CN104530164A - Synthesis technology for capecitabine - Google Patents
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis technology for capecitabine. The synthesis technology for the capecitabine particularly comprises the first step of ketoxime synthetic reaction, the second step of acetyl protection, the third step of reduction reaction, the fourth step of condensation reaction, and the fifth step of hydrolysis reaction; accordingly, the capecitabine end products are obtained, and the capecitabine is purified by recrystallization through a single solvent. Compared with the prior art, the synthesis technology for the capecitabine revises the synthesis technology of the capecitabine active pharmaceutical ingredients, and particularly improves the intermediate protection and amination process; industrial production is applicable, the quality of the capecitabine active pharmaceutical ingredients is significantly improved, and the number and limitation of relative impurities in the capecitabine active pharmaceutical ingredients are decreased.
Description
Technical field
The invention belongs to chemicals synthesis technical field, specifically, relate to a kind of synthesis technique of capecitabine.
Background technology
The commodity of capecitabine are called xeloda, it is the 5 FU 5 fluorouracil anticancer precursor medicine first developed by Basel, SUI Hao Fumai Roche company limited, itself and no cytotoxicity, but under the effect of enzyme in vivo, can be converted into through three steps and there is Cytotoxic 5 FU 5 fluorouracil.Organize high with the concentration compared with normal of capecitabine metabolism involved enzyme in tumor tissues, therefore can highly selective be accomplished.Capecitabine can T suppression cell division and RNA interfering and protein synthesis, is applicable to taxol and the further treatment including advanced primary that anthracycline antibiotics chemotherapy regimen fails to respond to any medical treatment or metastatic breast cancer.It is mainly used in advanced primary or metastatic breast cancer, the treatment of the rectum cancer, colorectal carcinoma and cancer of the stomach.
In existing synthetic technology, the synthetic method of capecitabine has a lot, be generally two fragment docking, wherein with 5-deoxidation-triacetyl ribose and 5-flurocytosine for raw material, first synthetic intermediate 2', 3'-diacetoxy-5'-deoxidation-5-fluorine cytidine, resynthesis capecitabine, there are α, β two kinds of isomer, by two kinds of isomer separation purifying, need very high cost, and there is risk.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of synthesis technique of capecitabine of energy industrialization scale operation.
The synthesis technique of a kind of capecitabine of the present invention, described synthesis technique specifically comprises the following steps: the 1) building-up reactions of ketoxime: 5 '-'-Deoxy-5-fluorouridine and oxammonium hydrochloride react obtained 5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin; 2) ethanoyl protection: make above-mentioned product and acetic anhydride, with obtained 2', 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin; 3) reduction reaction: make 2', reacts under the existence of 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin and zinc chloride and hydrochloric acid, with obtained 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine; 4) condensation reaction: make 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and haloformic acid n-pentyl ester react under the existence of organic bases, with obtained N-penta oxygen carbonyl-2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine; 5) hydrolysis reaction: make N-penta oxygen carbonyl-2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine is hydrolyzed reaction in the presence of an inorganic base, with obtained end product capecitabine.
The synthesis technique of a kind of capecitabine of the present invention, described step 1) in, reaction solvent is selected from the one in methyl alcohol, ethanol, methanol solution or ethanolic soln, and temperature of reaction is 50-100 DEG C; Described step 2) in, reaction solvent is selected from methylene dichloride or acetic anhydride, and temperature of reaction is 0-40 DEG C, and catalysts is selected from the one in triethylamine, salt of wormwood or sodium-acetate; Described step 3) in, reaction solvent is selected from the one in water, methyl alcohol or ethanol, and temperature of reaction is 5-100 DEG C; Described step 4) in, organic bases is selected from the one in DIPEA, pyridine or Dimethylamino pyridine, and reaction solvent is selected from the one in methylene dichloride, toluene and chloroform, and temperature of reaction is 0-20 DEG C; Described step 5) in, mineral alkali is selected from the one in lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium methylate, and the consumption of mineral alkali is 0.5-5 times of molar equivalent of substrate, and temperature of reaction is 0-20 DEG C.
The synthesis technique of a kind of capecitabine of the present invention, described step 1) in, reaction solvent is selected from methyl alcohol, and temperature of reaction is 50-60 DEG C.
The synthesis technique of a kind of capecitabine of the present invention, described step 2) in, reaction solvent is selected from methylene dichloride, and temperature of reaction is 10-15 DEG C, and catalysts is selected from salt of wormwood.
