CN101723945A - Method for preparing antiviral medicinal entecavir intermediate - Google Patents
Method for preparing antiviral medicinal entecavir intermediate Download PDFInfo
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- CN101723945A CN101723945A CN200810201332A CN200810201332A CN101723945A CN 101723945 A CN101723945 A CN 101723945A CN 200810201332 A CN200810201332 A CN 200810201332A CN 200810201332 A CN200810201332 A CN 200810201332A CN 101723945 A CN101723945 A CN 101723945A
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Abstract
The invention relates to a method for preparing an antiviral medicinal entecavir intermediate compound with a formula I. An oxidation system formed by TEMPO and iodine under an alkali condition is adopted to oxidize a compound with a formula III to obtain a compound with a formula II, and methylenation is carried out on the formula II by a methylenation system formed by titanium tetrachloride, magnesium, methylene chloride and tetrahydrofuran to obtain the compound with the formula I. The invention has easy acquirement of raw materials and simple and convenient method and is suitable for industrialized production.
Description
Technical field:
The present invention relates to medication preparation.Be specifically related to a kind of improved method for preparing the antiviral drug of Entecavir intermediate.
Background technology:
Entecavir (Entecavir) chemistry is by name: (1S, 3R, 4S)-9-[4-hydroxyl-(3-methylol)-2-methylene radical cyclopentyl]-guanine.Structural formula is;
Molecular formula is C
12H
15N
5O
3, molecular weight is 277.3
Entecavir is a kind of deoxyguanosine analogue that effectively, optionally suppresses hepatitis B replication, has the effect of extremely strong inhibition hepatitis B virus duplication, reduction serum-virus dna level.This compound selective is than higher simultaneously, and its cytotoxicity is 1/8000 of an anti-hepatitis B virus activities, can effectively treat chronic viral hepatitis B and does not disturb influenza virus and HIV virus, and safe in utilization, tolerance is good.
U.S. Pat 5206244 has announced the preparation of Entecavir in 1993 and as the purposes of HBV inhibitor, the preparation method after the improvement is disclosed in WO98/09964 and Bioorganic﹠amp; MedicinalChemistry Letters, Vol.7, No.2, pp.127-132,1997.Above-mentioned document has all been reported with formula III compound (1S; 2S; 3S; 5S)-and 3-benzyloxy-5-[-6-benzyloxy-2-[[(4-p-methoxy-phenyl) diphenyl-methyl]-amino] 9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanol is an important intermediate; after oxidation and methylenation reaction, obtain formula I (1S; 3R; 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine, thus and then remove protecting group and obtain Entecavir.
Formula III
Formula II formula I
With respect to US5206244, WO98/09964 and Bioorganic﹠amp; Medicinal ChemistryLetters; Vol.7; No.2; pp.127-132; 1997 greatest improvement part has been to use different oxygenants and methylenation reagent to come the formula III compound is transformed; they have used Dess-Martin reagent to come the hydroxyl in the oxidation formula III to become ketone to obtain formula II compound (2R first; 3S; 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl] the 2-[(benzyloxy) methyl]-cyclopentanone; obtain methylenation product formula I compound (1S through Nysted reaction or Tebbe reaction or improved Lombardo reaction again; 3R; 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine; at last, formula I compound removes protecting group and obtains Entecavir.Wherein, formula I compound (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine, be the important intermediate of preparation Entecavir.This improved method has improved the reaction yield of committed step by changing oxygenant and methylenation reagent, thereby has improved the whole yield of reaction.The report of a series of preparation Entecavirs of announcing has again all used the reaction of Dess-Martin oxidation and Nysted methylenation after this.Yet the Dess-Martin oxygenant costs an arm and a leg, and to air and water vapor sensitive, should not preserve.Nysted reagent costs an arm and a leg too, and is extremely responsive to air and steam, should not preserve, and the diverse and complicated again complexity of self-control process needs severe condition such as low temperature, unsuitable suitability for industrialized production.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the research and design easy handling, good stability, the circulation ratio height, supplementary material is easy to get, be easy to suitability for industrialized production Entecavir important intermediate formula I compound (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-preparation method of 9H-purine-2-amine.
The invention provides a kind of preparation antiviral drug of Entecavir intermediate formula I compound (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-method of 9H-purine-2-amine.
