CN112625041A - Novel preparation method and intermediate of entecavir - Google Patents

Novel preparation method and intermediate of entecavir Download PDF

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CN112625041A
CN112625041A CN202011563634.XA CN202011563634A CN112625041A CN 112625041 A CN112625041 A CN 112625041A CN 202011563634 A CN202011563634 A CN 202011563634A CN 112625041 A CN112625041 A CN 112625041A
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刘向群
陈宣福
李强
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Hunan Huana Large Pharmaceutical Factory Chiral Medicament Co ltd
Changzhou Bohaiwei Pharmaceutical Technology Co ltd
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Hunan Huana Large Pharmaceutical Factory Chiral Medicament Co ltd
Changzhou Bohaiwei Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a novel intermediate for synthesizing entecavir, compounds shown in formula II and formula III, and a novel method for synthesizing entecavir by utilizing the novel intermediate. The new intermediate of the invention is used for synthesizing the entecavir, which not only can obviously improve the synthesis yield, but also can reduce the production cost.

Description

Novel preparation method and intermediate of entecavir
Technical Field
The present invention relates to the field of chemical synthesis. In particular, the present invention relates to a novel process for the preparation of entecavir and to novel chiral intermediates involved therein.
Background
Entecavir (Entecavir) has the chemical name: (1S,3R,4S) -9- [ 4-hydroxy- (3-hydroxymethyl) -2-methylenecyclopentyl]-6H-purin-6-one. The molecular formula is as follows: c12H15O3N5Molecular weight: 277.3, structureThe formula is as follows:
Figure BDA0002861042090000011
entecavir was developed by Bristol-Myers squibb, USA and approved by the food and drug administration for marketing 3 months 2005. Is an effective and selective deoxyguanosine analogue for inhibiting the replication of hepatitis B virus, and has extremely strong effects of inhibiting the replication of hepatitis B virus and reducing the DNA level of serum virus. Meanwhile, the compound has high selectivity, the cytotoxicity of the compound is 1/8000 for resisting the activity of hepatitis B virus, the compound can effectively treat chronic hepatitis B without interfering influenza virus and HIV virus, and the compound is safe to use and good in tolerance.
US5206244 published in 1993 the preparation of entecavir and its use as an HBV inhibitor. The preparation method disclosed by the invention takes cyclopentadiene as an initial raw material, and entecavir is obtained through multi-step synthesis (flow 1). And then a plurality of patent documents are improved on the basis of the method. However, the control of optical impurities is difficult due to the gradual introduction of chiral centers in this route. More column chromatography steps are needed in the reaction process, and the yield is lower.
Scheme 1
Figure BDA0002861042090000021
WO2004/052310(Bristol-Myers squibb) discloses a number of synthetic methods, one of which employs a route which uses (+) -Corylactone diol as starting material (scheme 2). The initial raw material is an enantiomer obtained by splitting a prostaglandin initial raw material (-) -Coreylone diol, and the intermediate has no other use applications. Therefore, the intermediate is reasonably utilized, the cost can be reduced, the waste treatment cost is reduced, and the environment is protected. The advantage of using (+) -Corylactone diol as starting material is that all the chiral centres required for the product are already present in the starting material. The raw materials have good optical purity and extremely low optical isomers. Only part of functional groups need to be converted to synthesize the entecavir subsequently. The chiral purity of the final product is excellent.
Scheme 2
Figure BDA0002861042090000022
However, the process 2 has problems in that the yield of the intermediate I and 2-amino-6-chloropurine in the butt reaction is low, and the purity of the intermediate V is poor, which affects the economy of the whole route.
Therefore, the need exists in the art to develop a new method for synthesizing entecavir, which can use intermediate I as a starting material, and at the same time, can greatly improve the synthesis yield of entecavir and reduce the production cost.
Disclosure of Invention
The invention aims to provide a brand-new entecavir synthesis method, which can obviously improve the synthesis yield of entecavir and reduce the production cost.
It is another object of the present invention to provide novel intermediates useful in the synthesis of entecavir.