The synthesis technique of a kind of capecitabine of the present invention, described step 3) in, reaction solvent is selected from water, and temperature of reaction is 5-100 DEG C.
The synthesis technique of a kind of capecitabine of the present invention, described step 4) in, organic bases is selected from DIPEA, and haloformic acid n-pentyl ester is selected from n-amyl chlorocarbonate, and reaction solvent is selected from methylene dichloride, and temperature of reaction is 5-15 DEG C.
The synthesis technique of a kind of capecitabine of the present invention, described step 5) in, mineral alkali is selected from sodium hydroxide, and the consumption of mineral alkali is 2-3 times of molar equivalent of substrate, and temperature of reaction is 5-15 DEG C.
The synthesis technique of a kind of capecitabine of the present invention, described step 5) in, capecitabine is through single solvent recrystallization purifying, and single solvent is the one in ethyl formate, methyl tertiary butyl ether, isopropyl ether or ethyl acetate.
The synthesis technique of a kind of capecitabine of the present invention, described step 5) in, capecitabine is through re-crystallizing in ethyl acetate purifying.
Compared with prior art; the synthesis technique of the present invention to capecitabine bulk drug is revised; particularly improve for intermediate protection and aminating process; be applicable to suitability for industrialized production; and significantly improve the quality of capecitabine bulk drug, reduce quantity and the limit of relative substance in capecitabine bulk drug.
Accompanying drawing explanation
Fig. 1: the synthesis technique figure of capecitabine of the present invention.
Embodiment
Be described further below in conjunction with the synthesis technique of specific embodiment to capecitabine of the present invention, but protection scope of the present invention is not limited to this.
Embodiment 1
Add in 5 '-'-Deoxy-5-fluorouridine (40.7mmol) and oxammonium hydrochloride (40.7mmol) in methyl alcohol (100mL), triethylamine (5mL) is added under stirring, 50-60 DEG C of reaction 2h, after cooling, filter, wash to obtain white solid (10g, yield 94.4%).5'-deoxidation-ribose-5-fluoro-4-azanol base-3 is added in methylene dichloride (100mL), in 4 dihydro-pyrimidins (38.3mmol) and salt of wormwood (38.3mmol), acetic anhydride (91.9mmol) is added under stirring, 10-15 DEG C of reaction 5h, be concentrated into dry, resistates is washed, filter, drying, obtains white solid (12.9g, yield 97.7%).2' is added in water (50mL); 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3; in 4 dihydro-pyrimidins (28.9mmol) and hydrochloric acid (10ml); zinc chloride (57.8mmol) is added, 70-80 DEG C of reaction 3.5h, cooling after washing under stirring; filter; drying, obtains white solid (8.6g, yield 90.5%).Under ice bath; n-amyl chlorocarbonate (21.5mmo1) is slowly instilled N; N-diisopropylethylamine (0.46mL) and 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (14.5mmol) DCM (30mL) solution in, insulation reaction 2h.Use dilute hydrochloric acid (10mL), water (10mL) and saturated aqueous common salt (10mL) to wash successively, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains oily matter, and crystallization obtains white solid (1.1g, yield 83%).Previous step reaction product N-penta oxygen carbonyl-2' is added, 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (10mmol), methyl alcohol (40mL) in 100mL there-necked flask.Drip 2M sodium hydroxide (30mmol) after being cooled to 0 DEG C, holding temperature 5 to 15 DEG C, react after 1 hour and drip 2M hydrochloric acid adjust pH to about 6.Merge organic phase with after methylene dichloride (150mL) point three extractions, use deionized water (100mL), saturated sodium bicarbonate aqueous solution (100mL) to wash respectively.Concentrated after organic phase anhydrous sodium sulfate drying, with ethyl acetate (15mL) 55 DEG C of thermosols, 5 DEG C cold puts, and recrystallization purifying obtains capecitabine white powder 2.77g, yield: 77%.The configuration of capecitabine is analyzed, after adopting ethyl acetate to carry out recrystallization, 98.1% is β-D-capecitabine (the fluoro-N-of β-D-5-deoxidation-5-[(pentyloxy) carbonyl]-cytidin), and 1.9% is α-D-capecitabine.
