CN108440623A - A kind of preparation method and products thereof of capecitabine intermediate - Google Patents
A kind of preparation method and products thereof of capecitabine intermediate Download PDFInfo
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- CN108440623A CN108440623A CN201810309106.8A CN201810309106A CN108440623A CN 108440623 A CN108440623 A CN 108440623A CN 201810309106 A CN201810309106 A CN 201810309106A CN 108440623 A CN108440623 A CN 108440623A
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- 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
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The present invention relates to a kind of preparation methods of capecitabine intermediate; the capecitabine intermediate is 2 '; 3 ' two O acetyl group, 5 ' deoxidation, 5 fluorine cytidine; 5 Flucytosines are placed in solvent; 1,2,3 three O acetyl group, 5 deoxyribose is added; under stirring, adds lewis acid and carry out catalysis reaction；Sodium bicarbonate is added in the reaction solution obtained after completion of the reaction and water quenching is gone out, then detaches, crystallizes obtained capecitabine intermediate.5 Flucytosines need not be protected using silylation in the preparation method of the present invention, and directly with 1, glycosylation reaction occurs for 2,3 O triacetyls, 5 deoxyribose, reduces reaction step, shortens the reaction time；Energy consumption is reduced, production efficiency is improved, reduces the generation of waste, has saved resource；And obtained capecitabine intermediate purity is high, α type content of isomer is small, or even without detection, optical purity of products is up to 99.8% or more.
Description
Technical field
The invention belongs to pharmaceutical drug substance synthesis technical field, it is related to preparation method and its production of a kind of capecitabine intermediate
Product.
Background technology
Capecitabine (capecitabine) the entitled 5 '-deoxidation -5- of chemistry fluoro- N- [(amoxy) carbonyl] cytidine, be by
The oral nucleosides series antineoplastic medicament of Roche (Roche) drugmaker research and development.It is absorbed rapidly through intestinal mucosa after oral, then in liver
Dirty that inactive intermediate 5'- deoxidation -5' fluorine cytidines are converted by Carboxylesterase, the cytidine through liver and tumor tissues after is de-
The effect of ammonia enzyme is converted into 5'- deoxidation -5' floxuridines, is finally fluorouracil through thymidine phosphorylase catalysis in tumor tissues
(5-FU) and work.It is pernicious to be clinically mainly used for treatment metastatic colorectal cancer, breast cancer, colon cancer and gastric cancer etc.
Tumour.According to statistics, global capecitabine bulk pharmaceutical chemicals market demand in 2016 is about 200 tons, and only domestic market is as high as 50 tons,
Market demand is very big.
There are many route of capecitabine synthesis report, but in existing technology and the factors such as raw material supply, capecitabine
Preparation method mainly using 5-flurocytosine as starting material, with 1 after being protected using silylation, 2,3-O- triacetyl -5-
Glycosylation reaction occurs under lewis acidic catalysis for deoxyribose, and aminoacylation then occurs with n-amyl chlorocarbonate,
Most capecitabine is obtained through hydrolysis afterwards.Synthetic route is as follows：
And the most complicated reaction of this route is glycosylation reaction, the hydrolysis of aminoacylates and ester group is all easier to, therefore 2 ',
3 '-two-O- acetyl group -5 '-deoxidation -5- fluorine cytidines are the important intermediates of the synthesis of nucleoside antineoplastic capecitabine.
The route needs that silylating reagent HMDS (hexamethyldisilazane), Silanization reaction process is used to also need to use
Higher boiling such as toluene equal solvent, and need to generate a large amount of ammonias during Silanization reaction big to environmental hazard.But current document
The preparation method of report be required for first use silylation protection 5-flurocytosine after with 1,2,3-O- triacetyl -5- deoxidation cores
Glycosylation reaction occurs for sugar, if it is possible to save silylation protection, 5-flurocytosine is directly with 1,2,3-O- triacetyls
Glycosylation reaction occurs for base -5- deoxyriboses, will greatly reduce the manufacturing cost of capecitabine, while decreasing environment dirt
Dye.So there is an urgent need for a kind of new methods prepared by new capecitabine important intermediate.
Invention content
In view of this, the purpose of the present invention is to provide a kind of preparation method of simple capecitabine important intermediate,
And the obtained purity of this method is high and its micro α types isomers or the capecitabine midbody compound without α type isomers.
