CN102863444B - The Preparation Method And Their Intermediate of one class purine derivative - Google Patents
The Preparation Method And Their Intermediate of one class purine derivative Download PDFInfo
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- CN102863444B CN102863444B CN201210328164.8A CN201210328164A CN102863444B CN 102863444 B CN102863444 B CN 102863444B CN 201210328164 A CN201210328164 A CN 201210328164A CN 102863444 B CN102863444 B CN 102863444B
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- 0 *C(OCC1)O[C@@]1C=O Chemical compound *C(OCC1)O[C@@]1C=O 0.000 description 4
- OLFYATZNXPXIAY-VUWPPUDQSA-N OC[C@H]1OC(c2ccccc2)OCC1 Chemical compound OC[C@H]1OC(c2ccccc2)OCC1 OLFYATZNXPXIAY-VUWPPUDQSA-N 0.000 description 1
Abstract
The invention discloses the Preparation Method And Their Intermediate of a class purine derivative.This preparation method comprises the steps: in organic solvent, alkali, palladium catalyst effect under, compound ii and compound III are carried out coupling reaction,.Compared with prior art, the preparation method cheaper starting materials of the present invention easy, preparation method easy, efficiently, be suitable to industrialized production, the synthesis for Entecavir class medicine provides a new approach.
Description
Technical field
The present invention relates to the Preparation Method And Their Intermediate of a class purine derivative.
Background technology
Hepatitis B is the liver that a kind of hepatitis B virus (HBV) infection people's apes include the mankind, and causes the infectious disease of inflammation.This disease is considered as initially " serum hepatitis ", is widely current in Asia and Africa, and popular in selected areas of China, the route of transmission of hepatitis B virus mainly contact blood or the body fluid containing blood.Acute hepatitis B can cause the symptoms such as liver inflammation, vomiting, jaundice；And chronic hepatitis B, liver cirrhosis and hepatocarcinoma may finally be caused, wherein hepatocarcinoma is the fatal disease the lowest to chemotherapy sensing.At present, the population of the most about 1/3rd, more than 2,000,000,000 people, has infected hepatitis B virus, including 3.5 hundred million chronic hepatitis B virus carriers.
Hepatitis B virus is one of minimum peplos animal virus, and particle diameter is 42nm, belongs to Hepadna Virus.Hepatitis B virus is made up of the core of a covering and an icosahedron lipid core capsid protein.Wherein, the embedded virus albumen comprised in covering relates to viruses contact, and then enters permissive cell；Nucleocapsid is wrapped in viral DNA and archaeal dna polymerase, has the reverse transcriptase activity similar with retrovirus.
Entecavir, i.e. one hydration 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-3-(hydroxymethyl)-2-methylene cyclopentane base]-6,9-dimethyl-3 hydrogen-purine-6-one, it is a kind of nucleoside analog, it is possible in the reproduction process of virus, suppress reverse transcription, DNA replication dna and transcribe, being to be currently used for treating one of hepatitis b virus infected medicine.
Zahler Entecavir and the effect as antiviral drugs thereof reported in patent U.S.Pat.No.5,206,244.Zhou et al. in patent US2009/014358, Bisacchi et al. is in patent WO98/09964 and Pendri et al. discloses the improvement of Entecavir preparation technology in patent WO2004/052310 and US20040192912.Colonno et al. disclose in patent WO01/64221 some containing compositionss of low dosage Entecavir and/or the example of accompanying infection hepatitis B infected for daily treatment.
The production of Entecavir is with achiral substances by initiation material (being enumerated as in patent WO2004/052310) at present, owing to needs carry out chiral separation, reduces the utilization ratio of raw material, adds production cost.
Summary of the invention
The technical problem to be solved is to overcome in prior art the preparation of Entecavir class medicine with non-chiral compound as raw material, need to carry out chiral separation, the defect that complex operation, combined coefficient are low, cost is high, and provide the preparation method of a class purine derivative.The method cheaper starting materials easy, preparation method easy, efficiently, be suitable to industrialized production.
Therefore, the present invention relates to the preparation method of class purine derivative as shown in formula IV, it comprises the steps of in organic solvent, alkali, palladium catalyst effect under, compound ii and compound III are carried out coupling reaction,.