The present invention is that Dess-Martin oxidizing reaction and the reaction of Nysted methylenation improve to the committed step of preparation Entecavir, adopt TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyradical) and the oxidation system that under alkaline condition, forms of iodine replace the Dess-Martin oxidation system, employing replaces Nysted methylenation reaction system by the formed methylenation system of titanium tetrachloride, magnesium, methylene dichloride and tetrahydrofuran (THF), and is respond well.
The preparation method of Entecavir intermediate of the present invention (formula I compound) may further comprise the steps:
(a) be starting raw material with the formula III compound, under alkali and solvent existence condition, the acting in conjunction of TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyradical) and iodine, oxidation formula III compound production II compound.
Formula III formula II
Wherein alkali comprises: NaOH, KOH, Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, Et
3N, pyridine etc., preferred NaHCO
3Solvent comprises: methylene dichloride, toluene, benzene, tetrahydrofuran (THF) etc., preferred methylene dichloride.Preferred 0～30 ℃ of temperature of reaction, the reaction times is 2～10 hours.
(b) the product formula II compound that obtains is carried out methylenation reaction: formula II compound with by the formed methylenation system reaction of titanium tetrachloride, magnesium, methylene dichloride and tetrahydrofuran (THF), form methylenation product formula I compound.
Formula II formula I
Wherein: the mol ratio of formula II and titanium tetrachloride, magnesium, methylene dichloride, tetrahydrofuran (THF) is 1: 1～5: 2～10: 100～150: 30～50, preferred 1: 2 of the mol ratio of titanium tetrachloride and magnesium; Preferred 1: 2: 34 of the mol ratio of titanium tetrachloride, magnesium, methylene dichloride, tetrahydrofuran (THF): 11, the reaction times is 1～2 hour, temperature of reaction is 0～25 ℃.
Adopt the key intermediate formula I compound of the inventive method gained, after removing protecting group, promptly get antiviral drug of Entecavir.
Raw material used in the present invention all can conveniently be buied by commercially available, and starting raw material formula (III) compound also can be according to currently known methods (Bioorganic﹠amp; Medicinal Chemistry Letters, Vol.7, No.2, pp.127-132,1997) preparation voluntarily, be suitable for suitability for industrialized production.
Embodiment
By following examples the present invention is further elaborated.
Embodiment 1 preparation (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Add (1S in the 500ml three-necked bottle, 2S, 3S, 5S)-and 3-benzyloxy-5-[-6-benzyloxy-2-[[(4-p-methoxy-phenyl) diphenyl-methyl]-amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanol (formula III) (20g, 24.3mmol) and methylene dichloride (300ml), stirring and dissolving stirs adding saturated sodium bicarbonate aqueous solution (60ml) down, stirs 10 minutes.Add then iodine (13g, 51.2mmol) and TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyradical) (0.5g, 3.2mmol), reaction solution stirred 5 hours down at 20 ℃.Be cooled to 0 ℃, add 10% sodium sulfite solution (100ml), stirred 15 minutes.Separatory, water layer merges organic phase with ethyl acetate (80ml) extraction, uses the washing of saturated potassium hydrogen carbonate solution (160ml) and saturated aqueous common salt (160ml) respectively.Organic layer anhydrous sodium sulfate drying after the washing filters, and the filtrate evaporate to dryness gets spumescence solid type II (19.2g), yield 96%.
Embodiment 2 preparations (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Change the saturated sodium bicarbonate aqueous solution among the embodiment 1 (60ml) into saturated aqueous sodium carbonate (60ml), other is operated with embodiment 1, yield 90%.
Embodiment 3 (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Change the saturated sodium bicarbonate aqueous solution among the embodiment 1 (60ml) into saturated 2M aqueous sodium hydroxide solution (150ml) other operation with embodiment 1, yield 75%.
Embodiment 4 (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Change the saturated sodium bicarbonate aqueous solution among the embodiment 1 (60ml) into unsaturated carbonate aqueous solutions of potassium (60ml) other operation with embodiment 1, yield 73%.
Embodiment 5 (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Change the solvent among the embodiment 1 into toluene (300ml) by methylene dichloride (300ml), other is operated with embodiment 1, yield 70%.
