CN111434663B - Entecavir intermediate and synthesis method thereof, and synthesis method of entecavir - Google Patents

Entecavir intermediate and synthesis method thereof, and synthesis method of entecavir Download PDF

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CN111434663B
CN111434663B CN202010039744.XA CN202010039744A CN111434663B CN 111434663 B CN111434663 B CN 111434663B CN 202010039744 A CN202010039744 A CN 202010039744A CN 111434663 B CN111434663 B CN 111434663B
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刘沛
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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
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of organic synthesis, and provides an entecavir intermediate, a synthesis method thereof and a method for synthesizing entecavir by using the entecavir intermediate. The invention has the advantages of easily obtained raw materials, low price, shortest synthesis steps, mild reaction conditions, easy control, simple equipment requirement, high total product yield and easy industrial production.

Description

Entecavir intermediate and synthesis method thereof, and synthesis method of entecavir
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an entecavir intermediate and a synthesis method thereof, and a synthesis method of entecavir.
Background
For the treatment of chronic hepatitis B, six drugs approved by the FDA in the United states are all nucleoside analogs, except for two alpha interferons, which are DNA chain growth terminators in the replication process of hepatitis B virus genes (Table 1).
Figure RE-GDA0002446916240000011
Six nucleoside drugs for treating chronic hepatitis B shown in Table 1 are two prodrugs TDF and TAF of Lamivudine (Lamivudine), Adefovir (Adefovir), Entecavir (Entecavir), telbivudine (Telbevudine) and Tenofovir (Tenofovir), which can be structurally classified into three classes, Lamivudine and telbivudine are L-configuration nucleosides, Adefovir and Tenofovir belong to acyclic nucleosides, and Entecavir is a carbocyclic nucleoside.
The main characteristic of the entecavir structure different from other medicines is the existence of 3' -hydroxyl. The deletion of 3 '-hydroxyl group is recognized as the main characteristic of nucleic acid chain terminator, a large amount of 2', 3 '-dideoxy nucleosides show anti-HIV activity in the early development process of anti-HIV nucleoside drugs, and all current anti-HIV nucleoside drugs and reverse transcriptase inhibitors of HIV virus nucleic acid have no 3' -hydroxyl group. The carbon ring structure of the entecavir is strong in rigidity, after the entecavir is incorporated into a DNA single chain copied by hepatitis B virus, 3' -hydroxyl can be continuously combined with other nucleotides to continuously prolong the DNA copied chain, but the DNA copied chain newly containing the entecavir cannot be completely meshed with the template DNA single chain, and finally stops after a plurality of chain links grow. This behavior of entecavir is known as "delayed" chain termination, which has the advantage that evolution of viral resistance is difficult. In addition, it has been proved that entecavir acts at various stages of HBV DNA replication, competes with deoxyguanosine for the binding site of HBV DNA polymerase, and prevents HBV DNA chain growth from three links of initiation, reverse transcription and DNA plus strand synthesis, so that HBV DNA replication is inhibited. Entecavir is the anti-HBV drug with the strongest drug effect at present, and the HBV infection can be effectively inhibited by orally taking 0.5-1 mg/d.
Because of its extremely high antiviral activity and the low tendency of the virus to develop resistance after long-term use, entecavir is considered to be the most potent and effective of all anti-hepatitis B drugs. But is very expensive due to its difficult preparation.
The original approach to the synthesis of entecavir was reported by the Shibaobao company Bisacchi, 1997 (FIG. 1). Cheap and achiral sodium cyclopentadienide (1) is used as a raw material, a chiral boron reagent is used for asymmetric addition to construct a cyclopentanol carbocycle (2), and a target product is obtained through 12 steps of reaction. The latter people have improved the method (FIG. 1), but most of them are only the use of cheap reagents, the optimization of reaction conditions, or the change of local routes. The main characteristics of the original design, such as the construction of chiral carbocycle and the introduction of 6' -site exocyclic double bond, are reserved, and the improvement space is extremely limited. Thus, the improvement effect on the defects of long whole synthesis steps of the entecavir, severe reaction conditions, high production cost and the like is limited.
In view of the defects of the existing entecavir synthesis method, the invention provides a brand new synthesis route, and can greatly improve the defects of the existing synthesis process.
Disclosure of Invention
The invention aims to make up the defects of the existing entecavir preparation technology and provides a laboratory and industrial production practical process which has the advantages of simple equipment, convenient process, easy operation and greatly improved yield. The invention provides a brand new synthesis route design, the reaction equipment is simple, no special expensive reagent is used, the process condition is easy to control, and the yield is greatly improved.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an entecavir intermediate, which has a structure shown in a formula (1):
Figure RE-GDA0002446916240000031
the invention provides a synthesis method of an entecavir intermediate, which comprises the following steps:
(1) mixing D-2-deoxyribose, 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, organic solvent and acid-binding agent to carry out silicon ether protection reaction to generate compound1；
Figure RE-GDA0002446916240000032
(2) Subjecting the compound to1And ethynyl Grignard reagent in organic solventsTo produce a compound by nucleophilic addition reaction2；
Figure RE-GDA0002446916240000033
(3) Subjecting the compound to2Mixing acid-binding agent, ester protective agent and organic solvent, and reacting to obtain compound3；
The ester protective agent is acyl chloride or acid anhydride, or carboxylic acid and a condensing agent;
the acyl chloride is acetyl chloride or ethyl chloroformate, and acid anhydride such as acetic anhydride;
Figure RE-GDA0002446916240000041
(4) reaction according to 4.1 or 4.2 to give the compound4；
(4.1) subjecting the compound to3Mixing acid-binding agent, modifier and organic solvent, and reacting to obtain compound4(ii) a The modifier is thiocarbonyl chloride, or a mixture of methyl iodide and carbon disulfide, or N, N' -thiocarbonyl diimidazole;
Figure RE-GDA0002446916240000042
(4.2) subjecting the compound to3Mixing the acid-binding agent, the primary modifier and the organic solvent, and then carrying out primary reaction to generate a primary product; the first-stage modifier is methylsulfonyl chloride or trifluoromethylsulfonyl chloride;
carrying out a secondary reaction on the primary product and a secondary modifier to generate a compound4(ii) a The secondary modifier is phenylselenophenol, phenylselenophenol sodium salt or lithium bromide;
Figure RE-GDA0002446916240000043
(5) will make the saidCompound (I)4Mixing hydrogen source and organic solvent, and performing free radical cyclization reaction under the initiation of a free radical initiator to generate a compound5(ii) a The hydrogen source is tri-n-butylstannyl hydride, tri (trimethylsilyl) silane or phenyl silyl ether;
Figure RE-GDA0002446916240000044
(6) subjecting the compound to5And mixing the organic solvent and alkali, and then performing deprotection group reaction to generate the entecavir intermediate.
