CN104130297A - Method for synthesizing capecitabine key intermediate by using high-efficiency dehydrating agent - Google Patents
Method for synthesizing capecitabine key intermediate by using high-efficiency dehydrating agent Download PDFInfo
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- CN104130297A CN104130297A CN201410389693.8A CN201410389693A CN104130297A CN 104130297 A CN104130297 A CN 104130297A CN 201410389693 A CN201410389693 A CN 201410389693A CN 104130297 A CN104130297 A CN 104130297A
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- ribose
- methyl
- isopropylidene
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Abstract
The invention discloses a method for synthesizing a capecitabine key intermediate by using a high-efficiency dehydrating agent, belonging to the field of pharmaceutical chemistry. The method is characterized by comprising the step: by taking D-ribose as a starting raw material, and in the presence of high-efficiency dehydrating agents, such as trimethyl orthoformate, carrying out one step to obtain a high-yield and high-quality capecitabine key intermediate, namely 2,3-O-isopropylidene-1-O-methyl-O-ribose in methanol and acetone. On the basis of D-ribose, the yield of the 2,3-O-isopropylidene-1-O-methyl-O-ribose can be up to 93% (mole yield) which is far higher than literate yield, and the purity is more than 99.5%. The method has the advantages of being high in yield, good in product purity, low in production cost, safe, simple and convenient to operate, easy for large-scale industrial production, and the like.
Description
Technical field
The invention belongs to chemical industry, pharmaceutical chemistry field, relate to a kind of synthetic method of capecitabine key intermediate.Relate to more specifically the efficient dewatering agents such as a kind of employing original acid A ester, the method for preparation 2,3-O-isopropylidene-1-O-methyl-O-ribose.
Background technology
Capecitabine (capecitabine), the chemistry fluoro-N[(pentyloxy of 5 '-deoxidation-5-by name) carbonyl] cytidine, by Switzerland Hoffmann-La Roche company, researched and developed, within 1998, in Switzerland, go on the market first, be a kind of new oral fluorocytidine analogue, be clinically mainly used in treating the knot/rectum cancer in late period, mammary cancer and other solid tumor.In order to study this medicine synthetic route, use retrosynthetic analysis method, find that the synthetic of capecitabine mainly consists of 5 FU 5 fluorouracil and two key intermediates of 1,2,3-O-triacetyl-5-deoxy-D-ribose.5 FU 5 fluorouracil is as marketed drug, and suitability for industrialized production route is own through maturation.And 1,2,3-O-triacetyl-5-deoxy-D-ribose is as the key intermediate of synthesize capecitabine, need to further investigate.By capecitabine operational path is studied, be not difficult to find, intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose has the effect being even more important in capecitabine synthetic.And 1; 2; in the building-up process of 3-O-triacetyl-5-deoxy-D-ribose; 2; 3-O-isopropylidene-1-O-methyl-O-ribose is its vital intermediate; also be applicable to synthetic 5 '-deoxynucleoside compounds, the cost of this intermediate, yield, quality play conclusive impact to the cost of capecitabine, quality simultaneously.This intermediate market supply is at present few, price is high.In order fundamentally to reduce the production cost of capecitabine, need to reduce the production cost of 2,3-O-isopropylidene-1-O-methyl-O-ribose.Its structural formula is as follows:
According to periodical and patent literature, the synthetic method of this intermediate is to take D-ribose as starting raw material at present, in methanol solvate, first D-ribose generates the methylate 1-O-methyl D-ribose of 1-position through acidifying catalysis, without separated reaction with acetone, obtain forkization intermediate 2,3-O-isopropylidene-1-O-methyl D-ribose.Methylate and the process of propylidene in all can generate water, and this two step is all reversible reaction, the generation of water can suppress positive reaction, is beneficial to reversed reaction.As Journal of Organic Chemistry 43 (1), 161,1978, Carbohydrate Research 338 (4), 303,2003, Nuclear Medicinal and Biology 31 (8), 1033,2004 and US Patent No. 4340729A in do not add dewatering agent.Again just like Chinese patent CN101239998A and Chinese Journal of Pharmaceuticals, 2008,39 (11): in 804-807, mention and add common dewatering agent anhydrous CuSO4, anhydrous MgSO4.Reaction yield and product purity are lower, aftertreatment is complicated, and cost is higher, are unfavorable for suitability for industrialized production.
