CN116554194A - Synthesis method of capecitabine intermediate - Google Patents
Synthesis method of capecitabine intermediate Download PDFInfo
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- CN116554194A CN116554194A CN202310581565.2A CN202310581565A CN116554194A CN 116554194 A CN116554194 A CN 116554194A CN 202310581565 A CN202310581565 A CN 202310581565A CN 116554194 A CN116554194 A CN 116554194A
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- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 title claims abstract description 29
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960004117 capecitabine Drugs 0.000 title claims abstract description 29
- 238000001308 synthesis method Methods 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 239000002994 raw material Substances 0.000 claims abstract description 39
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- 238000007069 methylation reaction Methods 0.000 claims abstract description 20
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 14
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007348 radical reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 6
- 150000003254 radicals Chemical class 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000012044 organic layer Substances 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001340 alkali metals Chemical group 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- -1 carbon disulfide, alkali metal hydroxide Chemical class 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 230000032798 delamination Effects 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 12
- 239000013067 intermediate product Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000003756 stirring Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 238000004321 preservation Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000011946 reduction process Methods 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- COTCLZIUSPWWJJ-UHFFFAOYSA-M [Na+].[O-]S(=O)=S Chemical compound [Na+].[O-]S(=O)=S COTCLZIUSPWWJJ-UHFFFAOYSA-M 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of capecitabine intermediate, belonging to the technical field of drug intermediate synthesis. In order to solve the problems of high risk and low yield of the existing reaction operation, a synthesis method of capecitabine intermediate is provided, which comprises the steps of reacting a raw material compound shown in a formula I, carbon disulfide and alkali metal hydroxide in an organic solvent to synthesize an intermediate compound shown in a formula II, and adding dimethyl carbonate to carry out methylation reaction to obtain a compound shown in a formula III; the compound of formula III is converted into the capecitabine intermediate product by free radical reaction under the action of tributylstannane. The invention can realize the reaction under mild conditions, has high conversion rate of the reaction, can more effectively control the residual energy of the reaction raw materials in the middle control to be less than 0.5 percent, and has the advantages of less byproducts and easy post-treatment.
Description
Technical Field
The invention relates to a synthesis method of capecitabine intermediate, belonging to the technical field of drug intermediate synthesis.
Background
Capecitabine (capecitabine), which has the chemical name 5-deoxy-5-fluoro-N- [ (pentyloxy) carbonyl ] cytidine, is an oral nucleoside antitumor drug developed by Roche. The drug is first marketed in Switzerland in 8 in 1998, and is approved by the FDA in 9 in 1998 for treating advanced primary or metastatic breast cancer which is not effective on drugs such as paclitaxel and doxorubicin, and is approved by the FDA in 2001 for treating metastatic colorectal cancer, so that the drug has broad market prospect; therefore, the research on the synthesis process of the compound has great practical value, and the process research of the key intermediate 1-methyl-2, 3-O-isopropylidene-5-deoxy-D-ribofuranose is an important part of the capecitabine research. The synthetic routes of the intermediate compounds reported so far are as follows:
1. the D-ribose is obtained by protecting methanol and acetone, esterifying PTCS, and reducing sodium borohydride, such as CN105037453 and Chong, en Fa et al From Huagong Shikan,27 (11), 11-13;2013.
2. such as the D-ribose of Chinese patent application (publication No. CN 102212095A) is obtained by protecting methanol and acetone, esterifying PTCS, iodizing and reducing. The chemical reaction equation is as follows:
the above synthesis has mainly problems: the raw materials sodium borohydride and sodium iodide have the characteristics of higher price, flammability, explosiveness and difficult post-treatment, and the whole process is complex, has more synthesis steps, low yield and high operational risk, and is not beneficial to large-scale production.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis method of capecitabine intermediate, which solves the problems of mild reaction and high product yield.