Preferably, in the step (1), the molar ratio of the D-2-deoxyribose to the 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane is 1 (0.9-1.2);
the organic solvent is dichloromethane, pyridine, N-methyl pyrrolidone or dimethylformamide, and the volume mass ratio of the organic solvent to the D-2-deoxyribose is more than or equal to 3 mL/g;
the acid-binding agent is imidazole or pyridine, and the molar ratio of the acid-binding agent to the D-2-deoxyribose is more than or equal to 1.5;
the temperature of the silicon ether protection reaction in the step (1) is less than or equal to 35 ℃.
Preferably, the compound in step (2)1The molar ratio of the acetenyl Grignard reagent to the acetenyl Grignard reagent is 1 (3-5);
the organic solvent is tetrahydrofuran or dichloromethane;
the temperature of the nucleophilic addition reaction in the step (2) is less than or equal to 0 ℃.
Preferably, the acid-binding agent in the step (3) is triethylamine, diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine, and the compound is2The mol ratio of acyl chloride to the acid binding agent is 1 (1.1-2) to 1.5-3;
the carboxylic acid is benzoic acid, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the compound2The molar ratio of the carboxylic acid to the condensing agent to the acid-binding agent is 1 (1-1.6) to 1.1-2 to 1-20;
the organic solvent is dichloromethane, toluene, tetrahydrofuran or 1, 2-dichloroethane;
the reaction temperature in the step (3) is 0-35 ℃.
Preferably, in the step (4.1), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylaminopyridine;
the organic solvent is dichloromethane or dimethyl sulfoxide;
the reaction temperature is-10-35 ℃.
Preferably, in the step (4.2), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylaminopyridine;
the organic solvent is dichloromethane;
said compounds3The dosage ratio of the acid-binding agent, the primary modifier and the organic solvent is 0.3-1.2 mmol, 0.5-3.2 mmol, 0.5-1.6 mmol and 5-50 mL;
the temperature of the first-stage reaction is-5 ℃, and the time is 0.5-4 h;
the temperature of the secondary reaction is 10-35 ℃, and the time is 5-15 h.
Preferably, the organic solvent in the step (5) is benzene, toluene or dioxane;
the free radical initiator is azobisisobutyronitrile or triethylboron-oxygen;
said compounds4The dosage ratio of the hydrogen source, the free radical initiator and the organic solvent is 0.5-1 mmol: 0.5-2 mmol: 0.05-1 mmol: 10-100 mL;
the reaction temperature of the free radical cyclization reaction is not higher than the reflux temperature of the organic solvent, and the reaction time is 1-24 h.
Preferably, the organic solvent in the step (6) is methanol or ethanol;
the alkali is potassium carbonate, sodium ethoxide, ammonia methanol or ammonia water;
said compounds5The dosage ratio of the organic solvent to the alkali is 5-15 mmol: 40-60 mL: 5-50 mmol;
the temperature of the deprotection reaction is 0-35 ℃.
The invention also provides a method for synthesizing the entecavir by using the entecavir intermediate, which comprises the following steps:
(a) the entecavir intermediate and the compound7Mixing the active reagent, triphenylphosphine and an organic solvent, and then reacting to generate a compound8；
Wherein the active reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate;
compound (I)7Is composed of
Figure RE-GDA0002446916240000061
Compound (I)7Wherein R' is isopropyl;
compound (I)8Is composed of
Figure RE-GDA0002446916240000062
(b) Subjecting the compound to8And mixing with acid, and reacting to obtain entecavir.
Preferably, the organic solvent in step (a) is tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone or 2-methyltetrahydrofuran;
the entecavir intermediate and compound7The dosage ratio of the active reagent to the triphenylphosphine to the organic solvent is 0.5-2.5 mmol: 1-3.5 mmol: 1.5-5.5 mmol: 1.5-6 mmol: 5-100 mL;
the reaction temperature is 0-35 ℃.
Preferably, the acid in step (b) is trifluoroacetic acid, formic acid or hydrochloric acid;
the acids and compounds8The molar mass ratio of (A) is more than or equal to 2;
the reaction temperature is 40-100 ℃, and the reaction time is 1-24 h.
The invention has the advantages of easily obtained raw materials, low price, shortest synthesis steps, mild reaction conditions, easy control, simple equipment requirement, high total product yield and easy industrial production.
Drawings
Fig. 1 shows a traditional method for synthesizing entecavir and its evolution.
Detailed Description
The invention provides an entecavir intermediate, which has a structure shown in a formula (1):
Figure RE-GDA0002446916240000071
the invention also provides a synthesis method of the entecavir intermediate, which comprises the following steps:
(1) mixing D-2-deoxyribose, 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, organic solvent and acid-binding agent to carry out silicon ether protection reaction to generate compound1；
Figure RE-GDA0002446916240000072
(2) Subjecting the compound to1Nucleophilic addition reaction with ethynyl Grignard reagent in organic solvent to generate compound2；
Figure RE-GDA0002446916240000073
(3) Subjecting the compound to2Mixing acid-binding agent, modifier and organic solvent, and reacting to obtain compound3；
The modifier is acyl chloride or acid anhydride, or carboxylic acid and a condensing agent;
the acyl chloride is acetyl chloride or ethyl chloroformate, and the anhydride is acetic anhydride;
Figure RE-GDA0002446916240000081
(4) carrying out a reaction according to 4.1 or 4.2 to obtain a compound 4;
(4.1) subjecting the compound to3Mixing acid-binding agent, modifier and organic solvent, and reacting to obtain compound4(ii) a The modifier is thiocarbonyl chloride, or methyl iodide and carbon disulfideOr is N, N' -thiocarbonyldiimidazole;
Figure RE-GDA0002446916240000082
(4.2) subjecting the compound to3Mixing the acid-binding agent, the primary modifier and the organic solvent, and then carrying out primary reaction to generate a primary product; the first-stage modifier is methylsulfonyl chloride or trifluoromethylsulfonyl chloride;
carrying out a secondary reaction on the primary product and a secondary modifier to generate a compound4(ii) a The secondary modifier is phenylselenophenol, phenylselenophenol sodium salt or lithium bromide;
Figure RE-GDA0002446916240000083
(5) subjecting the compound to4Mixing a hydrogen source and an organic solvent, and carrying out free radical cyclization reaction under the initiation of a free radical initiator or under the excitation of oxygen to generate a compound5(ii) a The hydrogen source is tri-n-butylstannyl hydride, tri (trimethylsilyl) silane or phenyl silyl ether;
Figure RE-GDA0002446916240000084
(6) subjecting the compound to5And mixing the organic solvent and alkali, and then performing deprotection group reaction to generate the entecavir intermediate.
The invention mixes D-2-deoxyribose, 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, organic solvent and acid-binding agent to carry out silicon ether protection reaction, and two hydroxyls at 3-position and 5-position of D-2-deoxyribose are protected by 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane to generate compound1。
In the present invention, the molar ratio of D-2-deoxyribose to 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane is preferably 1 (0.9 to 1.2), and more preferably 1 (1 to 1.1).
In the invention, the organic solvent is preferably dichloromethane, pyridine, N-methyl pyrrolidone or dimethylformamide, and the volume mass ratio of the organic solvent to the D-2-deoxyribose is preferably more than or equal to 3 mL/g.