In order to achieve the above objectives, the present invention provides the following technical solutions：
1. a kind of preparation method of capecitabine intermediate, the capecitabine intermediate is 2 ', 3 '-two-O- acetyl group-
5 '-deoxidation -5- fluorine cytidines, structure are shown in formula I：
The preparation method comprises the following steps：
1) 5-flurocytosine (formula II) is placed in solvent, 1,2,3-, tri--O- acetyl group -5- deoxyribose (formulas is added
III) it, under stirring, adds lewis acid and carries out catalysis reaction；
2) sodium bicarbonate is added in the reaction solution obtained after completion of the reaction and water quenching is gone out, then detaches, crystallizes obtained capecitabine
Intermediate.
Its reaction equation is as follows：
Further, the solvent is dichloromethane or dichloroethanes.
Further, the molal weight ratio of the 5-flurocytosine and 1,2,3- tri--O- acetyl group -5- deoxyriboses is 1:1
~1.5.
Further, the molal weight ratio of the 5-flurocytosine and 1,2,3- tri--O- acetyl group -5- deoxyriboses is 1:1
~1.05.
Further, the mass ratio of the volume of solvent and 5-flurocytosine is 2~20ml：1g.
Further, the lewis acid is butter of tin, titanium tetrachloride, ferric trichloride or zinc chloride.
Further, the lewis acid is butter of tin.
Further, the 5-flurocytosine and lewis acidic molar ratio are 1：0.8~2.0.
Further, the temperature of the catalysis reaction is 10~40 DEG C.
Further, the temperature of the catalysis reaction is 10~20 DEG C.
Further, the molar ratio of the sodium bicarbonate and 5-flurocytosine is 6：1.
Further, the solvent of the crystallization is methanol, absolute ethyl alcohol, isopropanol, ethyl acetate, isopropyl acetate or methyl
One or more mixing in tertbutyl ether.
Further, the solvent of the crystallization is isopropanol.
2. the capecitabine intermediate obtained by the preparation method described in any of the above item.
The beneficial effects of the present invention are：1. 5-flurocytosine (formula II) need not use silicon in the synthetic method of the present invention
Alkyl is protected, directly with 1 under methylene chloride or dichloroethanes effect, 2,3-O- triacetyl -5- deoxyribose (formulas
III) glycosylation reaction occurs, reduces reaction step, shortens the reaction time；2. Silanization reaction needs under the high temperature conditions
It carries out, therefore reduces energy consumption, improve production efficiency, reduce Material Cost, while reducing the generation of waste, save
Resource；3. by obtained 99.5% or more capecitabine intermediate (Formulas I) purity of preparation method of the present invention, α type isomers
Content is less than 0.1%, or even without detection, optical purity of products is up to 99.8%.
Description of the drawings
In order to keep the purpose of the present invention, technical solution and advantageous effect clearer, the present invention provides following attached drawing and carries out
Explanation：
Fig. 1 is that the HPLC of 1 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates；
Fig. 2 is that the HPLC of 2 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates；
Fig. 3 is that the HPLC of 3 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates；
Fig. 4 is that the HPLC of 4 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates；
Fig. 5 is that the HPLC of 5 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates.
Specific implementation mode
Below in conjunction with attached drawing, the preferred embodiment of the present invention is described in detail.It is not specified in embodiment specific
The experimental method of condition, usually according to conventional conditions or according to the manufacturer's recommendations.
Embodiment 1：
5-flurocytosine (20.0g, 155mmol) is suspended in 200mL dichloromethane, addition is added 1 under room temperature,
10~20 DEG C 2,3- tri--O- acetyl group -5- deoxyriboses (40.3g, 155mmol), control of temperature, quickly stirring is lower is added dropwise tetrachloro
Change the dichloromethane solution that titanium (40.3g, 155mmol) is dissolved in 100mL, continues to react 4h at 10~20 DEG C after dripping off.Carbon is added
Sour hydrogen sodium (78.1g, 930mmol), is slowly added dropwise water 10g, continues stirring 3 hours, filtering, filter cake dichloromethane after dripping off
(40mL × 2) are washed, and filtrate washed once with saturated sodium bicarbonate aqueous solution 200mL, and organic phase is dry with anhydrous sodium sulfate 20g
Dry, filtering, filtrate decompression is concentrated into syrupy shape, and residue obtains capecitabine intermediate with 120mL recrystallisation from isopropanol
44.1g, white powder, yield 86.5%, purity 99.6%, maximum single miscellaneous 0.10%, α types isomers are not detected.Fig. 1 is real
Apply the HPLC analysis collection of illustrative plates of 1 gained capecitabine intermediate of example.
