CN1427006A - Preparation method of 2,2'-anhydro uridine compound - Google Patents
Preparation method of 2,2'-anhydro uridine compound Download PDFInfo
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- CN1427006A CN1427006A CN 01137397 CN01137397A CN1427006A CN 1427006 A CN1427006 A CN 1427006A CN 01137397 CN01137397 CN 01137397 CN 01137397 A CN01137397 A CN 01137397A CN 1427006 A CN1427006 A CN 1427006A
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Abstract
A process for preparing 2,2'-dewatered uridine compound from uridine compound includes such steps as dewatering reaction at 85-130 deg.C in anhydrous DMF (or DMA) solvent by use of biester carbonate as dewatering agent; after recovering solvent, adding the mixture solution composed of alcohol, acetone, dioxohexane, ethyl acetate or acetonitrile to the residue, stirring to educe out the crude product, and refining by mixed solvent. Its advantages are no environmental pollution and safe process.
Description
Technical field
The present invention relates to uridine compound (I) is former section, preparation of industrialization 2, the method for 2 '-anhydro uridine compound (II).
Background technology
2,2 '-anhydro uridine compound, as 2.2 '-anhydro uridine (CU), 2,2 '-dehydration-5-methyluridine (CMU) etc. is the basic raw material of important miazines nucleoside compound, can prepare (2 '-) deoxidation miazines nucleosides (as thymidine, deoxyuridine and Deoxyribose cytidine etc.) with them, 2 '-alkoxyl group, 2 '-halogen, 2 '-sulfydryl, 2 '-miazines nucleosides such as amino, arabinose class pyrimidine nucleoside, and other antiviral class nucleoside compound such as d4T, AZT etc.Along with the exploitation of antisense nucleoside acids and ribozyme class medicine, 2, the demand of 2 '-anhydro uridine compound is with increasing.
For a long time, in patent and the scientific paper published, always be and be prepared and purifying 22 '-anhydro uridine compound: uridine compound (I) is added to contains dewatering agent carbonic diester [(R " O) with following method
2CO] and dry DMF (the dimethyl formamide of a spot of sodium bicarbonate (or potassium), dimethyl formamide) or DMA (dimethyl acetamide, N,N-DIMETHYLACETAMIDE) in, (the DMF boiling temperature is 150 ℃ to reflux, the DMA boiling temperature is 165 ℃), or be heated to 140～150 ℃, after finishing to thin plate chromatography (TLC) detection reaction, to pour in a large amount of ether after the cooling of brown-black reaction solution, after the semi-solid taking-up of resulting precipitation or heavy-gravity, again with a large amount of ether washing or a large amount of ethyl alcohol recrystallizations, obtain 2,2 '-anhydro uridine compound (II) crude product, in order to obtain the high product of purity column chromatography purification commonly used, or with ethanol (or methyl alcohol) recrystallization.Referring to: AllaVRR., et.al., USP 5596087, (1997); Cook PD., et.al., USP 5861493, (1999); LegorburnU., et.al., Tetrahedron, 1999,55:5635～5640.The common drawback of these methods is: temperature of reaction is up to 140-150 ℃ during (1) reflux, and side reaction is more, and the reaction solution color is dark, is brown-black, for the purifying of product brings difficulty, needs column chromatography purification, perhaps will carry out repeatedly recrystallization; (2) reaction solvent DMF or DMA do not reclaim, and cause waste; (3) solvent that makes product separate out use is an ether, and not only consumption is big, and because the boiling point of ether is low, and volatility is very big, pollutes the preparation environment, has safety problem, can not produce higher season in temperature; (4) employed ether is difficult reclaims, and increases the cost of preparation.In a word, this preparation 2, the method for 2 '-anhydro uridine compound (II) should not be used for scale operation, only is applicable to prepared in laboratory.
Summary of the invention
The technical problem to be solved in the present invention is: the reform synthesis technique, reduce the dehydration reaction temperature, and reduce side reaction, reclaim solvent and utilize again, get rid of and use lower boiling ether, simplify the purge process of product, reduce preparation cost.