In the invention, the acid-binding agent is preferably imidazole or pyridine, and the molar ratio of the acid-binding agent to the D-2-deoxyribose is preferably not less than 1.5, more preferably 1.5 to 10 times, and still more preferably 3 to 5 times.
In the invention, the temperature of the silyl ether protection reaction is preferably less than or equal to 35 ℃, preferably-15-5 ℃, and more preferably-10-5 ℃; the reaction time was terminated by TLC detection when the starting material was consumed.
To obtain said compound1The invention then relates to said compounds1Nucleophilic addition reaction with ethynyl Grignard reagent in organic solvent to generate compound2。
In the present invention, the ethynyl grignard reagent in the step (2) is preferably ethynyl magnesium bromide grignard reagent, and the compound1The molar ratio of the ethynyl Grignard reagent to the ethynyl Grignard reagent is preferably 1 (3-5), and more preferably 1: 4.
In the present invention, the organic solvent is preferably tetrahydrofuran or dichloromethane.
In the present invention, the temperature of the nucleophilic addition reaction in the step (2) is preferably 0 ℃ or less, more preferably-15 to-5 ℃, and still more preferably-10 to-5 ℃; the reaction time was terminated by TLC detection when the starting material was consumed.
To obtain the compound2The invention then relates to said compounds2Mixing the acid-binding agent, the ester protective agent and the organic solvent, and then reacting to selectively obtain the compound with propargyl hydroxyl protected by carboxylic ester group or carbonic ester group3. In the invention, the ester protective agent is acyl chloride, or carboxylic acid and a condensing agent; the acyl chloride is acetyl chloride or ethyl chloroformate. When the acid chloride is acetyl chloride, the compound3Wherein R is a; when the acid chloride is ethyl chloroformate, the compound3Wherein R is c; when the ester protective agent is carboxylic acid and condensing agent, the compound3Wherein R is b.
In the present invention, the acid-binding agent in the step (3) is preferably an acid-binding agentIs triethylamine, diisopropylethylamine, pyridine or 4-N, N-Dimethylaminopyridine (DMAP)2The mole ratio of the acyl chloride to the acid binding agent is preferably 1 (1.1-2) to 1.5-3, and more preferably 1 (1.5-1.8) to 2-2.5.
In the present invention, the carboxylic acid is preferably benzoic acid, the condensing agent is preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (edc. hcl), and the compound is preferably a salt of a carboxylic acid with a carboxylic acid such as benzoic acid or a salt thereof2The molar ratio of the carboxylic acid to the condensing agent to the acid-binding agent is preferably 1 (1-1.6) to 1.1-2 to 1-20, and more preferably 1 (1.2-1.4) to 1.4-1.6 to 2-10.
In the present invention, the organic solvent is preferably dichloromethane, toluene, tetrahydrofuran or 1, 2-dichloroethane, the compound2The dosage ratio of the organic solvent to the organic solvent is preferably 1-15 mmol: 20-60 mL, more preferably 5-10 mmol: 40-50 mL.
In the invention, the reaction temperature in the step (3) is preferably 0-35 ℃, more preferably 10-25 ℃, and further preferably 15-20 ℃; the reaction time was terminated when the starting material was consumed by TLC.
To obtain the compound3Then, the invention proceeds according to 4.1 or 4.2 to obtain the compound4。
(4.1) subjecting the compound to3Mixing acid-binding agent, modifier and organic solvent, and reacting to obtain compound4。
In the invention, the modifier is thiocarbonyl chloride, or a mixture of methyl iodide and carbon disulfide, or N, N' -thiocarbonyl diimidazole; the thiocarbonylchloride is preferably PhOC (S) Cl or C6F5OC(S)Cl。
The invention relates to the obtained compound3Dissolving the mixture in an organic solvent, slowly dripping a modifier and a compound in the presence of an acid binding agent at the temperature of 0-5 DEG C3The hydroxyl group in (a) is converted to a thiocarbonyl derivative.
In the present invention, the compound3The preferred dosage ratio of the thiocarbonyl chloride to the organic solvent is (1-4) mmol, (1-6) mmol, (20-4) mL; said compounds3Of methyl iodide, carbon disulfide, acid-binding agent and organic solventThe dosage ratio is preferably (10-15) ((45-60)) ((20-30)) (10-20)) ((10-80) ((10-20)) ((10-80) ((12-13) ((50-55)) ((24-28)) ((14-18)) ((20-60)) inclusive).
In the invention, the reaction temperature is preferably 0-35 ℃, and more preferably 5-25 ℃; the reaction time was terminated by TLC detection when the starting material was consumed.
(4.2) subjecting the compound to3Mixing the acid-binding agent, the primary modifier and the organic solvent, and then carrying out primary reaction to generate a primary product; the first-stage modifier is methylsulfonyl chloride or trifluoromethylsulfonyl chloride;
carrying out a secondary reaction on the primary product and a secondary modifier to generate a compound4(ii) a The secondary modifier is phenylselenophenol, phenylselenophenol sodium salt or lithium bromide.
In the present invention, the acid-binding agent in the step (4.2) is preferably triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylaminopyridine; the organic solvent is preferably dichloromethane; said compounds3The dosage ratio of the acid-binding agent, the primary modifier and the organic solvent is preferably 0.3-1.2 mmol: 0.5-3.2 mmol: 0.5-1.6 mmol: 5-50 mL, and more preferably 0.5-1 mmol: 1-2 mmol: 1-1.5 mmol: 10-25 mL; the temperature of the first-order reaction is preferably-5 ℃, and more preferably 0 ℃; the time of the first-stage reaction is preferably 0.5-4 h, and more preferably 1-2 h; the temperature of the secondary reaction is preferably 10-35 ℃, and more preferably 15-25 ℃; the time is preferably 5 to 15 hours, and more preferably 10 to 12 hours.
In step 4.2 of the present invention, the compound3The free hydroxyl of the compound is firstly converted into a methyl sulfonate or trifluoromethyl sulfonate leaving group and then nucleophilic-substituted by a bromine anion or a phenylseleno anion to obtain a bromide or phenylseleno4。
In the invention, when the secondary modifier is lithium bromide, the primary product reacts with a lithium bromide nucleophilic reagent to generate bromide; when the secondary modifier is phenylselenophenol or phenylselenophenol sodium salt, the primary product and the secondary modifier serving as a nucleophilic reagent react under the condition of an organic solvent to generate the phenylselenopher.