The invention aims at realizing the following technical scheme, namely a synthesis method of capecitabine intermediate, which comprises the following steps:
A. reacting a raw material compound shown in a formula I, carbon disulfide and alkali metal hydroxide in an organic solvent to synthesize an intermediate compound shown in a formula II, and adding dimethyl carbonate to perform methylation reaction to obtain a compound shown in a formula III;
in the compound of the formula II, M is alkali metal;
B. the compound of the formula III is converted into a product compound of the formula IV through free radical reaction under the action of tributylstannane;
according to the invention, an intermediate compound of a formula II, namely a sodium thiosulfonate, is synthesized by adopting carbon disulfide and hydroxide of alkali metal, methyl is introduced into the intermediate compound of a formula III by adding dimethyl carbonate for methylation reaction, and then a tributylstannane free radical reaction is used for obtaining a product of a formula IV compound, namely a key intermediate of capecitabine, namely 1-methyl-2, 3-O-isopropylidene-5-deoxidization-D-ribofuranose. Specifically, the whole process reaction can be realized under mild conditions by adjusting and improving the raw materials, the conversion rate of the reaction is high, the residual energy of the reaction raw materials in the middle control is more effectively controlled to be less than 0.5%, the method has the advantages of less byproducts and easiness in post-treatment, and after the intermediate formula III compound thioxy ester is synthesized, only the post-treatment is needed to remove the solvent, and the next reaction can be directly carried out without refining treatment; meanwhile, in the whole reaction process, explosive sodium borohydride is not used as a reducing agent in the reduction process and the hydrogenation reduction process, so that the danger in the reaction process is reduced; and the heat release in the post-treatment process after the reaction is finished is not obvious, the method has the advantage of simple operation, solves the problems of severe temperature rise and the like when sodium borohydride is used for quenching, more effectively avoids the defects of impurity generation and the like caused by local heating, and has the advantages of obviously improved purity of the final product, high yield, low cost and suitability for large-scale industrial production.
In the above synthesis method of capecitabine intermediate, the hydroxide of alkali metal in the step a can better enable the reaction to proceed effectively, and the alkali metal M is introduced. Further, by using hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide as the above-mentioned alkali metal hydroxide, an intermediate product is produced in which M is a corresponding alkali metal, and when sodium hydroxide is used, the alkali metal M is sodium or the like. Preferably, M in step a is selected from sodium or potassium.
In the above synthesis method of capecitabine intermediate, preferably, at least DMF solvent is added to the organic solvent in step a. By adding a certain amount of DMF solvent into the organic solvent system, the solubility of raw materials and auxiliary materials in the reaction system is increased, the system can be kept to be alkalescent in the dissolving process, the stability is good, the reaction speed is favorably increased, the side reaction is reduced, and the conversion rate of intermediate products is improved. The volume ratio of DMF solvent to other organic solvents in the organic solvent is preferably 1:50 to 55.
As a further preferred aspect, the organic solvent is one or more selected from the group consisting of a water-insoluble organic solvent, a ketone solvent and an ether solvent. The method can ensure the effective proceeding of the reaction, has the advantage of high conversion rate, is more beneficial to further ensuring the proceeding of the post-treatment, does not need the subsequent refining treatment after the reaction is finished, and simplifies the operation. Still further preferably, the water-insoluble organic solvent is one or more selected from the group consisting of dichloromethane, chloroform and toluene; the ether solvent is selected from acetone and/or ethanone; the ether solvent is selected from tetrahydrofuran and/or propylene oxide. When the ether solvent or ketone solvent is adopted, after the reaction is finished, the solvent can be directly removed by distillation treatment, and the remainder is directly added into the solvent for the next reaction.
In the above synthesis method of capecitabine intermediate, preferably, the methylation reaction in step a is performed in the presence of a mixed solvent of a water-insoluble organic solvent one and DMF, and further comprises a post-treatment, wherein the post-treatment specifically comprises adding water to the reaction solution, standing for delamination, collecting an organic layer, and removing the solvent to obtain the compound of formula iii. Further, it is preferable that the volume ratio of the water-insoluble organic solvent I to DMF solvent is 50 to 55:1. the water-insoluble organic solvent is selected from dichloromethane, chloroform and the like, is favorable for improving the conversion rate of methylation reaction, and has the advantage of high product yield. As another embodiment, the methylation reaction is carried out in the presence of a mixed solvent of a water-soluble organic solvent and DMF, and after the reaction is finished, the organic solvent is distilled off, water and a water-insoluble organic solvent such as dichloromethane, toluene, chloroform and the like are added for extraction and washing, and the collected organic phase is used for the next free radical reaction.