Embodiment 2
Add in 5 '-'-Deoxy-5-fluorouridine (40.7mmol) and oxammonium hydrochloride (40.7mmol) in ethanol (100mL), triethylamine (5mL) is added under stirring, 70-80 DEG C of reaction 2h, after cooling, filter, wash to obtain white solid (9.6g, yield 90.6%).5'-deoxidation-ribose-5-fluoro-4-azanol base-3 is added in acetic anhydride (100mL), in 4 dihydro-pyrimidins (38.3mmol) and triethylamine (38.3mmol), acetic anhydride (91.9mmol) is added under stirring, 25-30 DEG C of reaction 5h, be concentrated into dry after cooling, resistates is washed, filter, drying, obtains white solid (12.3g, yield 92.8%).2' is added in methyl alcohol (50mL); 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3; in 4 dihydro-pyrimidins (27.7mmol) and hydrochloric acid (10ml); zinc chloride (54.9mmol) is added, 40-50 DEG C of reaction 3.5h, cooling after washing under stirring; filter; drying, obtains white solid (8.2g, yield 86.0%).Under ice bath; n-amyl chlorocarbonate (20.4mmo1) is slowly instilled N; N-diisopropylethylamine (0.43mL) and 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (13.8mmol) DCM (30mL) solution in, insulation reaction 2h.Use dilute hydrochloric acid (10mL), water (10mL) and saturated aqueous common salt (10mL) to wash successively, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains oily matter, and crystallization obtains white solid master (1.0g, yield 78.9%).Previous step reaction product N-penta oxygen carbonyl-2' is added, 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (9.5mmol), methyl alcohol (40mL) in 100mL there-necked flask.Drip 2M sodium methylate (30mmol) after being cooled to 0 DEG C, holding temperature 15-20 DEG C, react after 1 hour and drip 2M hydrochloric acid adjust pH to about 6.Merge organic phase with after methylene dichloride (150mL) point three extractions, use deionized water (100mL), saturated sodium bicarbonate aqueous solution (100mL) to wash respectively.Concentrated after organic phase anhydrous sodium sulfate drying, with isopropyl ether (15mL) 55 DEG C of thermosols, 5 DEG C cold puts, and recrystallization purifying obtains capecitabine white powder 2.63g, yield: 73%.The configuration of capecitabine is analyzed, after adopting isopropyl ether to carry out recrystallization, 91.3% is β-D-capecitabine (the fluoro-N-of β-D-5-deoxidation-5-[(pentyloxy) carbonyl]-cytidin), and 8.7% is α-D-capecitabine.
Embodiment 3
Add in 5 '-'-Deoxy-5-fluorouridine (40.7mmol) and oxammonium hydrochloride (40.7mmol) in the ethanolic soln (100mL) of 50%, triethylamine (5mL) is added under stirring, 65-70 DEG C of reaction 2h, after cooling, filter, wash to obtain white solid (9.4g, yield 88.7%).5'-deoxidation-ribose-5-fluoro-4-azanol base-3 is added in methylene dichloride (100mL), in 4 dihydro-pyrimidins (36.1mmol) and triethylamine (36.1mmol), acetic anhydride (86.3mmol) is added under stirring, 0-5 DEG C of reaction 5h, be concentrated into dry after cooling, resistates is washed, filter, drying, obtains white solid (12.1g, yield 91.8%).2' is added in ethanol (50mL); 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3; in 4 dihydro-pyrimidins (27.2mmol) and hydrochloric acid (10ml); zinc chloride (57.8mmol) is added, 50-55 DEG C of reaction 3.5h, cooling after washing under stirring; filter; drying, obtains white solid (8.1g, yield 85.1%).Under ice bath; n-amyl chlorocarbonate (20.2mmo1) is slowly instilled Dimethylamino pyridine (0.46mL) and 2'; in toluene (30mL) solution of 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (13.6mmol), insulation reaction 2h.Use dilute hydrochloric acid (10mL), water (10mL) and saturated aqueous common salt (10mL) to wash successively, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains oily matter, and crystallization obtains white solid master (1.0g, yield 78%).Previous step reaction product N-penta oxygen carbonyl-2' is added, 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine (9.4mmol), methyl alcohol (40mL) in 100mL there-necked flask.Drip 2M lithium hydroxide (27mmol) after being cooled to 0 DEG C, holding temperature 2-7 DEG C, react after 1 hour and drip 2M hydrochloric acid adjust pH to about 6.Merge organic phase with after methylene dichloride (150mL) point three extractions, use deionized water (100mL), saturated sodium bicarbonate aqueous solution (100mL) to wash respectively.Concentrated after organic phase anhydrous sodium sulfate drying, with ethyl formate (15mL) 55 DEG C of thermosols, 5 DEG C cold puts, and recrystallization purifying obtains capecitabine white powder 2.6g, yield: 72%.The configuration of capecitabine is analyzed, after adopting ethyl formate to carry out recrystallization, 92.1% is β-D-capecitabine (the fluoro-N-of β-D-5-deoxidation-5-[(pentyloxy) carbonyl]-cytidin), and 7.9% is α-D-capecitabine.