To obtain said compound4The invention then relates to said compounds4Mixing hydrogen source and organic solvent, and performing free radical cyclization reaction under the initiation of a free radical initiator to generate a compound5。
In the invention, the hydrogen source in the step (5) is tri-n-butylstannyl hydride, tri (trimethylsilyl) silane or phenyl silyl ether; the organic solvent is preferably benzene, toluene or dioxane; the radical initiator is preferably azobisisobutyronitrile or triethylboron-oxygen; said compounds4The preferred dosage ratio of the hydrogen source, the free radical initiator and the organic solvent is 0.5-1 mmol: 0.5-2 mmol: 0.05-1 mmol: 10-100 mL, and the more preferred dosage ratio is 0.7-0.8 mmol: 0.6-0.8 mmol: 0.08-0.8 mmol: 15-20 mL; the reaction temperature of the free radical cyclization reaction is not higher than the reflux temperature of the organic solvent, and the reaction time is preferably 1-24 hours, and more preferably 3-10 hours.
After obtaining the compound, the invention uses the compound5Mixing an organic solvent and alkali, and then carrying out deprotection group reaction to generate an entecavir intermediate, namely a compound6。
In the present invention, the organic solvent in the step (6) is preferably methanol or ethanol; the alkali is preferably potassium carbonate, sodium ethoxide, ammonia methanol or ammonia water; said compounds5The dosage ratio of the organic solvent to the alkali is preferably 5-15 mmol: 40-60 mL: 5-50 mmol, and more preferably 10-12 mmol: 50-55 mL: 10-30 mmol; the temperature of the deprotection reaction is preferably 0-35 ℃, more preferably 10-25 ℃, and the reaction time is finished when the raw materials are completely consumed through TLC detection.
The invention also provides a method for synthesizing the entecavir by the entecavir intermediate, which comprises the following steps:
(a) the entecavir intermediate6A compound of7Mixing the active reagent, triphenylphosphine and an organic solvent, and then reacting to generate a compound8；
Wherein the active reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate;
compound (I)7Is composed of
Figure RE-GDA0002446916240000121
Compound (I)7Wherein R' is isopropyl;
compound (I)8Is composed of
Figure RE-GDA0002446916240000122
(b) Subjecting the compound to8And mixing with acid, and reacting to obtain entecavir.
In the present invention, the organic solvent in the step (a) is preferably tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone or 2-methyltetrahydrofuran; the entecavir intermediate6The dosage ratio of the compound 7, the active reagent, the triphenylphosphine and the organic solvent is preferably 0.5-2.5 mmol: 1-3.5 mmol: 1.5-5.5 mmol: 1.5-6 mmol:5 to 100mL, more preferably 1 to 2mmol: 2-3 mmol: 2-3 mmol: 2-4 mmol: 10-40 mL; the reaction temperature is preferably 0-35 ℃, more preferably 10-25 ℃, and the reaction time is finished when the raw materials are completely consumed through TLC detection.
In the present invention, the acid in the step (b) is preferably trifluoroacetic acid, formic acid or hydrochloric acid; the acids and compounds8The molar mass ratio of (A) is preferably not less than 2, more preferably not less than 5; the reaction temperature is preferably 40-100 ℃, and more preferably 50-90 ℃; the reaction time is preferably 1-24 hours, and more preferably 5-10 hours.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Figure RE-GDA0002446916240000131
A500 mL round bottom flask was charged with D-2-deoxyribose (13.4g,0.1mol) and dry pyridine (200mL), and a solution of 1, 3-dichloro-1, 1,3, 3-tetraisopropyl siloxane (31.8mL, 0.11mol) in pyridine was slowly added dropwise at-10 deg.C(50 mL). The mixture was stirred overnight at the same temperature, and the reaction was stopped by TLC after completion of the reaction by addition of methanol. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (300mL), the organic phase was washed with a saturated ammonium chloride solution and water, respectively, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 10) to give a colorless oily product130g (yield 80%).
And performing nuclear magnetic detection on the obtained product 1, wherein the result is as follows, and the obtained product 1 is the target product compound 1 according to the analysis of the nuclear magnetic detection result.
1H NMR(500MHz,DMSO-d6)δ6.31(m,1H),5.26(m,1H),4.61(m, 0.5H),4.23(m,0.5H),3.92(m,1H),3.60-3.79(m,2H),2.46(m,0.5H), 2.09(m,0.5H),1.94(m,0.5H),1.70(m,0.5H),0.80–1.20(m,28H)。
Example 2
Figure RE-GDA0002446916240000132
The compound1(18.5g,49.2mmol) was dissolved in dry tetrahydrofuran (100mL), ethynylmagnesium bromide Grignard reagent (0.5M,300mL,150mmol) was slowly added dropwise at-10 deg.C, and after completion of the reaction (which was 5h reaction at this time), the reaction was quenched by addition of saturated ammonium chloride solution (100mL) and extracted with ethyl acetate (100 mL. times.2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated and the residue is separated by preparative SFC column chromatography to give the d.e. value>97% white solid product2。
The obtained product 2 is subjected to nuclear magnetic detection characterization, and the result is as follows, and the obtained product can be known through nuclear magnetic detection result analysis2Namely the target product compound2。
[α]28-9.2(c 2.37EtOAc)；
1H NMR(400Hz,CDCl3)δ4.59(s,1H),4.48(s,br,1H),4.15(d,J＝11.6Hz,1H),4.05-4.10(m,1H),3.78(dd,J1＝11.6Hz,J2＝2.0Hz,1H), 3.48(d,J＝8.4Hz,1H),2.92(s,br,1H),2.41(d,J＝2.4Hz,1H),2.13(t,J ＝5.6Hz,2H),0.88-1.05(m,28H)；13C NMR(400Hz,CDCl3)δ85.00, 75.33,73.52,67.90,62.53,59.48,43.61,17.76,17.61,17.53,17.47,17.43, 13.56,13.44,12.76,12.60。
Example 3
Figure RE-GDA0002446916240000141
Acetyl chloride (1.1mmol) was added slowly to the compound at-10 deg.C2(400mg,1.0 mmol) and triethylamine (140. mu.L, 3.0mmol) in dichloromethane (20mL), and then the reaction was stirred at room temperature for 2h with the cooling bath removed until the starting material was consumed. Adding water to quench and react, drying the separated organic phase with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 4:1) to obtain colorless oily product3a。
The nuclear magnetic results show that the compound is a target product compound3a。
1H NMR(400Hz,CDCl3)δ5.88-5.91(m,1H),5.18(d,J＝12.0Hz,1H), 3.89-3.92(m,1H),3.72-3.83(m,1H),3.36-3.40(m,1H),2.43-2.50(m,2H), 2.20-2.28(m,2H),2.18(s,3H),0.85-1.24(m,28H).
Example 4
Figure RE-GDA0002446916240000142
The compound2(910mg,2.3mmol), EDC.HCl (520mg,2.7mmol), benzoic acid (420mg,3.5mmol) and DMAP (55mg,0.2mmol) were dissolved in 30mL of dichloromethane, triethylamine (3.8mL,2.8mmol) was slowly added dropwise with cooling in an ice bath, and the reaction was stirred at room temperature for 24 hours with removal of the ice bath. The reaction was quenched with water, the aqueous phase was extracted twice with dichloromethane (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (n-hexane: ethyl acetate 10:1) to give a colorless oil3b(1.05g, 90%) and left to solidify slowly over time to a white solid.