Wherein, R1For H or R1a；R2For H or R2a；R3For halogen, OH or OR3a；R4For H or R4a；R5For H or R5a。
Wherein, R1aFor CH2OR1a’、C(O)R1a’、C(O)OR1a’、C(O)NHR1a’、CH2R1d’、SiR1a’R1b’R1c' or C (O) NR1b’R1c’；
R2aFor CH2OR2a’、C(O)R2a’、C(O)OR2a’、C(O)NHR2a’、CH2R2d’、SiR2a’R2b’R2c' or C (O) NR2b’R2c’；
R3aFor CH2OR3a’、C(O)R3a’、C(O)OR3a’、C(O)NHR3a’、CH2R3d’、SiR3a’R3b’R3c' or C (O) NR3b’R3c’；
R4aFor CH2OR4a’、C(O)R4a’、C(O)OR4a’、C(O)NHR4a’、CH2R4d’、SiR4a’R4b’R4c' or C (O) NR4b’R4c’；
R5aFor OC (O) R5a’、OC(O)OR5a' or OSO2R5a’。
Wherein, R1a’、R2a’、R3a’、R4a’、R1b’、R2b’、R3b’、R4b’、R1c’、R2c’、R3c’、R4c' and R5a' independently be:
(1) straight chained alkyl containing 1 to 8 carbon, containing the straight-chain alkenyl of 2 to 8 carbon, containing the straight-chain alkynyl of 2 to 8 carbon, the cycloalkyl containing 3 to 8 carbon or the saturated heterocyclyl containing 2 to 8 carbon；
(2) straight chained alkyl containing 1 to 8 carbon being replaced, the straight-chain alkenyl containing 2 to 8 carbon being replaced, the straight-chain alkynyl containing 2 to 8 carbon being replaced, the cycloalkyl containing 3 to 8 carbon being replaced or the saturated heterocyclyl containing 2 to 8 carbon being replaced；
The aryl of (3) 6 to 12 carbon；
(4) aryl of 6 to 12 carbon being replaced；
The heteroaryl of (5) 3 to 12 carbon；
Or the heteroaryl of 3 to 12 carbon that (6) are replaced；
Or, R1b' and R1c' be connected, form one 3 to 12 yuan saturated or unsaturated rings by nitrogen-atoms or silicon atom；R2b' and R2c' be connected, form one 3 to 12 yuan saturated or unsaturated rings by nitrogen-atoms or silicon atom；R3b' and R3c' be connected, form one 3 to 12 yuan saturated or unsaturated rings by nitrogen-atoms or silicon atom；R4b' and R4c' be connected, form one 3 to 12 yuan saturated or unsaturated rings by nitrogen-atoms or silicon atom.
Wherein, R1d’、R2d’、R3d' and R4d' independently be:
(1) straight-chain alkenyl containing 2 to 8 carbon, containing the straight-chain alkynyl of 2 to 8 carbon；
(2) straight-chain alkenyl containing 2 to 8 carbon being replaced, the straight-chain alkynyl containing 2 to 8 carbon being replaced；
The aryl of (3) 6 to 12 carbon；
(4) aryl of 6 to 12 carbon being replaced；
The heteroaryl of (5) 3 to 12 carbon；
Or the heteroaryl of 3 to 12 carbon that (6) are replaced.
In the present invention, described " being replaced " refers to that one, two, three or more than three hydrogen atoms are replaced by one or more following groups independently: fluorine, chlorine, bromine, iodine, hydroxyl, the hydroxyl of protection, nitro, cyano group, amino, the amino of protection, carbonyl, thiocarbonyl ,-NH-(C1-C12Alkyl) ,-NH-(C2-C8Thiazolinyl) ,-NH-(C2-C8Alkynyl) ,-NH-(C3-C12Cycloalkyl) ,-NH-(C6-C12Aryl) ,-NH-(C3-C12Heteroaryl) ,-NH-(C3-C12Saturated heterocyclyl) ,-NH-(C3-C12Unsaturated heterocycle base), two (C1-C12Alkyl) substituted amino, two (C6-C12Aryl) substituted