and the molar yield was 97.8%.
Example 2: as in fig. 1: the invention provides a technical scheme that: a method for preparing gemcitabine hydrochloride intermediate with beta configuration, which comprises the following specific steps: in 700 g toluene, 100 g (0.22M) of gemcitabine hydrochloride intermediate I, 280 g (1.1 mol) of silanized cytosine and 20 g Amberlyst15 catalyst were reacted at 120℃for 6 hours, after which the catalyst was separated by filtration, 700 g of Tetrahydrofuran (THF) was slowly added and stirred at 25 to 30℃for 2 hours to induce crystallization, followed by filtration, washing and drying to yield beta configuration gemcitabine hydrochloride intermediate II; amberlyst-15 catalyst is treated for reuse; the purity of the gemcitabine hydrochloride intermediate II obtained in this example was 97.24% and the molar yield was 91.2%.
Example 2: as in fig. 1: the invention provides a technical scheme that: a method for preparing gemcitabine hydrochloride intermediate with beta configuration, which comprises the following specific steps: in 700 g of xylene, 100 g (0.22M) of gemcitabine hydrochloride intermediate I, 280 g (1.1 mol) of silanized cytosine and 20 g of Amberlyst15 catalyst are reacted at 120 ℃ for 6 hours, after the reaction, 700 g of Tetrahydrofuran (THF) is slowly added by filtration to separate the catalyst, crystallization is induced by stirring at 25 to 30 ℃ for 2 hours, and the beta configuration gemcitabine hydrochloride intermediate II is produced by subsequent filtration, washing and drying, and Amberlyst-15 catalyst is treated for reuse. The purity of the gemcitabine hydrochloride intermediate II obtained in this example was 85.58% and the molar yield was 89.47%.
The invention effectively inhibits the generation of the undesirable alpha-configuration gemcitabine hydrochloride intermediate II' and enhances the conversion rate by introducing Amberlyst-15 catalyst, thereby obtaining the beta-configuration gemcitabine hydrochloride intermediate II which has higher purity and higher yield, and can be realized by a relatively simple post-treatment method, so that the simplicity of the preparation method, the operation steps and the simplicity of the post-treatment process make the preparation method very suitable for industrial-scale production.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.
Claims (5)
1. A process for preparing gemcitabine hydrochloride intermediate in the beta configuration, characterized by: the method comprises the following specific steps:
s1: placing gemcitabine hydrochloride intermediate I and silanized cytosine in a solvent;
s2: then Amberlyst15 catalyst is added, evenly stirred and reacted for 3 to 5 hours at the temperature of 150 to 160 ℃;
s3: after the reaction, amberlyst15 catalyst was isolated by filtration followed by slow addition of tetrahydrofuran and crystallization induced by stirring at 25-30 ℃ for 2 hours;
s4: then filtering, washing with tetrahydrofuran to obtain a filter cake, and drying to obtain a beta-configuration gemcitabine hydrochloride intermediate II;
s5: and finally, recycling Amberlyst-15 catalyst.
2. A process for preparing gemcitabine hydrochloride intermediate in the β configuration as claimed in claim 1 wherein: the mass ratio of the solvent to the gemcitabine hydrochloride intermediate I is 5-8:1.
3. a process for preparing gemcitabine hydrochloride intermediate in the β configuration as claimed in claim 1 wherein: the molar ratio between the gemcitabine hydrochloride intermediate I and the silanized cytosine is 1:5-10.
4. A process for preparing gemcitabine hydrochloride intermediate in the β configuration as claimed in claim 1 wherein: the solvent is any one of Sulfolane, toulene and Xylene.
5. A process for preparing gemcitabine hydrochloride intermediate in the β configuration as claimed in claim 1 wherein: the Amberlyst-15 catalyst in the step S5 is recovered and treated as follows:
s51: washing with HCl, neutralizing with NaOH solution to induce solid precipitation;
s52: crystallizing at 0-10deg.C;
s53: the catalyst was filtered and dried to give the alpha-configuration gemcitabine hydrochloride intermediate II and ready for reuse.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311572695.6A CN117567526A (en) | 2023-11-23 | 2023-11-23 | Method for preparing beta-configuration gemcitabine hydrochloride intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311572695.6A CN117567526A (en) | 2023-11-23 | 2023-11-23 | Method for preparing beta-configuration gemcitabine hydrochloride intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117567526A true CN117567526A (en) | 2024-02-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311572695.6A Pending CN117567526A (en) | 2023-11-23 | 2023-11-23 | Method for preparing beta-configuration gemcitabine hydrochloride intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117567526A (en) |
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2023
- 2023-11-23 CN CN202311572695.6A patent/CN117567526A/en active Pending
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