In the above-mentioned method for synthesizing capecitabine intermediate, preferably, the methylation reaction in the step A is carried out at a temperature of 15℃to 30 ℃; the free radical reaction in the step B is carried out at the temperature of 60-80 ℃. The intermediate product is obtained by adopting the raw material of the compound shown in the formula I, carbon disulfide and alkali metal hydroxide for reaction, and then the intermediate product is subjected to methylation reaction with dimethyl carbonate, so that the reaction can be carried out at room temperature, methylation can be effectively carried out in the forward direction, the advantage of high conversion rate is achieved, and the reaction temperature is preferably controlled at room temperature, namely, the reaction temperature is controlled to be 15-25 ℃, so that the reaction is mild, the convenience of operation is greatly improved, the advantage of high safety is achieved, the quality of the product is better ensured, the advantage of low impurity content is achieved, and the control is easier. The reaction temperature of the first and second steps in the step A is preferably controlled to 15 to 30 ℃. Even if the reaction temperature and the methylation reaction temperature during the synthesis of the intermediate compound of formula II are independently controlled to be 15-30 ℃, preferably 15-25 ℃, further at room temperature. The reaction temperature of the step is mild, the operation is facilitated, the temperature controllability is high, the purity quality and the yield of the intermediate product of the step are ensured better, and the generation of impurities is reduced.
In the above-mentioned synthesis method of capecitabine intermediate, preferably, the radical reaction in step B is performed in a second water-insoluble organic solvent having a boiling point of 60 ℃. The method can effectively carry out the reaction, ensure the purity and quality of the product, be beneficial to the subsequent treatment and simplify the operation. As a further preferred aspect, the water-insoluble organic solvent is one or more selected from toluene, 1, 2-dichloroethane, chloroform and n-hexane.
In the above synthesis method of capecitabine intermediate, preferably, the molar ratio of the compound of formula i, carbon disulfide, alkali metal hydroxide and dimethyl carbonate in step a is 1:1.0 to 1.3:1.0 to 1.2:1.0 to 1.3; the addition amount of tributylstannane in the step B is 1-2% of the addition mass of the compound of the formula I. The method is more beneficial to fully utilizing the raw materials, reducing the cost, enabling the raw materials to react completely, improving the purity and quality of the product and reducing the existence of raw material impurities.
The synthesis method of the capecitabine intermediate of the present invention can be represented by the following reaction equation (taking M as Na as an example):
in summary, compared with the prior art, the invention has the following advantages:
1. the intermediate compound of the formula II, namely the sodium thiosulfonate, is synthesized by adopting carbon disulfide and alkali metal hydroxide, methyl is introduced into methyl carbonate for methylation reaction to obtain the intermediate compound of the formula III, and tributylstannane free radical reaction is used to obtain the product compound of the formula IV, so that the reaction can be realized under mild conditions, the conversion rate of the reaction is high, the residual energy of reaction raw materials in central control is more effectively controlled to be less than 0.5%, and the method has the advantages of less byproducts and easiness in post-treatment.
2. The explosive sodium borohydride is not needed to be used as a reducing agent in the reduction process and the hydrogenation reduction process, so that the danger in the reaction process is reduced; and the heat release is not obvious in the post-treatment process after the reaction is finished, so that the method has the advantages of simplicity in operation, obvious improvement of the purity of the final product, high yield, low cost and suitability for large-scale industrial production.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Adding 20.4g of a raw material compound shown in formula I, 100ml of dichloromethane and 2ml of DMF solvent into a 500ml clean three-neck flask, stirring and dissolving at room temperature, then adding 4.4g of sodium hydroxide and 8g of carbon disulfide, stirring and preserving heat at room temperature for reaction for 3 hours, detecting 99.1% by using a medium-control HPLC, wherein the raw material residue is 0.39%; then, 10g of dimethyl carbonate (DMC) is added, the methylation reaction is continuously controlled under the room temperature condition and the temperature is kept for 3 hours, the detection of 99.3% by a medium-control HPLC (high performance liquid chromatography) is carried out, and the raw material residue is 0.25%;
after the reaction is finished, 200ml of water is added into the reaction solution, stirring is carried out for 0.5h, standing and layering are carried out, 50ml of water is added into the collected organic layer for washing once, the organic layer is distilled under reduced pressure until the solvent is evaporated, 100ml of toluene is added into the residue, 0.2g of tributylstannane is added after the dissolution, the temperature is heated to 70-80 ℃ for carrying out heat preservation reaction for 5h, the detection of 98.2% by using a central control HPLC (high performance liquid chromatography) is carried out, the raw material residue is 0.48%, after the reaction is finished, the temperature is slowly reduced to below 50 ℃, the fraction (1500 Pa) at 70-80 ℃ is collected by vacuum distillation, 17.9g of colorless transparent liquid formula IV compound is obtained, the purity of the detection HPLC is 99.8%, and the yield is 95.2%.