Embodiment 6 (2R, 3S, 5S)-and 3-benzyloxy-5-[6-benzyloxy-2-[[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone (formula II)
Add (1S in the 1000ml three-necked bottle, 2S, 3S, 5S)-and 3-benzyloxy-5-[-6-benzyloxy-2-[[(4-p-methoxy-phenyl) diphenyl-methyl]-amino] 9H-purine-9-yl]-2-(benzyloxy) methyl-cyclopentanol (formula III) (20g, 24.3mmol) and methylene dichloride (300ml), stirring and dissolving stirs adding saturated sodium bicarbonate aqueous solution (60ml) down, stirs 10 minutes.Add then iodine (65g, 256mmol) and TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyradical) (2.5g, 16mmol), reaction solution stirred 1 hour down at 20 ℃.Be cooled to 0 ℃, add 10% sodium sulfite solution (500ml), stirred 15 minutes.Separatory, water layer merges organic phase with ethyl acetate (80ml) extraction, uses the washing of saturated potassium hydrogen carbonate solution (160ml) and saturated aqueous common salt (160ml) respectively.Organic layer anhydrous sodium sulfate drying after the washing filters, and the filtrate evaporate to dryness gets spumescence solid type II (18.6g), yield 93%.
Embodiment 7 (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine (formula I)
Under the nitrogen atmosphere, in three-necked bottle, add magnesium (4.07g, 167.4mmol) and methylene dichloride (92ml 1436mmmol), is cooled to 0 ℃, stir add down titanium tetrachloride (9.2ml, 83.7mmol).With formula II (19.2g, methylene dichloride 23.4mmol) (92ml, 1436mmol) and tetrahydrofuran (THF) (77ml, mixed solution 950mmol) is added dropwise in the reaction solution, temperature was not higher than 5 ℃ in the control rate of addition made, and dripped off back 0 ℃ and stirred 20 minutes.Rise to stirring at room half an hour then, be cooled to 0 ℃ again.Add unsaturated carbonate potassium solution (220ml) and ethyl acetate (220ml), stirred separatory 15 minutes.The water layer ethyl acetate extraction merges organic phase, the saturated common salt water washing, and separatory, the organic layer anhydrous sodium sulfate drying filters, and the filtrate evaporate to dryness gets pure products formula I (10.3g), yield 54% behind the column chromatography.The detected result of formula I is:
1HNMR(DMSO-d
6)：7.83(s，1H)，7.13-7.35(m，29H)，6.75(d，2H)，5.25(br，1H)，5.07(s，2H)，4.41-4.52(m，5H)，3.95(b，1H)，3.67(s，3H)，3.51(m，1H)，3.40(br，1H)，2.91(m，1H)，2.23(m，1H)，2.06(m，IH)
Embodiment 8 (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine (formula I)
The amount of the magnesium among the embodiment 7 is changed to (2.04g, 83.7mmol), other operation is constant, yield 42%.
Embodiment 9 (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine (formula I)
The amount of the magnesium among the embodiment 7 is changed to (2.04g, 83.7mmol), the amount of titanium tetrachloride is changed to that (4.5ml, 41.9mmol), other operation is constant, yield 35%
Embodiment 10 (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine (formula I)
Under the nitrogen atmosphere, in three-necked bottle, add magnesium (4.07g, 167.4mmol) and methylene dichloride (46ml 718mmol), is cooled to 0 ℃, stir add down titanium tetrachloride (9.2ml, 83.7mmol).With formula II (19.2g, methylene dichloride 23.4mmol) (46ml, 718mmol) and tetrahydrofuran (THF) (38.5ml, mixed solution 475mmol) is added dropwise in the reaction solution, temperature was not higher than 5 ℃ in the control rate of addition made, and dripped off back 0 ℃ and stirred 20 minutes.Rise to stirring at room half an hour then, be cooled to 0 ℃ again.Add unsaturated carbonate potassium solution (220ml) and ethyl acetate (220ml), stirred separatory 15 minutes.The water layer ethyl acetate extraction merges organic phase, the saturated common salt water washing, and separatory, the organic layer anhydrous sodium sulfate drying filters, and the filtrate evaporate to dryness gets pure products formula I (9.15g), yield 48% behind the column chromatography
Claims (6)
1. method for preparing the antiviral drug of Entecavir intermediate, described intermediate is formula I compound (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine, its structural formula is as follows:
Formula I
It is characterized in that this method may further comprise the steps:
(a) with formula III compound (1S, 2S, 3S, 5S)-and 3-benzyloxy-5-[-6-benzyloxy-2-[[(4-p-methoxy-phenyl) diphenyl-methyl]-amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanol is a starting raw material, under alkali and solvent existence condition, TEMPO and iodine acting in conjunction, oxidation formula III compound production II compound (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[(4-p-methoxy-phenyl) diphenyl methyl] amino]-9H-purine-9-yl]-the 2-[(benzyloxy) methyl]-cyclopentanone:
Formula III formula II
；
(b) the formula II compound that obtains is carried out methylenation reaction: formula II compound with by the formed methylenation system reaction of titanium tetrachloride, magnesium, methylene dichloride and tetrahydrofuran (THF), obtain formula I compound (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene radical-4-benzyloxy-3-(benzyloxy) methyl]-cyclopentyl]-the N-[(4-p-methoxy-phenyl) diphenyl-methyl]-9H-purine-2-amine:
Formula II formula I
。
2. a kind of method for preparing the Entecavir intermediate according to claim 1, the alkali that it is characterized in that described step (a) is NaOH, KOH, Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, Et
3N or pyridine; Solvent is a methylene dichloride, toluene, benzene or tetrahydrofuran (THF); Temperature of reaction is 0～30 ℃, and the reaction times is 0～10 hour.