In a first aspect, the present invention provides a method for synthesizing entecavir, comprising the steps of:
1) reacting a compound shown in a formula I with a compound shown in a formula II to obtain a compound shown in a formula III; and
Figure BDA0002861042090000031
2) reacting the compound shown in the formula III to obtain entecavir;
Figure BDA0002861042090000032
wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
In a preferred embodiment, the reaction solvent in step 1) is tetrahydrofuran or toluene.
In a specific embodiment, the compound of formula II is synthesized as follows:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure BDA0002861042090000033
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure BDA0002861042090000034
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure BDA0002861042090000041
in a particular embodiment, in step a), the polar solvent is selected from DMF, DMSO, methanol or ethanol or a combination thereof; and/or
In step b), the non-polar solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate or a combination thereof; the organic basic reagent is selected from triethylamine, N-diisopropylethylamine, DBU or a combination thereof; and/or
In step c), the polar solvent is selected from methanol, ethanol or a combination thereof; the inorganic alkaline agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
In a second aspect, the present invention provides a compound of formula II,
Figure BDA0002861042090000042
wherein R is1Is an optionally substituted trityl or (4-methoxyphenyl) benzhydryl.
In a third aspect, the present invention provides a method of synthesizing a compound of formula II, said method comprising the steps of:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure BDA0002861042090000043
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure BDA0002861042090000051
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure BDA0002861042090000052
in a preferred embodiment, in step a), the polar solvent is selected from DMF, DMSO, methanol or ethanol or a combination thereof; and/or
In step b), the non-polar solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate or a combination thereof; the organic basic reagent is selected from triethylamine, N-diisopropylethylamine, DBU or a combination thereof; and/or
In step c), the polar solvent is selected from methanol, ethanol or a combination thereof; the inorganic alkaline agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
In a fourth aspect, the invention provides a compound of formula III
Figure BDA0002861042090000053
Wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
In a fifth aspect, the present invention provides a method of synthesizing a compound of formula III, the method comprising the steps of:
1) reacting a compound shown in a formula I with a compound shown in a formula II to obtain a compound shown in a formula III;
Figure BDA0002861042090000061
8. the method of claim 7, wherein the compound of formula II is synthesized by:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure BDA0002861042090000062
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure BDA0002861042090000063
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure BDA0002861042090000064
in a preferred embodiment, in step a), the polar solvent is selected from DMF, DMSO, methanol or ethanol or a combination thereof; and/or
In step b), the non-polar solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate or a combination thereof; the organic basic reagent is selected from triethylamine, N-diisopropylethylamine, DBU or a combination thereof; and/or
In step c), the polar solvent is selected from methanol, ethanol or a combination thereof; the inorganic alkaline agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
In a sixth aspect, the invention provides a use of a compound shown as a formula II or a compound shown as a formula III for synthesizing entecavir
Figure BDA0002861042090000071
Wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have conducted extensive and intensive studies and unexpectedly found a novel intermediate with a novel structure for synthesizing entecavir. The intermediate is used for synthesizing the entecavir, so that the yield of the entecavir can be obviously improved, and the production cost is reduced. The present invention has been completed based on this finding.
Intermediates of the invention and uses thereof
The invention provides a brand new intermediate for synthesizing entecavir. As used herein, "intermediate" or "intermediate of the invention" have the same meaning and refer to a compound of formula II or formula III
Figure BDA0002861042090000081
Wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
As used herein, the term "optionally substituted" means that the group modified by the term may be substituted with one or more (e.g., 1, 2, or 3) substituents selected from the group consisting of: hydroxyl, nitro, halogen (e.g., F, Cl or Br), C1-C4 alkyl (e.g., methyl, ethyl, propyl), C1-C4 alkoxy (e.g., methoxy, ethoxy), etc., as long as such substitution is in accordance with valence principles or is synthetically feasible.
The intermediate shown in the formula II can be synthesized by the following method:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure BDA0002861042090000082
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure BDA0002861042090000083
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure BDA0002861042090000091
wherein R is1As described above.