The nuclear magnetic results show that the compound is a target product compound3b。
1H NMR(400Hz,CDCl3)δ8.03-8.06(m,2H),7.53-7.55(m,1H),7.24- 7.42(m,2H),5.87-5.89(m,1H),5.14(d,J＝12.0Hz,1H),3.89-3.92(m,1 H),3.75(dd,J1＝11.6Hz,J2＝2.0Hz,1H),3.39(t,J＝9.6Hz,1H),2.43- 2.48(m,2H),2.20-2.28(m,2H),0.85-1.24(m,28H)。
Example 5
Figure RE-GDA0002446916240000151
Under the protection of nitrogen at 0 DEG C2(5.35g,13.3mmol) in dichloromethane (60mL) was slowly added anhydrous pyridine (2.10g,26.6mmol) and ethyl chloroformate (2.89g,26.6 mmol), respectively. The resulting bright yellow solution was stirred for 1.5 hours, then the reaction was quenched with water (4mL), diluted with dichloromethane (100mL), and the organic phase was then washed with 1N HCl (100mL x 3) and saturated sodium bicarbonate solution (100mLx 3), respectively, and dried (Na)2SO4) After filtration and concentration, the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 10:1) the product was isolated as a colorless oil3c(6.06g,96％)。
The nuclear magnetic results show that the target product compound 3c is obtained.
1HNMR(400Hz,CDCl3)δ5.89-5.93(m,1H),5.22(d,J＝12.0Hz,1H), 4.24(q,J＝7.2Hz,2H),3.91-3.95(m,1H),3.72-3.83(m,1H),3.48-3.40(m, 1H),2.43-2.50(m,2H),2.20-2.28(m,2H),1.31(t,J＝7.1Hz,3H), 0.85-1.24(m,28H)。
Example 6
Figure RE-GDA0002446916240000152
Under the protection of nitrogen at 0 DEG C3a(490mg,1.1mmol), DMAP (24mg,0.2 mmol), dry pyridine (2mL) and dichloromethane (20mL) was added slowly dropwise to a mixed solution of chlorothiocarbamic acid-O-phenyl ester (290mg,1.7mmol), the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of ice water (20g), the organic phase separated and extracted with dichloromethane (20 mL. times.2)The aqueous phases are repeated twice, the organic phases are combined and dried (Na)2SO4) The mixture was filtered, concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: dichloromethane ═ 5: 1) the product was obtained as a brown-yellow oil4a(550mg,86％)：1H NMR(CDCl3,400MHz)δ7.98-8.00(m,2H),7.51-7.55(m,1H),7.36-7.41(m,2 H),5.13(d,J＝9.6Hz,1H),4.60(m,1H),4.37-4.42(m,1H),4.13-4.21(m,2 H),2.39(m,1H),2.21(s,3H),1.93-2.06(m,2H),1.00-1.10(m,28H)。
Example 7
Figure RE-GDA0002446916240000161
Thiocarbonyldiimidazole (TCDI,360mg,2mmole) was added to the compound at zero degrees3b(507mg,1mmol) and DMAP (25mg,0.2mmol) in dichloromethane (50mL), the reaction was slowly warmed to room temperature and stirred for 24 hours. TLC detecting reaction, adding water to quench reaction, drying organic phase, filtering, concentrating, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 3: 1) to the residue to obtain white solid product4b(560mg,91％)：[α]25-26.25(c 0.16 EtOAc).1HNMR(400Hz,CDCl3)δ8.33(s,1H),7.98-8.00(m,2H),7.63(s, 1H),7.51-7.55(m,1H),7.36-7.41(m,2H),7.05(s,1H),5.80-5.84(m,1H), 5.37(d,J＝9.6Hz,1),4.54-4.57(m,1H),4.16-4.17(m,2H),2.52(d,J＝2.0 Hz,1H),2.20-2.23(m,2H),0.95-1.88(m,28H).
Example 8
Figure RE-GDA0002446916240000162
To the compound3b(6.54g,12.9mmol) of DMSO solution (80mL) is slowly added with 5M NaOH aqueous solution (2.84mL,14.2mmol), 3.19mL (51.6mmol) of carbon disulfide is slowly added dropwise at a temperature controlled below 15 ℃, 1.60mL (25.7mmol) of methyl iodide is added and stirred for 10 minutes, the reaction mixture is immediately poured into a mixture of 80mL of ethyl acetate and 80mL of water, the organic phase is separated, dried, filtered, concentrated, and the residue is chromatographed on a silica gel column(n-hexane: ethyl acetate ═ 10:1) to give the product as a foam4c(5.17g,71％):1H NMR(CDCl3,400MHz)δ 7.96-8.01(m,2H),7.51-7.54(m,1H),7.37-7.41(m,2H),5.14(d,J＝9.6Hz,1 H),4.62(m,1H),4.35-4.42(m,1H),4.12-4.21(m,2H),2.65(s,3H)， 2.37-2.39(m,1H),1.93-2.06(m,2H),1.00-1.10(m,28H)。
Example 9
Figure RE-GDA0002446916240000171
Under the protection of nitrogen at 0 DEG C3b(1.67g,3.3mmol), DMAP (40mg,0.33 mmol), a mixed solution of dried pyridine (2mL) and dichloromethane (20mL) was slowly dropped O-pentafluorophenyl thiocarbonate (0.8mL,5.0mmol), and after removing the ice bath, it was stirred at room temperature overnight. The reaction was quenched by addition of ice water (20g), the organic phase separated and the aqueous phase extracted twice with dichloromethane (20 mL. times.2), the organic phases combined and dried (Na)2SO4) The mixture was filtered, concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: dichloromethane ═ 5: 1) the product was obtained as a brown-yellow oil4d(1.9g,77％)：1H NMR(CDCl3, 400MHz)δ7.98-8.00(m,2H),7.51-7.55(m,1H),7.36-7.41(m,2H),5.13(m, 1H),4.59-4.61(m,1H),4.37-4.42(m,1H),4.13-4.21(m,2H),2.39(d,J＝2.0 Hz,1H),1.93-2.06(m,2H),1.00-1.10(m,28H)。
Example 10
Figure RE-GDA0002446916240000172
Under the protection of nitrogen at 0 DEG C3a(210mg,0.47mmol) and triethylamine (0.1mL,0.68 mmol) in dichloromethane (10mL) were slowly added dropwise to methanesulfonyl chloride (0.05mL,0.65 mmol), the reaction was stirred for 1h, ice water (5mL) and dichloromethane (10mL) were added to quench the reaction, the organic phase was separated, washed with cold 1N HCl (10mL), cold saturated aqueous sodium bicarbonate (10mL) and cold brine (10mL), and dried (MgSO 2)4) Filtered and concentrated to obtain crude methylsulfonate, which is dissolved in dry DMF.