The present invention prepares 2, and the reaction equation of 2 '-anhydro uridine compound (II) is expressed as follows:
In the formula: R can be H, C
1～C
4Alkyl, vinyl, propenyl, proyl, halogen, phenyl; R ' can be H, C
1～C
3Alkyl; R " can be methyl, ethyl, sec.-propyl, phenyl.
Preparation method of the present invention is: uridine compound I is added among anhydrous DMF or the DMA, adds minor N aHCO routinely in DMF or DMA
3Or KHCO
3, with carbonic diester [(R " O)
2CO] be dewatering agent, the mol ratio of carbonic diester and Compound I is 1.1～1.5, and more excellent is 1.2～1.4, and even more ideal is 1.3.
Temperature of reaction is 85～130 ℃, and more excellent is 95～120 ℃; Even more ideal temperature of reaction is 100～110 ℃.Reaction times exceeds with the no raw material I of TLC detection, and CO is arranged in the reaction
2Emit.After reaction was finished, decompression and solvent recovery under temperature of reaction, recovered solvent can be used for secondary response down.In the stiff residue, add mixed solvent, described mixed solvent is mainly to be made up of ethanol and other organic solvents, other organic solvents can be mainly be made up of acetone, dioxane, ethyl acetate and/or acetonitrile, and its (volume) usage ratio is 1: 10～10: 1.
The preparation method of above-mentioned anhydro uridine compound (II) is characterized in that: add the mixing solutions that ethanol and acetone are formed in residue, the ratio of ethanol and acetone is 1: 1-2: 1.
The preparation method of above-mentioned anhydro uridine compound (II) is characterized in that: add the mixing solutions that ethanol and acetonitrile are formed in residue, the ratio of ethanol and acetonitrile is 1: 1-2: 1.
The preparation method of above-mentioned anhydro uridine compound (II) is characterized in that: add the mixing solutions that ethanol and dioxane are formed in residue, the ratio of ethanol and dioxane is 7: 1-9: 1.
The preparation method of above-mentioned anhydro uridine compound (II) is characterized in that: add the mixing solutions that ethanol and ethyl acetate are formed in residue, the ratio of ethanol and ethyl acetate is 1: 1-9: 1; The ratio of ethanol and ethyl acetate mixture is 1 preferably: 1-7: 1.
Also can add the mixed solution that ethanol and other two or more organic solvents are formed in residue, described other organic solvents can be acetone, acetonitrile, ethyl acetate or dioxane.The ratio (volume) of the mixed solution that ethanol and other two or more organic solvents are formed is 1: 10～10: 1.
Stir under the room temperature or under the situation of heating, promptly have 2,2 '-anhydro uridine compound (II) is separated out with the white solid form, 1～2 hour after-filtration of ice-water bath cooling, filter cake adds heat soaking with mixed solvent, cooled and filtered can obtain chromatographically pure product, and its purity can reach the assay determination requirement.Mixed solvent is recyclable to be utilized again.
Reduced the dehydration reaction temperature in the technical scheme of the present invention, reduced the side reaction in the reaction, the color of reaction solution is not changeed deeply, and the by product of reaction is less.
After reaction finishes, decompression and solvent recovery DMA or DMF under temperature of reaction while hot, the meaning that reclaims solvent has three: (1) takes away part to the influential by product of product I I purity, as phenol etc.; (2) recovered solvent is recycling, reduces cost, and reduces waste liquid amount; (3) use the lower boiling ether that the basis is provided for getting rid of.
Add the higher mixed solvent of mainly forming of mixed solvent, especially boiling point in the residue after recovery by ethanol and other organic solvents.Residue and mixed solvent stir, and after the cooling, can obtain the purity high product easily.The present invention replaces the low ether that is difficult for recovery of boiling point with the higher mixed solvent of boiling point, improves the security of producing, and makes synthesis technique be applicable to the production in any season.Get rid of for a long time and adopt ether to separate out the method for solvent in the document, improved the environment of preparation, improved security as product; The all recyclable utilization of solvent for use alleviates the pollution to environment, reduces the cost of production technique.
Above-mentioned advantage of the present invention makes 2, and 2 '-anhydro uridine compound (II) can carry out industrialized scale operation safely.