Summary of the invention
For the deficiency of above background technology, the object of this invention is to provide improving one's methods of a kind of synthetic 2,3-O-isopropylidene-1-O-methyl-O-ribose, improved reaction yield.The invention provides a kind of 2, the synthetic method of 3-O-isopropylidene-1-O-methyl-O-ribose, D-ribose is raw material, synthetic 2,3-O-isopropylidene-1-O-methyl-O-ribose under the condition existing in high-efficiency dehydration agent, principle is as follows:
Comprise the following steps:
In methyl alcohol, acetone mixed solvent, add a certain amount of high-efficiency dehydration agent, D-ribose generates 2 through acid catalysis, 3-O isopropylidene-1-O-methyl-O-ribose, is adjusted to pH to 8 ~ 9 with sodium carbonate, removes acetone and methyl alcohol under reduced pressure, with extraction agent, extract, decompression steams extraction agent, obtains target product 2,3-O-isopropylidene-1-O-methyl-O-ribose
Preferably, described high-efficiency dehydration agent is trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate and tributyl orthoformate, preferred trimethyl orthoformate, and the mol ratio of high-efficiency dehydration agent and D-ribose is 1:1 ~ 5, preferably 1:2.Temperature of reaction is 30 ~ 50 ℃, preferably 35 ~ 45 ℃.Described acid is the vitriol oil, concentrated hydrochloric acid, HCl and tosic acid, preferred tosic acid wherein, and D-ribose and sour mol ratio are 2 ~ 3:1, preferably 2.5:1.
Method of the present invention, can obtain high yield, high-quality synthetic 2,3-O-isopropylidene-1-O-methyl-O-ribose.In D-ribose 2,3-O-isopropylidene-1-O-methyl-O-ribose yield reaches 93% (molar yield), and far above document yield, purity is greater than 99.5%.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60mL, tosic acid 4.6g, 40-45 ℃ of stirring reaction, TLC detection reaction degree, after reaction finishes, adds sodium carbonate and adjusts pH to 8 ~ 9, filter, decompression and solvent recovery, obtains light yellow oil 10.1g, and HPLC detects purity and is greater than 97.9%.
Embodiment 2
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60 mL, tosic acid 4.6g, anhydrous cupric sulfate 4.2 g, 40-45 ℃ of stirring reaction, TLC detection reaction degree, after reaction finishes, add sodium carbonate and adjust pH to 8 ~ 9, decompression and solvent recovery, obtains light yellow oil 10.2g, and HPLC detects purity and is greater than 98.5%.
Embodiment 3
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60 mL, tosic acid 4.6g, trimethyl orthoformate 3.7mL, 40-45 ℃ of stirring reaction, TLC detection reaction degree, after reaction finishes, add sodium carbonate and adjust pH to 8 ~ 9, filter decompression and solvent recovery, obtain light yellow oil 12.7g, HPLC detects purity and is greater than 99.5%.
Embodiment 4
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60 mL, concentrated hydrochloric acid 2.5mL, trimethyl orthoformate 3.7mL, 40-45 ℃ of stirring reaction, TLC detection reaction degree, after reaction finishes, add sodium carbonate and adjust pH to 8 ~ 9, filter decompression and solvent recovery, obtain light yellow oil 12.2g, HPLC detects purity and is greater than 99.5%.
Embodiment 5
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60 mL, tosic acid 4.6g, trimethyl orthoformate 2mL, 40-45 ℃ of stirring reaction, TLC detection reaction degree, after reaction finishes, add sodium carbonate and adjust pH to 8 ~ 9, filter decompression and solvent recovery, obtain light yellow oil 11.4g, HPLC detects purity and is greater than 99.5%.