Example 2
Adding 20.4g of a raw material compound shown in the formula I, 100ml of solvent acetone and 2ml of DMF into a 500ml three-neck flask, stirring and dissolving at room temperature, then adding 4.4g of sodium hydroxide and 8g of carbon disulfide, stirring and reacting at room temperature for 3 hours under the condition of heat preservation, detecting 98.8% by using a medium-control HPLC, wherein the raw material residue is 0.41%; then, 10g of dimethyl carbonate (DMC) is added into the reaction liquid, methylation reaction is continuously carried out under the condition of room temperature for 3 hours, the detection of 98.3 percent by using a medium-control HPLC (high performance liquid chromatography) is carried out, after the reaction is finished, acetone is removed by reduced pressure distillation until the reaction is dried, 200ml of water and 100ml of toluene are added into the residue, the mixture is stirred for 0.5 hour, the mixture is kept stand for layering, 50ml of water is added into the collected organic layer for washing once, 0.2g of tributylstannane is added into the layered organic layer, the mixture is heated to 70-80 ℃ for 5 hours, the detection of 97.6 percent by using the medium-control HPLC is carried out, the raw material residue is cooled to below 50 ℃, the temperature is reduced to below 50 ℃, the fraction (1500 Pa) of 70-80 ℃ is collected by vacuum distillation, and 17.1g of colorless transparent liquid IV is obtained, the purity of the detected HPLC is 99.3 percent, and the yield is 90.9 percent.
Example 3
Adding 20.4g of a raw material compound shown in the formula I, 100ml of tetrahydrofuran and 2ml of DMF into a 500ml three-neck flask, stirring and dissolving at room temperature, then adding 4.4g of sodium hydroxide and 8g of carbon disulfide, stirring and reacting at room temperature for 3 hours, detecting 99.0% by using a medium-control HPLC, wherein the raw material residue is 0.4%; then, 10.5g of dimethyl carbonate (DMC) is added into the reaction liquid, the methylation reaction is continuously controlled under the condition of room temperature for 3 hours, the detection of a central control HPLC is carried out for 98.8 percent, the raw material residue is 0.29 percent, after the reaction is finished, tetrahydrofuran is removed by reduced pressure distillation until the tetrahydrofuran is dried, 200ml of water and 100ml of toluene are added into the residue, the mixture is stirred for 0.5 hour, the mixture is stood for layering, 50ml of water is added into the collected organic layer for washing once, the layering, 0.2g of tributylstannane is added into the organic layer, the mixture is heated to 70-80 ℃ for 5 hours, the detection of the central control HPLC is carried out for 98.3 percent, the raw material residue is 0.35 percent, then the temperature is reduced to below 50 ℃, the fraction (1500 Pa) of 70-80 ℃ is collected by vacuum distillation, the colorless transparent liquid type IV compound 17.3g is obtained, the purity of the detected HPLC is 99.5 percent, and the yield is 92.0 percent.
Example 4
Adding 20.4g of a raw material compound shown in a formula I and 100ml of toluene into a 500ml three-neck flask, stirring and dissolving the mixture at room temperature, adding 4.5g of sodium hydroxide and 8.5g of carbon disulfide, performing heat preservation reaction for 3 hours at 70-80 ℃ under the control of temperature, detecting 98.1% of raw material residues by using a medium-control HPLC, then adding 11g of dimethyl carbonate (DMC), performing heat preservation for 3 hours at 70-80 ℃, detecting 97.5% of raw material residues by using 0.2% of water, adding 200ml of water, stirring for 0.5 hours, standing and layering, adding 50ml of water into an organic layer for washing, layering, adding 0.3g of tributylstannane into the collected organic layer, heating to 70-80 ℃ and performing heat preservation for 5 hours, detecting 95.2% of the medium-control HPLC, detecting 0.16% of raw material residues, cooling to below 50 ℃, and performing vacuum distillation and collecting fractions (1500 Pa) at 70-80 ℃ to obtain a colorless transparent liquid compound 15.7g, the detected purity of which is 98.3%, and the yield is 83.5%.