3. according to the method for claim 2, the alkali that it is characterized in that described step (a) is NaHCO
3Solvent is a methylene dichloride.
4. a kind of method for preparing the Entecavir intermediate according to claim 1, it is characterized in that in the described step (b): the mol ratio of formula II and titanium tetrachloride, magnesium, methylene dichloride, tetrahydrofuran (THF) is 1: 1～5: 2～10: 100～150: 30～50; Temperature of reaction is 0～25 ℃; Reaction times is 1～2 hour.
5. according to the method for claim 4, it is characterized in that the mol ratio of described step (b) titanium tetrachloride, magnesium, methylene dichloride, tetrahydrofuran (THF) is 1: 2: 34: 11.
6. according to the method for claim 4, the mol ratio that it is characterized in that described titanium tetrachloride and magnesium is 1: 2.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103739603A (en) * | 2013-12-27 | 2014-04-23 | 辰欣药业股份有限公司 | Preparation method of hepatitis B therapeutic entecavir |
| CN106749251A (en) * | 2017-01-17 | 2017-05-31 | 博瑞生物医药泰兴市有限公司 | A kind of synthesis of entecavir midbodies and method of purification |
| CN108586460A (en) * | 2018-05-30 | 2018-09-28 | 石家庄学院 | A kind of preparation method of entecavir midbodies |
| CN111732589A (en) * | 2020-06-08 | 2020-10-02 | 王乔 | Improved entecavir intermediate synthesis process and improved entecavir synthesis process |
| CN112274516A (en) * | 2020-10-26 | 2021-01-29 | 中山大学附属第三医院 | Novel iodine-containing antiviral drug |
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| CN110713491B (en) * | 2018-07-13 | 2022-03-11 | 罗欣药业(上海)有限公司 | Synthetic method of entecavir intermediate |
Family Cites Families (2)
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| CA2508811C (en) * | 2002-12-11 | 2014-11-18 | Bristol-Myers Squibb Company | Process for preparing the antiviral agent [1s-(1.alpha., 3.alpha., 4.beta.)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one |
| CN101210015B (en) * | 2006-12-26 | 2010-09-22 | 上海国创医药有限公司 | Method for preparing hepatitis B therapeutic medicament entecavir |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103739603A (en) * | 2013-12-27 | 2014-04-23 | 辰欣药业股份有限公司 | Preparation method of hepatitis B therapeutic entecavir |
| CN106749251A (en) * | 2017-01-17 | 2017-05-31 | 博瑞生物医药泰兴市有限公司 | A kind of synthesis of entecavir midbodies and method of purification |
| CN108586460A (en) * | 2018-05-30 | 2018-09-28 | 石家庄学院 | A kind of preparation method of entecavir midbodies |
| CN111732589A (en) * | 2020-06-08 | 2020-10-02 | 王乔 | Improved entecavir intermediate synthesis process and improved entecavir synthesis process |
| CN112274516A (en) * | 2020-10-26 | 2021-01-29 | 中山大学附属第三医院 | Novel iodine-containing antiviral drug |
| CN112274516B (en) * | 2020-10-26 | 2022-08-05 | 中山大学附属第三医院 | Novel iodine-containing antiviral drug |
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