Cesium carbonate anhydrous (460mg,1.41mmol) was added to the above solution of methylsulfonate DMF (10mL), followed by slow dropwise addition of PhSeH (0.1mL,0.94mmol) at 0 deg.C and the reaction solution was stirred overnight at room temperature. After the TLC detection reaction was completed, water (50mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with water, dried, filtered, and concentrated, and the obtained residue was separated by silica gel column chromatography (n-hexane: ethyl acetate ═ 10:1) to obtain an orange oil4e(180mg，64％)；1H NMR(CDCl3,400MHz)δ7.25-7.46(m,5H),5.12- 5.13(m,1H),4.59-4.62(m,1H),4.37-4.42(m,1H),4.13-4.21(m,2H),2.22(s, 3H),1.96-2.16(m,2H),1.39-1.43(m,1H),1.00-1.10(m,28H)。
Example 11
Figure RE-GDA0002446916240000181
Under the protection of nitrogen at 0 DEG C3b(253mg,0.5mmol) and triethylamine (0.21mL,1.5 mmol) in dichloromethane (10mL) was slowly added dropwise trifluoromethanesulfonyl chloride (0.08mL,0.75 mmol), the reaction was continued at 0 ℃ for 1h with stirring, then the reaction was quenched by addition of ice water (5mL) and dichloromethane (10mL), the organic phase was separated and washed with cold 1N HCl (5mL), cold saturated aqueous sodium bicarbonate (5mL) and cold brine (5mL), dried (MgSO 5)4) The crude triflate was dried by oil pump for 1 hour and dissolved in anhydrous THF (5 mL).
In another reaction flask PhSeH (0.1mL,0.94mmol) was reacted with NaH (22mg,0.9 mmol) in dry THF (5mL) at 0 deg.C for 1h, followed by the addition of 0.2mL of dry HMPA and the resulting solution of phenylselenophenol sodium salt in THF was transferred to the triflate solution with a double-ended needle and stirred at room temperature overnight. TLC indicated the starting material was depleted and quenched by addition of water (50mL), the aqueous phase was extracted with ethyl acetate (100mL x 3), the combined organic phases were washed with water, dried, filtered and concentrated, and the resulting residue was separated by silica gel column chromatography (n-hexane: ethyl acetate 10:1) to give an orange oil4f(244mg，74％):1H NMR(CDCl3,400MHz)δ7.99-8.03(m,2H), 7.27-7.52(m,8H),5.11-5.13(m,1H),4.59-4.61(m,1H),4.36-4.41(m,1H), 4.13-4.21(m,1H),2.39(m,1H),1.96-2.16(m,2H),1.39-1.43(m,1H), 0.98-1.10(m,28H)。
Example 12
Figure RE-GDA0002446916240000191
Under the protection of nitrogen at 0 DEG C3c(475mg,1mmol), triethylamine (0.42mL, 3mmol) in dichloromethane (20mL) was added dropwise trifluoromethanesulfonyl chloride (0.16mL,1.5 mmol) slowly, the reaction was stirred at 0 ℃ for 1h, ice water (5mL) and dichloromethane (10mL) were added to quench the reaction, the organic phase was separated and washed with cold 1N HCl (10mL), cold saturated aqueous sodium bicarbonate (10mL) and cold brine (10mL), dried (MgSO 5mL)4) The crude triflate was dried by oil pump for 1 hour and dissolved in anhydrous THF (10 mL).
To the above triflate solution was added anhydrous LiBr (260mg, 3mmol) at 0 deg.C, and the ice bath was removed and stirred at room temperature overnight. The reaction was quenched with water (20mL), the aqueous phase was extracted with ethyl acetate (50mL × 3), the combined organic phases were washed with water, dried, filtered, and concentrated, and the resulting residue was separated by silica gel column chromatography (n-hexane: ethyl acetate 10:1) to give a colorless oil4g(312mg，58％):1H NMR(CDCl3,400MHz)δ5.89-5.95(m,1H), 5.20-5.21(m,1H),4.32(q,J＝7.2Hz,2H),3.92-3.95(m,1H),3.70-3.81(m, 1H),3.48-3.40(m,1H),2.43-2.50(m,1H),2.01-2.22(m,2H),2.18(s,3H), 1.31(t,J＝7.2Hz,3H),0.89-1.20(m,28H)。
Example 13
Figure RE-GDA0002446916240000192
Under the protection of nitrogen, the compound4aA solution of (465mg,0.80mmol), tri-n-butylstannyl hydride (240. mu.L, 0.89mmol) and AIBN (14mg,0.08mmol) in benzene (15mL) was reacted at reflux temperature for 3 hours, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (bisMethyl chloride: petroleum ether is 1: 4) the product is obtained in the form of a pale yellow oil5a(130mg,38％)：1H NMR(400Hz, CDCl3)δ5.70-5.76(m,1H),5.17-5.18(m,1H),4.93-4.94(m,1H),4.49(t,J＝ 4.0Hz,1H),3.90-3.93(m,1H),3.75-3.80(m,1H),2.87-2.93(m,1H), 2.34-2.37(m,1H),2.07(s,3H),1.66-1.69(m,1H),0.86-1.06(m,28H).
Example 14
Figure RE-GDA0002446916240000201
Under the protection of argon, the compound4b(493mg,0.80mmol), tri-n-butylstannyl hydride (240. mu.L, 0.89mmol) and AIBN (140mg,0.8mmol) in toluene (15mL) were reacted at reflux temperature for 3 hours, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: petroleum ether ═ 1: 4) to give a pale yellow oily product5a(153mg,45％):1H NMR(400Hz,CDCl3)δ8.03-8.05(m,2H),7.52-7.56(m,1H),7.40-7.44(m, 2H),5.60-5.62(m,1H),5.28-5.30(m,1H),5.13-5.14(m,1H),4.16-4.23(m, 1H),4.05-4.09(m,1H),3.88-3.93(m,1H),2.63-2.71(m,2H),1.88-1.94(m, 1H),0.77-1.08(m,28H)。
Example 15
Figure RE-GDA0002446916240000202
Compound (I)4gA solution of (430mg,0.80mmol), TTMSS (280. mu.L, 0.89mmol) and AIBN (140mg,0.8mmol) in benzene (15mL) was reacted at reflux temperature for 3 hours, cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: petroleum ether ═ 1: 4) to give the product as a pale yellow oil5c(100mg,28％):1H NMR(400Hz,CDCl3)δ 5.27-5.28(m,1H),5.21-5.23(m,1H),5.12-5.13(m,1H),4.18(q,J＝7.2Hz, 2H),3.99-4.11(m,2H),3.85-3.90(m,1H),2.53-2.59(m,2H),1.78-1.86(m,1 H),1.29(t,J＝7.2Hz,3H),0.96-1.06(m,28H)。
Example 16
Figure RE-GDA0002446916240000203
Compound (I)5a(4.29g,10mmol) was dissolved in methanol (50mL), potassium carbonate (4g) was added and stirred at room temperature for 3h, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give a white solid product6(92-97％):1HNMR(400Hz,CDCl3)δ 5.20-5.22(m,1H),4.98-4.99(m,1H),4.32(s,1H),4.13-4.18(m,1H), 3.98-4.02(m,1H),3.72-3.76(m,1H),2.66-2.69(m,1H),2.31-2.37(m,1H), 2.18(s,1H),1.66-1.74(m,1H),0.88-1.06(m,28H)；13C NMR(400Hz, CDCl3)δ152.52,109.07,72.63,72.11,64.06,53.14,43.04,17.80,17.66, 17.60,17.53,17.38,17.29,17.24,13.64,13.05,12.80.