Example 5
Adding 20.4g of a raw material compound shown in formula I and 150ml of a solvent dichloromethane and 3ml of a DMF solvent into a 500ml clean three-neck flask, stirring and dissolving at room temperature, then adding 4.8g of sodium hydroxide and 9.8g of carbon disulfide, stirring and preserving heat for reaction for 4 hours at room temperature, detecting 99.3% by using a medium-control HPLC, wherein the raw material residue is 0.42%; then, 10.5g of dimethyl carbonate (DMC) is added, the methylation reaction is continuously controlled under the room temperature condition and the temperature is kept for 3 hours, the detection of the medium-control HPLC is 98.7%, and the raw material residue is 0.26%;
after the reaction is finished, 200ml of water is added into the reaction solution, stirring is carried out for 0.5h, standing and layering are carried out, 50ml of water is added into the collected organic layer for washing once, the organic layer is distilled under reduced pressure until the solvent is evaporated, 100ml of toluene is added into the residue, 0.4g of tributylstannane is added after the dissolution, the temperature is heated to 70-80 ℃ for carrying out heat preservation reaction for 5h, the detection of 98.5% by using a central control HPLC (high performance liquid chromatography) is carried out, the raw material residue is 0.44%, after the reaction is finished, the temperature is slowly reduced to below 50 ℃, the fraction (1500 Pa) at 70-80 ℃ is collected by vacuum distillation, 17.7g of colorless transparent liquid formula IV compound is obtained, the purity of the detection HPLC is 99.8%, and the yield is 94.2%.
Example 6
Adding 20.4g of a raw material compound shown in the formula I, 130ml of tetrahydrofuran serving as a solvent and 2.5ml of DMF into a 500ml three-neck flask, stirring and dissolving at room temperature, then adding 4.6g of sodium hydroxide and 8.6g of carbon disulfide, stirring and reacting at room temperature for 3 hours under the condition of heat preservation, detecting 98.7% by using a medium-control HPLC, wherein the raw material residue is 0.43%; then, 10g of dimethyl carbonate (DMC) is added into the reaction liquid, methylation reaction is continuously carried out under the condition of room temperature for 3 hours, the detection of 98.2 percent by using a medium-control HPLC (high performance liquid chromatography) is carried out, the residue of the raw material is 0.33 percent, after the reaction is finished, acetone is removed by reduced pressure distillation until the reaction is dried, 200ml of water and 100ml of toluene are added into the residue, the mixture is stirred for 0.5 hours, the mixture is kept stand and layered, 50ml of water is added into the collected organic layer for washing once, 0.3g of tributylstannane is added into the layered organic layer, the mixture is heated to 70-80 ℃ for 5 hours, the detection of 98.0 percent by using the medium-control HPLC, the residue of the raw material is 0.35 percent, the temperature is reduced to below 50 ℃, the fraction (1500 Pa) of 70-80 ℃ is collected by vacuum distillation, and 17.4g of colorless transparent liquid IV is obtained, the purity of the detected HPLC is 99.5 percent, and the yield is 92.6 percent.
Example 7
Adding 20.4g of a raw material compound of formula I, 110ml of dichloromethane and 2ml of DMF solvent into a 500ml clean three-neck flask, stirring and dissolving at 20-25 ℃, then adding 6.7g of potassium hydroxide and 9.9g of carbon disulfide, stirring and reacting for 3 hours at 20-25 ℃, detecting 99.3% by using a medium-control HPLC, wherein the raw material residue is 0.42%; then, 11.7g of dimethyl carbonate (DMC) is added, the methylation reaction is continuously controlled at room temperature for 3.5 hours, the detection by a medium-control HPLC is 99%, and the raw material residue is 0.31%;
after the reaction is finished, 200ml of water is added into the reaction solution, stirring is carried out for 0.5h, standing and layering are carried out, 50ml of water is added into the collected organic layer for washing once, the organic layer is distilled under reduced pressure until the solvent is evaporated, 100ml of normal hexane is added into the residue, 0.4g of tributylstannane is added after the organic layer is dissolved, the mixture is heated to 65-70 ℃ for carrying out heat preservation reaction for 4h, the content of the residual material is 98.5 percent by using a central control HPLC (high performance liquid chromatography), the content of the residual material is 0.44 percent, after the reaction is finished, the temperature is slowly reduced to below 50 ℃, the fraction (1500 Pa) at 70-80 ℃ is collected by vacuum distillation, and the colorless transparent liquid type IV compound is obtained, the purity of the detected HPLC is 99.8 percent, and the yield is 96.8 percent.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (10)
1. A method for synthesizing a capecitabine intermediate, which is characterized by comprising the following steps:
A. reacting a raw material compound shown in a formula I, carbon disulfide and alkali metal hydroxide in an organic solvent to synthesize an intermediate compound shown in a formula II, and adding dimethyl carbonate to perform methylation reaction to obtain a compound shown in a formula III;
in the compound of the formula II, M is alkali metal;
B. the compound of the formula III is converted into a product compound of the formula IV through free radical reaction under the action of tributylstannane;
2. the method for synthesizing capecitabine intermediate according to claim 1, wherein M in step a is selected from sodium or potassium.