In specific embodiments, the polar solvent in step a) is selected from DMF, DMSO, methanol or ethanol or a combination thereof; and/or, the non-polar solvent in step b) is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate or combinations thereof; the organic basic reagent is selected from triethylamine, N-diisopropylethylamine, DBU or a combination thereof; and/or, the polar solvent in step c) is selected from methanol, ethanol or a combination thereof; the inorganic alkaline agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
The invention further provides an intermediate shown in a formula III on the basis of the intermediate shown in the formula II. The intermediate of formula III can be synthesized as follows:
reacting a compound shown in a formula I with a compound shown in a formula II to obtain a compound shown in a formula III;
Figure BDA0002861042090000092
wherein R is1And R2As described above.
Method for synthesizing entecavir
The invention provides a method for synthesizing entecavir (entecavir) on the basis of the intermediate of the invention, namely the compound shown in formula II or formula III. The method is as follows:
Figure BDA0002861042090000093
wherein R is1And R2As described above.
The main advantages of the invention include:
1. the invention provides a new intermediate for synthesizing the entecavir, thereby laying a new material foundation for the synthesis of the entecavir;
2. by adopting the entecavir synthesis method, the synthesis yield of the entecavir is obviously improved;
3. by adopting the entecavir synthesis method, the production cost of the entecavir is obviously reduced, thereby having obvious economic value.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples are experimental procedures without specific conditions noted, or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1 preparation of Compound represented by formula (II-1)
Figure BDA0002861042090000101
Adding 1.0kg of 2-amino-6-chloropurine into DMF9.5kg, cooling to-5-0 ℃ by a cold well, adding (Boc)2O1400g and DMAP 1.5g, controlling the temperature to be 0-5 ℃ to react for 2-3 hours, changing the reaction liquid from white turbid liquid to light yellow clear liquid, detecting the reaction by TLC completely, slowly adding ice water 20.0kg into the reaction liquid to separate out a large amount of white solid, stirring for 1 hour, filtering, and leaching the filter cake with pure water. Drying to obtain 1511.0g of structural formula (II-1) with the yield of 95%.
Example 2 preparation of Compound represented by formula (II-2)
Wherein R is1Is trityl
Figure BDA0002861042090000102
Adding 1.0kg of a compound shown in a structural formula (II-1) into 13.25kg of dichloromethane, adding 2688.0g of triphenylchloromethane and 18.1g of DMAP, cooling to 10-15 ℃ through a cold well, slowly adding triethylamine, controlling the temperature within T to be less than 20 ℃, completely reacting at 23-28 ℃ for 5 days, detecting by TLC to completely react, adding 10.0kg of ice water into a reaction solution, stirring for 10 minutes, standing for layering, carrying out back extraction on a water layer for 2 times by using 4.5kg of dichloromethane 2, combining dichloromethane layers, washing by using saturated saline, stirring for layering, drying an organic layer by using magnesium sulfate, filtering and concentrating to obtain 1860.0g of a brown oily structural formula (II-2), wherein the yield is 98%.
Example 3 preparation of Compound represented by formula (II-2)
Wherein R is1Is (4-methoxyphenyl) benzhydryl
Figure BDA0002861042090000111
Adding 13.25kg of dichloromethane into 1.0kg of structural formula (II-1), adding 3131.7g of (4-methoxyphenyl) diphenylchloromethane and 18.1g of DMAP, cooling to 10-15 ℃ through a cold well, slowly adding triethylamine, controlling the temperature within T to be less than 20 ℃, completely controlling the temperature to be 23-28 ℃ to react for 5 days, detecting the reaction by TLC (thin layer chromatography), adding 10.0kg of ice water into the reaction liquid, stirring for 10 minutes, standing for layering, carrying out back extraction on a water layer by using 4.5kg of dichloromethane 2 for 2 times, combining dichloromethane layers, washing by using saturated saline, stirring for layering, drying an organic layer by using magnesium sulfate, filtering and concentrating to obtain 1889.0g of brown oily matter structural formula (II-2), wherein the yield is 94%.