Embodiment 6
In the there-necked flask of the 250mL with agitator and thermometer, add D-ribose 10.0g, methyl alcohol 40mL, acetone 60 mL, tosic acid 4.6g, trimethyl orthoformate 3.7mL, 60 ℃ of stirring reactions, TLC detection reaction degree, after reaction finishes, add sodium carbonate and adjust pH to 8 ~ 9, filter decompression and solvent recovery, obtain light yellow oil 12.3g, HPLC detects purity and is greater than 94.5%.
Although above-mentioned, the specific embodiment of the present invention is described in conjunction with the embodiments; but be not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various modifications that creative work can make or distortion still in protection scope of the present invention.
Claims (4)
1. one kind 2, the synthetic method of 3-O-isopropylidene-1-O-methyl-O-ribose, take D-ribose as raw material, under existing, high-efficiency dehydration agent synthesizes 2,3-O-isopropylidene-1-O-methyl-O-ribose, comprise the following steps: in methyl alcohol, acetone mixed solvent, add a certain amount of high-efficiency dehydration agent, D-ribose generates 2,3-O isopropylidene-1-O-methyl-O-ribose through acid catalysis, with sodium carbonate, be adjusted to pH to 8-9, remove acetone and methyl alcohol under reduced pressure, with extraction agent extraction, decompression steams extraction agent, obtain target product 2,3-O-isopropylidene-1-O-methyl-O-ribose.
2. as claimed in claim 12, the synthetic method of 3-O-isopropylidene-1-O-methyl-O-ribose, it is characterized in that, described high-efficiency dehydration agent is trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate and tributyl orthoformate, preferred trimethyl orthoformate, the mol ratio of high-efficiency dehydration agent and D-ribose is 1:1-5, preferably 1:2.
3. as claimed in claim 12, the synthetic method of 3-O-isopropylidene-1-O-methyl-O-ribose, is characterized in that, temperature of reaction is 30-50 ℃, preferably 35-45 ℃.
4. as claimed in claim 12, the synthetic method of 3-O-isopropylidene-1-O-methyl-O-ribose, is characterized in that, described acid is the vitriol oil, concentrated hydrochloric acid, HCl and tosic acid, preferred tosic acid wherein, D-ribose and sour mol ratio are 2-3:1, preferably 2.5:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110183432A (en) * | 2019-06-28 | 2019-08-30 | 珠海市柏瑞医药科技有限公司 | A kind of preparation process of 5,6-O- isopropylidene-L-AA |
| CN116396324A (en) * | 2023-03-17 | 2023-07-07 | 南雄志一精细化工有限公司 | Preparation method of light-colored diphenyl phosphite |
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| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| CN101845066A (en) * | 2010-05-28 | 2010-09-29 | 河南省健康伟业医药科技有限公司 | Synthetic method of capecitabine intermediate 5-deoxy-D-ribofuranose |
| CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
| WO2013163892A1 (en) * | 2012-05-02 | 2013-11-07 | Sunshine Lake Pharma Co., Ltd. | Novel triazolo pyrimidine compounds and a process of preparation thereof |
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- 2014-08-11 CN CN201410389693.8A patent/CN104130297A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
| CN101845066A (en) * | 2010-05-28 | 2010-09-29 | 河南省健康伟业医药科技有限公司 | Synthetic method of capecitabine intermediate 5-deoxy-D-ribofuranose |
| WO2013163892A1 (en) * | 2012-05-02 | 2013-11-07 | Sunshine Lake Pharma Co., Ltd. | Novel triazolo pyrimidine compounds and a process of preparation thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183432A (en) * | 2019-06-28 | 2019-08-30 | 珠海市柏瑞医药科技有限公司 | A kind of preparation process of 5,6-O- isopropylidene-L-AA |
| CN110183432B (en) * | 2019-06-28 | 2021-08-31 | 珠海市柏瑞医药科技有限公司 | Preparation process of 5, 6-O-isopropylidene-L-ascorbic acid |
| CN116396324A (en) * | 2023-03-17 | 2023-07-07 | 南雄志一精细化工有限公司 | Preparation method of light-colored diphenyl phosphite |
| CN116396324B (en) * | 2023-03-17 | 2024-01-02 | 南雄志一精细化工有限公司 | Preparation method of light-colored diphenyl phosphite |
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Application publication date: 20141105 |