3. The method for synthesizing capecitabine intermediate according to claim 1, wherein at least DMF solvent is added to the organic solvent in step a.
4. A method for synthesizing a capecitabine intermediate according to claim 3, wherein the organic solvent is further selected from one or more of a water-insoluble organic solvent, a ketone solvent and an ether solvent.
5. The method for synthesizing capecitabine intermediate according to claim 4, wherein the water-insoluble organic solvent is one or more selected from the group consisting of dichloromethane, chloroform and toluene; the ether solvent is selected from acetone and/or ethanone; the ether solvent is selected from tetrahydrofuran and/or propylene oxide.
6. The method for synthesizing capecitabine intermediate according to any one of claims 1 to 5, wherein the methylation reaction in step a is performed in the presence of a mixed solvent of a water-insoluble organic solvent one and DMF, and further comprising a post-treatment, which specifically comprises adding water to the reaction solution, standing for delamination, collecting an organic layer, and removing the solvent to obtain the compound of formula iii.
7. The method for synthesizing capecitabine intermediate according to any one of claims 1-5, wherein the methylation reaction in step a is performed at a temperature of 15 ℃ to 30 ℃; the free radical reaction in the step B is carried out at the temperature of 60-80 ℃.
8. The process for the synthesis of capecitabine intermediate according to any one of claims 1 to 5, wherein the radical reaction in step B is carried out in a second water-insoluble organic solvent having a boiling point of not less than 60 ℃.
9. The method for synthesizing capecitabine intermediate according to claim 8, wherein the water-insoluble organic solvent is one or more selected from toluene, 1, 2-methylene chloride, chloroform and n-hexane.
10. The method for synthesizing capecitabine intermediate according to any one of claims 1-5, wherein the molar ratio of the compound of formula i, carbon disulfide, alkali metal hydroxide and dimethyl carbonate in step a is 1:1.0 to 1.3:1.0 to 1.2:1.0 to 1.3; the addition amount of tributylstannane in the step B is 1-2% of the addition mass of the compound of the formula I.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024450A2 (en) * | 1997-11-08 | 1999-05-20 | Glaxo Group Limited | Adensine a1 receptor agonists |
| CN101830953A (en) * | 2010-05-26 | 2010-09-15 | 南京亚东启天药业有限公司 | Method for preparing capecitabine and intermediate thereof |
| CN110483593A (en) * | 2019-08-14 | 2019-11-22 | 贵州永诺菲特生物制药有限公司 | A kind of preparation method of capecitabine intermediate |
| CN111527099A (en) * | 2017-08-09 | 2020-08-11 | 普莱鲁德疗法有限公司 | Selective inhibitors of protein arginine methyltransferase 5(PRMT5) |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024450A2 (en) * | 1997-11-08 | 1999-05-20 | Glaxo Group Limited | Adensine a1 receptor agonists |
| CN101830953A (en) * | 2010-05-26 | 2010-09-15 | 南京亚东启天药业有限公司 | Method for preparing capecitabine and intermediate thereof |
| CN111527099A (en) * | 2017-08-09 | 2020-08-11 | 普莱鲁德疗法有限公司 | Selective inhibitors of protein arginine methyltransferase 5(PRMT5) |
| CN110483593A (en) * | 2019-08-14 | 2019-11-22 | 贵州永诺菲特生物制药有限公司 | A kind of preparation method of capecitabine intermediate |
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