Example 4 preparation of a Compound of formula (II)
Figure BDA0002861042090000112
Adding 1000.0g of a compound shown as a formula (II-2) into 7.9kg of methanol, stirring for dissolving, adding 350.0g of potassium carbonate at 20-25 ℃, reacting for 1-2 hours at 20-25 ℃, detecting by TLC that the reaction is complete, filtering the reaction solution, concentrating the filtrate to remove the methanol, adding 10.0kg of dichloromethane and 10.0kg of water, stirring for layering, extracting an aqueous layer with 2.5kg of dichloromethane 2 for 2 times, combining organic layers, adding 10.0kg of water, stirring for layering, adding 10.0kg of saturated saline, stirring for layering, drying the organic layer with magnesium sulfate, filtering, concentrating to obtain a crude product, and recrystallizing with toluene to obtain 683.8g of a white solid shown as a formula (II). The yield thereof was found to be 85%.
1H-NMR(CDCl3)δ6.614(s,1H),δ7.137-7.357(m,15H),δ7.456(s,1H),δ10.155(bs,1H)。
MS(M+Na)434.14。
Example 5 preparation of the Compound of formula (III)
Wherein R is1Is trityl, R2Is tert-butyl dimethyl silicon base
Figure BDA0002861042090000121
Under the protection of nitrogen, 1000.0g of the compound shown in the formula (I) is dissolved in 20.0L of THF, 1326.3g of the compound shown in the formula (II) and 915.4g of triphenylphosphine are added, the temperature of a cold well is reduced to-45 to-40 ℃, DIAD 705.7g is added dropwise, the temperature is controlled to-40 ℃ for reaction for 2 hours, the TLC detects the reaction is complete, the THF is removed from the reaction solution, and the residue is purified by a silica gel column to obtain 2016.0g of the compound shown in the formula (III) with the yield of 98%.
1H-NMR(CDCl3)δ0.013-0.081(m,12H),δ0.876-0.918(dm,18H),δ1.302(s,1H),δ1.763(bs,2H),δ2.501(s,1H),δ3.675-3.686(dm,2H),δ4.240(d,1H),δ4.612(s,1H),δ4.901-4.998(bs,1H),δ5.092(s,1H),δ6.610(s,1H),δ7.180-7.676(m,15H)。
MS(ES+)766.19。
Example 6 preparation of Compound of formula (III)
Wherein R is1Is (4-methoxyphenyl) benzhydryl, R2Is tert-butyl dimethyl silicon base
Figure BDA0002861042090000122
Under the protection of nitrogen, 1000.0g of the compound shown in the formula (I) is dissolved in 20.0L of THF, 1423.0g of the compound shown in the formula (II) and 915.4g of triphenylphosphine are added, the temperature of a cold well is reduced to-45 to-40 ℃, DIAD 705.7g is added dropwise, the temperature is controlled to-40 ℃ for reaction for 2 hours, the TLC detects the reaction is complete, the THF is removed from the reaction solution, and the residue is purified by a silica gel column to obtain 2030.0g of the compound shown in the formula (III) with the yield of 95%.
Example 7 preparation of Compound of formula (III)
Wherein R is1Is trityl, R2Is benzyl
Figure BDA0002861042090000131
Under the protection of nitrogen, 1000.0g of the compound shown in the formula (I) is dissolved in 20.0L of THF, 1523.6g of the compound shown in the formula (II) and 1051.1g of triphenylphosphine are added, the temperature of a cold well is reduced to-45 to-40 ℃, 810.3g of DIAD is added dropwise, the temperature is controlled to-40 ℃ for reaction for 2 hours, the TLC detects the reaction is complete, the THF is removed from the reaction solution, and the residue is purified by a silica gel column to obtain 2103.0g of the structural formula (III) with the yield of 96%.
EXAMPLE 8 preparation of Entecavir
Wherein R is1Is trityl, R2Is tert-butyl dimethyl silicon base
Figure BDA0002861042090000132
Dissolving 1000.0g of crude product of the compound shown in the formula (III) in 2.0L of methanol at 80 ℃ in an external bath, slowly adding 2.0L of 3N HCl, keeping reflux reaction for 8 hours, completely detecting by TLC, cooling to 20-25 ℃, adding 3.0L of dichloromethane, stirring for layering, back-extracting a water layer with 1.0L of 3 dichloromethane, concentrating the water layer to remove the methanol, adjusting the pH of a residual water layer to 7.0 by using 50% NaOH, separating out a large amount of white solid, stirring for 30min at 0-5 ℃, filtering to obtain the crude product, recrystallizing the crude product by using pure water, filtering, and drying to obtain 262.0g of white solid (entecavir), wherein the yield is 68%, and the HPLC is 99.8%.