Claims (9)
1. the synthesis technique of a capecitabine, it is characterized in that, described synthesis technique specifically comprises the following steps: the 1) building-up reactions of ketoxime: 5 '-'-Deoxy-5-fluorouridine and oxammonium hydrochloride react obtained 5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin; 2) ethanoyl protection: make above-mentioned product and acetic anhydride, with obtained 2', 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin; 3) reduction reaction: make 2', reacts under the existence of 3'-bis--O-ethanoyl-5'-deoxidation-ribose-5-fluoro-4-azanol base-3,4 dihydro-pyrimidin and zinc chloride and hydrochloric acid, with obtained 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine; 4) condensation reaction: make 2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine and haloformic acid n-pentyl ester react under the existence of organic bases, with obtained N-penta oxygen carbonyl-2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine; 5) hydrolysis reaction: make N-penta oxygen carbonyl-2', 3'-bis--O-ethanoyl-5'-deoxidation-5-fluorine cytidine is hydrolyzed reaction in the presence of an inorganic base, with obtained end product capecitabine.
2. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 1) in, reaction solvent is selected from the one in methyl alcohol, ethanol, methanol solution or ethanolic soln, and temperature of reaction is 50-100 DEG C; Described step 2) in, reaction solvent is selected from methylene dichloride or acetic anhydride, and temperature of reaction is 0-40 DEG C, and catalysts is selected from the one in triethylamine, salt of wormwood or sodium-acetate; Described step 3) in, reaction solvent is selected from the one in water, methyl alcohol or ethanol, and temperature of reaction is 5-100 DEG C; Described step 4) in, organic bases is selected from the one in DIPEA, pyridine or Dimethylamino pyridine, and reaction solvent is selected from the one in methylene dichloride, toluene and chloroform, and temperature of reaction is 0-20 DEG C; Described step 5) in, mineral alkali is selected from the one in lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium methylate, and the consumption of mineral alkali is 0.5-5 times of molar equivalent of substrate, and temperature of reaction is 0-20 DEG C.
3. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 1) in, reaction solvent is selected from methyl alcohol, and temperature of reaction is 50-60 DEG C.
4. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 2) in, reaction solvent is selected from methylene dichloride, and temperature of reaction is 10-15 DEG C, and catalysts is selected from salt of wormwood.
5. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 3) in, reaction solvent is selected from water, and temperature of reaction is 5-100 DEG C.
6. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 4) in, organic bases is selected from DIPEA, and haloformic acid n-pentyl ester is selected from n-amyl chlorocarbonate, reaction solvent is selected from methylene dichloride, and temperature of reaction is 5-15 DEG C.
7. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 5) in, mineral alkali is selected from sodium hydroxide, and the consumption of mineral alkali is 2-3 times of molar equivalent of substrate, and temperature of reaction is 5-15 DEG C.
8. the synthesis technique of a kind of capecitabine according to claim 1, it is characterized in that, described step 5) in, capecitabine is through single solvent recrystallization purifying, and single solvent is the one in ethyl formate, methyl tertiary butyl ether, isopropyl ether or ethyl acetate.
9. the synthesis technique of a kind of capecitabine according to claim 1, is characterized in that, described step 5) in, capecitabine is through re-crystallizing in ethyl acetate purifying.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110066307A (en) * | 2019-05-22 | 2019-07-30 | 蚌埠学院 | A kind of method that immobilized base catalysis takes off riboacetyl |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110066307A (en) * | 2019-05-22 | 2019-07-30 | 蚌埠学院 | A kind of method that immobilized base catalysis takes off riboacetyl |
| CN110066307B (en) * | 2019-05-22 | 2022-08-23 | 蚌埠学院 | Method for removing ribose acetyl by immobilized base catalysis |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
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