Example 17
Figure RE-GDA0002446916240000211
At zero degrees, diisopropyl azodicarboxylate (DIAD,400mg,2mmol) was slowly added dropwise to the compound6(386mg,1mmol), triphenylphosphine (580mg,2.2mmol) and 6-chloro-2-aminopurine (37a) (255mg,1.5mmol) in THF-DMF (10mL,9:1), the resulting pale yellow suspension was stirred at room temperature for 24 hours, TLC showed the exhaustion of the starting material and the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5: 1) to give a yellowish foam8a(365mg, 68%) to obtain the Compound8aDoped with the DIAD reduction product.1HNMR(400Hz,CDCl3)δ8.15(s,1H),5.66-5.68(m,1 H),5.33-5.35(m,1H),4.99(d,J＝2.08Hz,1H),4.52-4.56(m,1H),4.06-4.19 (m,2H),2.57-2.59(m,1H),2.35-2.43(m,1H),2.20-2.27(m,1H),1.00-1.12 (m,28H)。
Example 18
Figure RE-GDA0002446916240000212
Slowly dropping at 0 deg.CAdd DIAD (0.95mL,4.8mmol) to triphenylphosphine (1.5g,5.7 mmol), Compound6(730mg,1.9mmol) and N, N-bis-Boc protected 6-chloro-2-aminopurine (N-Boc)7b) (1.05g,2.86mmol) in THF (50mL) and the ice bath removed and the reaction stirred at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure, and the residue was chromatographed on a silica gel column (n-hexane: ethyl acetate 10:1) to give a colorless foamy product8b(1.08g,77％):1HNMR(400Hz,CDCl3)δ 8.13(s,1H),5.64-5.66(m,1H),5.35(d,J＝2.08Hz,1H),4.98(d,J＝2.08Hz, 1H),4.50-4.56(m,1H),4.06-4.19(m,2H),2.57-2.59(m,1H),2.35-2.43(m,1 H),2.20-2.27(m,1H),1.45(s,18H),1.01-1.11(m,28H)。
Example 19
Figure RE-GDA0002446916240000221
At zero degrees, diisopropyl azodicarboxylate (DIAD,400mg,2mmol) was slowly added dropwise to the compound6(386mg,1mmol), triphenylphosphine (580mg,2.2mmol) and 6-chloro-2-isobutyramidopurine (II) ((III))7c) (360mg,1.5mmol) in tetrahydrofuran (10mL), the resulting pale yellow suspension was stirred at room temperature for 24 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5: 1) thus, the product 8c (750mg) was obtained as a pale yellow foam, and the compound 8c thus obtained was doped with the DIAD reduction product.1HNMR(400Hz,CDCl3)δ8.87(s,br,1H),7.93(s,1H),5.61(d,J＝7.2Hz,1 H),5.26(s,1H),5.03(s,1H),4.46-4.53(m,1H),4.01-4.13(m,2H), 2.90-2.92(m,1H),2.49-2.52(m,1H),2.31-2.39(m,1H),2.15-2.21(m,1H), 0.90-1.25(m,34H)。
Example 20
Figure RE-GDA0002446916240000222
The compound8a(530mg,1mmol) was dissolved in 10mL of formic acid, the reaction mixture was heated at 90 ℃ for 1 hour, cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was dissolved in 10mL of saturated ammonia methanol and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting pale yellow crude product was purified by C18 silica gel column chromatography, gradient eluted with a mixed solvent of methanol and water (0-50%) to give entecavir (230mg, 83%) as a white solid product. Mp.234-236 ℃ (dec.); [ alpha ] to]25+34o(c 0.1H2O)；1H NMR(400Hz,MeOH-d4)δ7.75(s,1H),5.50(t,J＝9.0Hz,1H),5.23-5.24 (m,1H),4.78-4.79(m,1H),4.38-4.39(m,1H),3.77(d,J＝6.0Hz,2H), 2.67(s,1H),2.35-2.41(m,1H),2.18-2.23(m,1H)；13C NMR(400Hz, MeOH-d4)δ158.22,153.86,151.87,150.24,137.65,116.41,110.34,71.91, 63.47,56.34,54.11,39.43。
Example 21
Figure RE-GDA0002446916240000231
The compound8b(738mg,1mmol) was dissolved in a mixed solvent of 20mL of methanol and 1mL of concentrated hydrochloric acid, the reaction mixture was heated at 50 ℃ for 5 hours, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in 10mL of saturated ammonia methanol and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting pale yellow crude product was purified by C18 silica gel column chromatography, gradient eluted with a mixed solvent of methanol and water (0-50%) to give entecavir (258mg, 93%) as a white solid product.