Embodiment 2：
5-flurocytosine (20.0g, 155mmol) is suspended in 200mL dichloroethanes, 1,2,3- is added under room temperature
10~20 DEG C three-O- acetyl group -5- deoxyriboses (40.3g, 155mmol), control of temperature, quickly stirring is lower is added dropwise titanium tetrachloride
(40.3g, 155mmol) is dissolved in the dichloroethane solution of 100mL, continues to react 4h at 10~20 DEG C after dripping off.Bicarbonate is added
Sodium (78.1g, 930mmol), is slowly added dropwise water 10g, continues stirring 3 hours, filtering, filter cake dichloroethanes (40mL after dripping off
× 2) it washs, filtrate washed once with saturated sodium bicarbonate aqueous solution 200mL, and organic phase is dried with anhydrous sodium sulfate 20g, mistake
Filter, filtrate decompression are concentrated into syrupy shape, and residue obtains capecitabine intermediate 45.0g with 120mL recrystallisation from isopropanol, white
Powder, yield 85.2%, purity 99.0%, maximum single miscellaneous 0.25%, α types isomers 0.05%.Fig. 2 is 2 gained of embodiment
The HPLC of capecitabine intermediate analyzes collection of illustrative plates.
Embodiment 3：
5-flurocytosine (20.0g, 155mmol) is suspended in 200mL dichloromethane, 1,2,3- is added under room temperature
10~20 DEG C three-O- acetyl group -5- deoxyriboses (40.3g, 155mmol), control of temperature, quickly stirring is lower is added dropwise titanium tetrachloride
(40.3g, 155mmol) is dissolved in the dichloromethane solution of 100mL, continues to react 4h at 10~20 DEG C after dripping off.Bicarbonate is added
Sodium (78.1g, 930mmol), is slowly added dropwise water 10g, continues stirring 3 hours, filtering, filter cake dichloromethane (40mL after dripping off
× 2) it washs, filtrate washed once with saturated sodium bicarbonate aqueous solution 200mL, and organic phase is dried with anhydrous sodium sulfate 20g, mistake
Filter, filtrate decompression are concentrated into syrupy shape, and residue obtains capecitabine intermediate 41.7g with 200mL re-crystallizing in ethyl acetate, in vain
Color powder, yield 84.7%, purity 99.5%, maximum single miscellaneous 0.25%, α types isomers are not detected.Fig. 3 is 3 institute of embodiment
The HPLC for obtaining capecitabine intermediate analyzes collection of illustrative plates.
Embodiment 4：
5-flurocytosine (20.0g, 155mmol) is suspended in 200mL dichloromethane, 1,2,3- is added under room temperature
10~20 DEG C three-O- acetyl group -5- deoxyriboses (40.3g, 155mmol), control of temperature, quickly stirring is lower is added dropwise titanium tetrachloride
(40.3g, 155mmol) is dissolved in the dichloromethane solution of 100mL, continues to react 4h at 10~20 DEG C after dripping off.Bicarbonate is added
Sodium (78.1g, 930mmol), is slowly added dropwise water 10g, continues stirring 3 hours, filtering, filter cake dichloromethane (40mL after dripping off
× 2) it washs, filtrate washed once with saturated sodium bicarbonate aqueous solution 200mL, and organic phase is dried with anhydrous sodium sulfate 20g, mistake
Filter, filtrate decompression are concentrated into syrupy shape, and residue is warming up to 80 DEG C with 200mL isopropyl acetates and is beaten 0.5 hour, is cooled to 0
DEG C crystallization 1 hour, filtering are dried to obtain capecitabine intermediate 46.2g, yield 86.5%, and purity 99.3% is maximum single miscellaneous
0.19%, α type isomers are not detected.Fig. 4 is that the HPLC of 4 gained capecitabine intermediate of embodiment analyzes collection of illustrative plates.
Embodiment 5：
5-flurocytosine (200.0g, 1.55mol) is suspended in 2L dichloromethane, 1,2,3- is added under room temperature
10~20 DEG C three-O- acetyl group -5- deoxyriboses (403.0g, 1.55mol), control of temperature, quickly stirring is lower is added dropwise four chlorinations
Titanium (403.0g, 1.55mol) is dissolved in the dichloromethane solution of 1L, continues to react 4h at 10~20 DEG C after dripping off.Bicarbonate is added
Sodium (781.0g, 9.3mol), is slowly added dropwise water 100g, continues stirring 3 hours, filtering, filter cake dichloromethane (0.4L after dripping off
× 2) it washs, filtrate washed once with saturated sodium bicarbonate aqueous solution 2.0L, and organic phase is small with anhydrous sodium sulfate 200g dryings 1
When, filtering, filtrate decompression is concentrated into syrupy shape, and residue obtains capecitabine intermediate 452g with 2.0L recrystallisation from isopropanol,
White powder, yield 88.6%, purity 99.7%, maximum single miscellaneous 0.11%, α types isomers are not detected.Fig. 5 is embodiment 5
The HPLC of gained capecitabine intermediate analyzes collection of illustrative plates.