EXAMPLE 9 preparation of Entecavir (entecavir)
Wherein R is1Is (4-methoxyphenyl) benzhydryl, R2Is tert-butyl dimethyl silicon base
Figure BDA0002861042090000133
Dissolving 1000.0g of crude product of the compound shown in the formula (III) in 1.9L of methanol at 80 ℃ in an external bath, slowly adding 1.9L of 3N HCl, keeping reflux reaction for 8 hours, completely detecting by TLC, cooling to 20-25 ℃, adding 2.7L of dichloromethane, stirring and layering, back-extracting a water layer with 1.0L of 3 dichloromethane, concentrating the water layer to remove the methanol, adjusting the pH of a residual water layer to 7.0 by using 50% NaOH, separating out a large amount of white solid, stirring at 0-5 ℃ for 30min, filtering to obtain the crude product, recrystallizing the crude product by using pure water, filtering, and drying to obtain 237.3g of white solid (entecavir), wherein the yield is 64% and the HPLC is 99.8%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (9)

1. A method for synthesizing entecavir, comprising the steps of:
1) reacting a compound shown in a formula I with a compound shown in a formula II to obtain a compound shown in a formula III; and
Figure FDA0002861042080000011
2) reacting the compound shown in the formula III to obtain entecavir;
Figure FDA0002861042080000012
wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
2. The method of claim 1, wherein the compound of formula II is synthesized as follows:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure FDA0002861042080000013
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure FDA0002861042080000014
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure FDA0002861042080000021
3. the method of claim 2,
in step a), the polar solvent is selected from DMF, DMSO, methanol or ethanol or a combination thereof; and/or
In step b), the non-polar solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate or a combination thereof; the organic basic reagent is selected from triethylamine, N-diisopropylethylamine, DBU or a combination thereof; and/or
In step c), the polar solvent is selected from methanol, ethanol or a combination thereof; the inorganic alkaline agent is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
4. A compound of the formula II,
Figure FDA0002861042080000022
wherein R is1Is an optionally substituted trityl or (4-methoxyphenyl) benzhydryl.
5. A method for synthesizing a compound of formula II, comprising the steps of:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure FDA0002861042080000023
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure FDA0002861042080000031
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure FDA0002861042080000032
6. a compound of formula III
Figure FDA0002861042080000033
Wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl; r2Is an optionally substituted silyl or benzyl group.
7. A method for synthesizing a compound of formula III, comprising the steps of:
1) reacting a compound shown in a formula I with a compound shown in a formula II to obtain a compound shown in a formula III;
Figure FDA0002861042080000034
8. the method of claim 7, wherein the compound of formula II is synthesized by:
a) reacting 2-amino-6-chloropurine with di-tert-butyl dicarbonate in a polar solvent to obtain a compound shown as a formula II-1;
Figure FDA0002861042080000041
b) reacting a compound represented by the formula II-1 with R1Adding organic alkaline reagent into Cl in a nonpolar solvent to react to obtain a compound shown as a formula II-2;
Figure FDA0002861042080000042
c) reacting a compound shown as a formula II-2 with an inorganic alkaline reagent in a polar solvent to obtain a compound shown as a formula II;
Figure FDA0002861042080000043
9. application of compound shown as formula II or compound shown as formula III in synthesizing entecavir
Figure FDA0002861042080000044
Wherein R is1Is optionally substituted trityl or (4-methoxyphenyl) benzhydryl；R2Is an optionally substituted silyl or benzyl group.
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Citations (11)

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US5206244A (en) * 1990-10-18 1993-04-27 E. R. Squibb & Sons, Inc. Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines
WO2012006964A1 (en) * 2010-07-15 2012-01-19 台州市奥翔医药科技有限公司 Entecavir synthesis method and intermediate compound thereof
CN102596956A (en) * 2009-10-12 2012-07-18 韩美控股株式会社 Novel method for preparing entecavir and intermediate used therein
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