Embodiment
Embodiment 1: preparation 2,2 '-anhydro uridine (CU) raw material sources, specification: uridine is purchased in Suzhou associating chemical industry company limited, chemical pure.Other reagent and solvent are the commercial goods, chemical pure or analytical pure.DMF or DMA carry out processed according to a conventional method.20g uridine (82mmol) and 20g diphenyl carbonate (94mmol) are suspended among the anhydrous 20mL DMF, are warmed up to 90 ℃ under stirring, and add 0.5g NaHCO
3After have more carbonic acid gas to emit immediately, be warmed up to 115 ℃, afterreaction liquid changeed clarification in several minutes, soon have solid to produce, TLC detects no uridine, reclaim under reduced pressure DMF after 4 hours, in light brown residue, added 100mL ethanol-ethyl acetate (9: 1, v/v) mixed solution, 70 ℃ are stirred down, have solid to produce, cooled and filtered, filter cake soaks with the above mixed solvent of 50mL, and 50 ℃ were stirred 15 minutes down, and cold filtration gets clear crystal pulverous 2,2 '-anhydro uridine 17.18g (yield 93.7%), m.p.238～240 ℃ (dec.), and Rf=0.12 on TLC in CHCl3/MeOH (85: 15, v/v).1H-NMR(DMSO-D6，ppm)δ：3.17-3.27(m，CH2)，4.06(m，OH)，4.37(m，CH)，4.98(t，OH)，5.19(d，CH)，5.83(d，CH)，5.89(br，CH)，6.30(d，CH)，7.83(d，CH)。
Embodiment 2:
Preparation 2,2 '-anhydro uridine (CU)
500g uridine (2.05moles) and 484g diphenyl carbonate (2.26moles) and 5g NaHCO
3Be added among the anhydrous DMA of 500mL, be warmed up to 110 ℃ under stirring, react after 5 hours, TLC detects no uridine, and reclaim under reduced pressure DMA added 1.2L ethanol-acetonitrile (9: 1 in light brown residue, v/v) mixed solution, 60 ℃ are stirred down, and the adularescent solid produces, cooled and filtered, the filter cake alcohol immersion is heated to and refluxed 15 minutes, and cold filtration gets clear crystal pulverous 2,2 '-anhydro uridine 412g (yield 89%), m.p.239～240 ℃ (dec.)
Embodiment 3:
Preparation 2,2 '-dehydration-5-methyluridine (CMU)
Raw material sources, specification:
The 5-methyluridine is a Suzhou match Kant Wan Ma chemical company product, chemical pure.
Other reagent and solvent are the commercial goods, chemical pure or analytical pure.
DMF or DMA carry out processed according to a conventional method.
100g 5-methyluridine (0.39mol) and 100g diphenyl carbonate (0.47mol) are suspended among the anhydrous 100mL DMF, are warmed up to 90 ℃ under stirring, and add 2g NaHCO
3After have more carbonic acid gas to emit immediately, be warmed up to 110 ℃, TLC detects no 5-methyluridine after 5 hours, reclaim under reduced pressure DMF, adding 160mL ethanol-acetone in light brown residue (1: 1, v/v) mixed solution refluxes and stirs down, there is solid to produce, cooled and filtered, filter cake soaks with the above mixed solvent of 80mL, and 40 ℃ were stirred 15 minutes down, cold filtration gets pulverous 2, the 2 '-dehydration-5-of clear crystal methyluridine 76g (yield 81%).m.p.：226-227℃；Rf＝0.17?on?TLCin?AcOEt/MeOH(9∶1，v/v)。1H-NMR(DMSO-D6，ppm)δ：1.86(s，CH3)，3.24(m，CH2)，4.07(m，OH)，4.38(m，OH)，4.70(m，CH)，5.18(m，CH)，5.89(d，CH)，6.29(d，CH)，7.74(s，CH)。
Embodiment 4:
Preparation 2,2 '-dehydration-5-methyluridine (CMU)
100g 5-methyluridine (0.39mol) and 65g diethyl carbonate (0.55mol) and 2g KHCO
3, add among the anhydrous 100mL DMA, be warmed up to 110 ℃ under stirring, TLC detects no 5-methyluridine after 5 hours, and reclaim under reduced pressure DMA added 180mL ethanol-ethyl acetate (4: 6 in light brown residue, v/v) mixed solution, 70 ℃ are stirred down, have solid to produce cooled and filtered, filter cake soaks with the above mixed solvent of 80mL, stirred 20 minutes down at 50 ℃, cold filtration gets 2,2 ' of colorless solid-dehydration-5-methyluridine 78g (yield 84%).