Example 22
Figure RE-GDA0002446916240000232
The compound8c(608mg,1mmol) was dissolved in a mixed solvent of 10mL of trifluoroacetic acid and 2mL of water, the reaction mixture was heated at 50 ℃ for 5 hours, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in 10mL of saturated ammonia methanol and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting pale yellow crude product was purified by C18 silica gel column chromatography, gradient eluted with a mixed solvent of methanol and water (0-50%) to give entecavir (260mg, 94%) as a white solid product.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (12)

1. An entecavir intermediate, the structure of which is shown in formula (1):
Figure 409847DEST_PATH_IMAGE001
。
2. the method for synthesizing the entecavir intermediate as claimed in claim 1, which comprises the following steps:
(1) mixing D-2-deoxyribose, 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, organic solvent and acid-binding agent to carry out silicon ether protection reaction to generate compound1；
Figure 28785DEST_PATH_IMAGE002
The organic solvent in the step (1) is dichloromethane, pyridine, N-methyl pyrrolidone or dimethylformamide;
the acid-binding agent in the step (1) is imidazole or pyridine;
(2) subjecting the compound to1Nucleophilic addition reaction with ethynyl Grignard reagent in organic solvent to generate compound2；
Figure 746206DEST_PATH_IMAGE003
The organic solvent in the step (2) is tetrahydrofuran or dichloromethane;
(3) subjecting the compound to2Mixing acid-binding agent, ester protective agent and organic solvent, and reacting to obtain compound3；
The ester protective agent is acyl chloride or acid anhydride, or carboxylic acid and a condensing agent;
the acyl chloride is acetyl chloride or ethyl chloroformate, and the anhydride is acetic anhydride;
Figure 79098DEST_PATH_IMAGE004
said compounds3R in (1) is selected from one of Me, Ph and OEt;
the organic solvent in the step (3) is dichloromethane, toluene, tetrahydrofuran or 1, 2-dichloroethane;
the acid-binding agent in the step (3) is triethylamine, diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine;
the carboxylic acid in the step (3) is benzoic acid;
the condensing agent in the step (3) is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
(4) reaction according to 4.1 or 4.2 to give the compound4；
(4.1) subjecting the compound to3Mixing acid-binding agent, modifier and organic solvent, and reacting to obtain compound4(ii) a The modifier is thiocarbonyl chloride, or a mixture of methyl iodide and carbon disulfide, or N, N' -thiocarbonyl diimidazole;
Figure 831153DEST_PATH_IMAGE005
the compound in the step (4.1)4X in (1) is selected from one of MeS-, Im-, PhO-and CgFsO-; r is selected from one of Me, Ph and OEt;
in the step (4.1), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylamino pyridine;
the organic solvent is dichloromethane or dimethyl sulfoxide;
(4.2) subjecting the compound to3Mixing acid-binding agent, first-stage modifier and organic solvent, and performing first-stage reactionAnd then, generating a primary product; the first-stage modifier is methylsulfonyl chloride or trifluoromethylsulfonyl chloride;
carrying out a secondary reaction on the primary product and a secondary modifier to generate a compound4(ii) a The secondary modifier is phenylselenophenol, phenylselenophenol sodium salt or lithium bromide;
Figure 27517DEST_PATH_IMAGE006
the compound in the step (4.2)4X in (1) is selected from Br or PhSe; r is selected from one of Me, Ph and OEt;
in the step (4.2), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylamino pyridine; the organic solvent in the step (4.2) is dichloromethane;
(5) subjecting the compound to4Mixing hydrogen source and organic solvent, and performing free radical cyclization reaction under the initiation of a free radical initiator to generate a compound5(ii) a The hydrogen source is tri-n-butylstannyl hydride, tri (trimethylsilyl) silane or phenyl silyl ether;
Figure 232234DEST_PATH_IMAGE007
said compounds5R in (1) is selected from one of Me, Ph and OEt;
the organic solvent in the step (5) is benzene, toluene or dioxane;
the free radical initiator in the step (5) is azobisisobutyronitrile or triethylboron-oxygen;
(6) subjecting the compound to5Mixing an organic solvent and alkali, and then performing deprotection group reaction to generate an entecavir intermediate; the organic solvent in the step (6) is methanol or ethanol.
3. The synthesis method according to claim 2, wherein the molar ratio of D-2-deoxyribose to 1, 3-dichloro-1, 1,3, 3-tetraisopropyldisiloxane in the step (1) is 1 (0.9-1.2);
the volume-mass ratio of the organic solvent to the D-2-deoxyribose is more than or equal to 3 mL/g;
the molar ratio of the acid-binding agent to the D-2-deoxyribose is more than or equal to 1.5;
the temperature of the silicon ether protection reaction in the step (1) is less than or equal to 35 ℃.
4. The method of claim 3, wherein the compound of step (2)1The molar ratio of the acetenyl Grignard reagent to the acetenyl Grignard reagent is 1 (3-5);
the temperature of the nucleophilic addition reaction in the step (2) is less than or equal to 0 ℃.
5. The synthesis method according to claim 4, wherein the acid-binding agent in step (3) is triethylamine, diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine, and the compound is2The mol ratio of acyl chloride to the acid binding agent is 1 (1.1-2) to 1.5-3;
the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the compound2The molar ratio of the carboxylic acid to the condensing agent to the acid-binding agent is 1 (1-1.6) to 1.1-2 to 1-20;
the reaction temperature in the step (3) is-10-35 ℃.
6. The synthesis method according to claim 5, wherein in the step (4.1), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylaminopyridine;
the reaction temperature is 0-35 ℃.
7. The synthesis method according to claim 6, wherein in the step (4.2), the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or 4-N, N-dimethylaminopyridine;
said compounds3The dosage ratio of the acid-binding agent, the primary modifier and the organic solvent is 0.3-1.2 mmol, 0.5-3.2 mmol, 0.5-1.6 mmol and 5-50 mL;
the temperature of the first-stage reaction is-5 ℃, and the time is 0.5-4 h;
the temperature of the secondary reaction is 0-35 ℃.
8. The method of claim 6, wherein the compound of step (5)4The dosage ratio of the hydrogen source, the free radical initiator and the organic solvent is 0.5-1 mmol: 0.5-2 mmol: 0.05-1 mmol: 10-100 mL;
the reaction temperature of the free radical cyclization reaction is not higher than the reflux temperature of the organic solvent, and the reaction time is 1-24 h.
9. The synthesis method according to claim 7 or 8, wherein the base in the step (6) is potassium carbonate, sodium ethoxide, ammonia methanol or ammonia water;
said compounds5The dosage ratio of the organic solvent to the alkali is 5-15 mmol: 40-60 mL: 5-50 mmol;
the temperature of the deprotection reaction is 0-35 ℃.
10. A process for synthesizing entecavir from an entecavir intermediate as claimed in claim 1, comprising the steps of:
(a) the entecavir intermediate and the compound7Mixing the active reagent, triphenylphosphine and an organic solvent, and then reacting to generate a compound8；
Wherein the active reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate;
compound (I)7Is composed of
Figure 103238DEST_PATH_IMAGE008
Wherein R is1And R2Are all H, R1And R2Are both Boc or R1Is H, R2Is R 'CO, R' is isopropyl;
compound (I)8Is composed of
Figure 491492DEST_PATH_IMAGE009
Wherein R is1And R2Are all H, R1And R2Are both Boc or R1Is H, R2Is R 'CO, R' is isopropyl;
(b) subjecting the compound to8Mixing with acid, and reacting to obtain entecavir;
the organic solvent in the step (a) is tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone or 2-methyltetrahydrofuran;
the acid in the step (b) is trifluoroacetic acid, formic acid or hydrochloric acid.
11. The method of claim 10, wherein the entecavir intermediate, compound, or intermediates of step (a) are purified from the purified entecavir mixture7The dosage ratio of the active reagent to the triphenylphosphine to the organic solvent is 0.5-2.5 mmol: 1-3.5 mmol: 1.5-5.5 mmol: 1.5-6 mmol: 5-100 mL;
12. the method of claim 10 or 11, wherein the acid and the compound in step (b) are8The molar weight ratio of (A) is more than or equal to 2; the reaction temperature is 40-100 ℃, and the reaction time is 1-24 h.
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CN102417506A (en) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 Preparation method of antiviral drug Entecavir

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CN102417506A (en) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 Preparation method of antiviral drug Entecavir

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《Introduction of 2-O-benzyl abasic nucleosides to the 30-overhang regions of siRNAs greatly improves nuclease resistance》;Yuki Nagaya;《Bioorganic & Medicinal Chemistry Letters》;20171028;第27卷;参见第5455页方案1； *
《RADICAL CYCLIZATICINT O THE TRIFLUOROMETHYL-SUBSTITUTEDD OUBLE BOND:REGIOSELECTIVITY AND TANDEM CYCLIZATION》;Tsutomu Morikawa;《Tetrahedron Letters》;19891231;第30卷(第18期);参见第2408页 *
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