Reaction temperature may be controlled to 10~40 DEG C, preferably 10~20 DEG C in the preparation method of the present invention, if warm
Spend it is high can generate more impurity, temperature crosses that low reaction is relatively slow and reaction is incomplete.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (10)
1. a kind of preparation method of capecitabine intermediate, which is characterized in that the capecitabine intermediate is 2 ', 3 '-two-O-
Acetyl group -5 '-deoxidation -5- fluorine cytidines, structure are shown in formula I：
The preparation method comprises the following steps：
1) 5-flurocytosine is placed in solvent, 1,2,3-, tri--O- acetyl group -5- deoxyriboses is added, under stirring, add road
Lewis acid carries out catalysis reaction；
2) sodium bicarbonate is added in the reaction solution obtained after completion of the reaction and water quenching is gone out, then detaches, crystallizes among obtained capecitabine
Body.
2. preparation method according to claim 1, which is characterized in that the solvent is dichloromethane or dichloroethanes.
3. preparation method according to claim 1, which is characterized in that the 5-flurocytosine and 1,2,3- tri--O- acetyl
The molal weight ratio of base -5- deoxyriboses is 1:1~1.5.
4. preparation method according to claim 1, which is characterized in that the volume of solvent and the mass ratio of 5-flurocytosine are
2~20ml：1g.
5. preparation method according to claim 1, which is characterized in that the lewis acid be butter of tin, titanium tetrachloride,
Ferric trichloride or zinc chloride.
6. preparation method according to claim 1, which is characterized in that the 5-flurocytosine and lewis acidic molar ratio
It is 1：0.8~2.0.
7. preparation method according to claim 1, which is characterized in that the temperature of the catalysis reaction is 10~40 DEG C.
8. preparation method according to claim 1, which is characterized in that the molar ratio of the sodium bicarbonate and 5-flurocytosine
It is 6：1.
9. preparation method according to claim 1, which is characterized in that the solvent of the crystallization is methanol, absolute ethyl alcohol, different
One or more mixing in propyl alcohol, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether(MTBE).
10. the capecitabine intermediate obtained by claim 1~9 any one of them preparation method.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111377988A (en) * | 2018-12-30 | 2020-07-07 | 山东新时代药业有限公司 | Capecitabine intermediate |
| CN113321693A (en) * | 2021-05-25 | 2021-08-31 | 神隆医药（常熟）有限公司 | Preparation method of capecitabine intermediate suitable for industrial production |
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|---|---|---|---|---|
| WO2008145403A1 (en) * | 2007-06-01 | 2008-12-04 | Synthon B.V. | Processes related to making capecitabine |
| CN101812104A (en) * | 2010-04-20 | 2010-08-25 | 江苏吴中苏药医药开发有限责任公司 | New method for continuously operating to synthesize capecitabine |
| CN102993253A (en) * | 2012-12-18 | 2013-03-27 | 浙江先锋科技有限公司 | Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine |
| CN104926900A (en) * | 2014-03-22 | 2015-09-23 | 上海创诺制药有限公司 | Method for preparing Capecitabine intermediate represented by formula I |
-
2018
- 2018-04-09 CN CN201810309106.8A patent/CN108440623A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008145403A1 (en) * | 2007-06-01 | 2008-12-04 | Synthon B.V. | Processes related to making capecitabine |
| CN101812104A (en) * | 2010-04-20 | 2010-08-25 | 江苏吴中苏药医药开发有限责任公司 | New method for continuously operating to synthesize capecitabine |
| CN102993253A (en) * | 2012-12-18 | 2013-03-27 | 浙江先锋科技有限公司 | Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine |
| CN104926900A (en) * | 2014-03-22 | 2015-09-23 | 上海创诺制药有限公司 | Method for preparing Capecitabine intermediate represented by formula I |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111377988A (en) * | 2018-12-30 | 2020-07-07 | 山东新时代药业有限公司 | Capecitabine intermediate |
| CN111377988B (en) * | 2018-12-30 | 2023-06-27 | 鲁南制药集团股份有限公司 | Capecitabine intermediate |
| CN113321693A (en) * | 2021-05-25 | 2021-08-31 | 神隆医药（常熟）有限公司 | Preparation method of capecitabine intermediate suitable for industrial production |
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Application publication date: 20180824 |