Claims (9)
1,2, following graphic being expressed as follows of the preparation method of 2 '-anhydro uridine compound (II):
In the formula: R can be H, C
1-C
4Alkyl, vinyl, propenyl, proyl, halogen, phenyl; R ' can be H, C
1-C
3Alkyl; R " can be methyl, ethyl, sec.-propyl or phenyl; Uridine derivatives (I) is added to and contains small amount of N aHCO
3Or KHCO
3Anhydrous DMF or DMA in, with carbonic diester [(R " O)
2CO] be dewatering agent, temperature of reaction is 85-130 ℃, it is characterized in that: decompression and solvent recovery after reaction is finished adds the mixing solutions of mainly being made up of ethanol and acetone, dioxane, ethyl acetate and/or acetonitrile in residue.
2, according to the preparation method of the described anhydro uridine compound of claim 1 (II), it is characterized in that: temperature of reaction is 95-120 ℃, decompression and solvent recovery under temperature of reaction.
3, according to the preparation method of the described anhydro uridine compound of claim 2 (II), it is characterized in that: temperature of reaction is 100-110 ℃, decompression and solvent recovery under temperature of reaction.
4, according to the preparation method of the described anhydro uridine compound of claim 1 (II), it is characterized in that: add the mixing solutions of mainly being made up of ethanol and acetone, dioxane, ethyl acetate and/or acetonitrile in residue, the ratio of ethanol and acetone, dioxane, ethyl acetate and/or acetonitrile is 1: 1-10: 1.
5, according to the preparation method of the described anhydro uridine compound of claim 4 (II), it is characterized in that: add the mixing solutions that ethanol and acetone are formed in residue, the ratio of ethanol and acetone is 1: 1-2: 1.
6, according to the preparation method of the described anhydro uridine compound of claim 4 (II), it is characterized in that: add the mixing solutions that ethanol and acetonitrile are formed in residue, the ratio of ethanol and acetonitrile is 1: 1-2: 1.
7, according to the preparation method of the described anhydro uridine compound of claim 4 (II), it is characterized in that: add the mixing solutions that ethanol and dioxane are formed in residue, the ratio of ethanol and dioxane is 7: 1-9: 1.
8, according to the preparation method of the described anhydro uridine compound of claim 4 (II), it is characterized in that: add the mixing solutions that ethanol and ethyl acetate are formed in residue, the ratio of ethanol and ethyl acetate is 1: 1-9: 1.
9, the preparation method of described according to Claim 8 anhydro uridine compound (II) is characterized in that: add the mixing solutions that ethanol and ethyl acetate are formed in residue, the ratio of ethanol and ethyl acetate is 1: 1-7: 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011373970A CN1169823C (en) | 2001-12-18 | 2001-12-18 | Preparation method of 2,2'-anhydro uridine compound |
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|---|---|---|---|
| CNB011373970A CN1169823C (en) | 2001-12-18 | 2001-12-18 | Preparation method of 2,2'-anhydro uridine compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500446A (en) * | 2020-12-11 | 2021-03-16 | 平江县吉成科技有限责任公司 | Synthetic method of 2 '-fluoro-2' -deoxyuridine |
| CN117551155A (en) * | 2024-01-08 | 2024-02-13 | 苏州诺维康生物科技有限公司 | Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine |
-
2001
- 2001-12-18 CN CNB011373970A patent/CN1169823C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500446A (en) * | 2020-12-11 | 2021-03-16 | 平江县吉成科技有限责任公司 | Synthetic method of 2 '-fluoro-2' -deoxyuridine |
| CN117551155A (en) * | 2024-01-08 | 2024-02-13 | 苏州诺维康生物科技有限公司 | Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine |
| CN117551155B (en) * | 2024-01-08 | 2024-03-29 | 苏州诺维康生物科技有限公司 | Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine |
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| CN1169823C (en) | 2004-10-06 |
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