amino, two (C3-C12Heteroaryl) substituted amino ,-O-(C1-C12Alkyl) ,-O-(C2-C8Thiazolinyl) ,-O-(C2-C8Alkynyl) ,-O-(C3-C12Cycloalkyl) ,-O-(C6-C12Aryl) ,-O-(C3-C12Heteroaryl) ,-O-(C3-C12Saturated heterocyclyl) ,-O-(C3-C12Unsaturated heterocycle base) ,-C (O)-(C1-C12Alkyl) ,-C (O)-(C2-C8Thiazolinyl) ,-C (O)-(C2-C8Alkynyl) ,-C (O)-(C3-C12Cycloalkyl) ,-C (O)-(C6-C12Aryl) ,-C (O)-(C3-C12Heteroaryl) ,-C (O)-(C3-C12Saturated heterocyclyl) ,-C (O)-(C3-C12Unsaturated heterocycle base) ,-CONH2、-CONH-(C1-C12Alkyl) ,-CONH-(C2-C8Thiazolinyl) ,-CONH-(C2-C8Alkynyl) ,-CONH-(C3-C12Cycloalkyl) ,-CONH-(C6-C12Aryl) ,-CONH-(C3-C12Heteroaryl) ,-CONH-(C3-C12Saturated heterocyclyl) ,-CONH-(C3-C12Unsaturated heterocycle base) ,-OCO2-(C1-C12Alkyl) ,-OCO2-(C2-C8Thiazolinyl) ,-OCO2-(C2-C8Alkynyl) ,-OCO2-(C3-C12Cycloalkyl) ,-OCO2-(C6-C12Aryl) ,-OCO2-(C3-C12Heteroaryl) ,-OCO2-(C3-C12Saturated heterocyclyl) ,-OCO2-(C3-C12Unsaturated heterocycle base) ,-OCONH2、-OCONH-(C1-C12Alkyl) ,-OCONH-(C2-C8Thiazolinyl) ,-OCONH-(C2-C8Alkynyl) ,-OCONH-(C3-C12Cycloalkyl) ,-OCONH-(C6-C12Aryl) ,-OCONH-(C3-C12Heteroaryl) ,-OCONH-(C3-C12Saturated heterocyclyl) ,-OCONH-(C3-C12Unsaturated heterocycle base) ,-NHC (O)-(C1-C12Alkyl) ,-NHC (O)-(C2-C8Thiazolinyl) ,-NHC (O)-(C2-C8Alkynyl) ,-NHC (O)-(C3-C12Cycloalkyl) ,-NHC (O)-(C6-C12Aryl) ,-NHC (O)-(C3-C12Heteroaryl) ,-NHC (O)-(C3-C12Saturated heterocyclyl) ,-NHC (O)-(C3-C12Unsaturated heterocycle base) ,-NHCO2-(C1-C12Alkyl) ,-NHCO2-(C2-C8Thiazolinyl) ,-NHCO2-(C2-C8Alkynyl) ,-NHCO2-(C3-C12Cycloalkyl) ,-NHCO2-(C6-C12Aryl) ,-NHCO2-(C3-C12Heteroaryl) ,-NHCO2-(C3-C12Saturated heterocyclyl) ,-NHCO2-(C3-C12Unsaturated heterocycle base) ,-NHC (O) NH2、-NHC(O)NH-(C1-C12Alkyl) ,-NHC (O) NH-(C2-C8Thiazolinyl) ,-NHC (O) NH-(C2-C8Alkynyl) ,-NHC (O) NH-(C3-C12Cycloalkyl) ,-NHC (O) NH-(C6-C12Aryl) ,-NHC (O) NH-(C3-C12Heteroaryl) ,-NHC (O) NH-(C3-C12Saturated heterocyclyl) ,-NHC (O) NH-(C3-C12Unsaturated heterocycle base) ,-NHC (S) NH2、-NHC(S)NH-(C1-C12Alkyl) ,-NHC (S) NH-(C2-C8Thiazolinyl) ,-NHC (S) NH-(C2-C8Alkynyl) ,-NHC (S) NH-(C3-C12Cycloalkyl) ,-NHC (S) NH-(C6-C12Aryl) ,-NHC (S) NH-(C3-C12Heteroaryl) ,-NHC (S) NH-(C3-C12Saturated heterocyclyl) ,-NHC (S) NH-(C3-C12Unsaturated heterocycle base) ,-NHC (NH) NH2、-NHC(NH)NH-(C1-C12Alkyl) ,-NHC (NH) NH-(C2-C8Thiazolinyl) ,-NHC (NH) NH-(C2-C8Alkynyl) ,-NHC (NH) NH-(C3-C12Cycloalkyl) ,-NHC (NH) NH-(C6-C12Aryl) ,-NHC (NH) NH-(C3-C12Heteroaryl) ,-NHC (NH) NH-(C3-C12Saturated heterocyclyl) ,-NHC (NH) NH-(C3-C12Unsaturated heterocycle base) ,-NHC (NH)-(C1-C12Alkyl) ,-NHC (NH)-(C2-C8Thiazolinyl) ,-NHC (NH)-(C2-C8Alkynyl) ,-NHC (NH)-(C3-C12Cycloalkyl) ,-NHC (NH)-(C6-C12Aryl) ,-NHC (NH)-(C3-C12Heteroaryl) ,-NHC (NH)-(C3-C12Saturated heterocyclyl) ,-NHC (NH)-(C4-C12Unsaturated heterocycle base) ,-C (NH) NH-(C1-C12Alkyl) ,-C (NH) NH-(C2-C8Thiazolinyl) ,-C (NH) NH-(C2-C8Alkynyl) ,-C (NH) NH-(C3-C12Cycloalkyl) ,-C (NH) NH-(C6-C12Aryl) ,-C (NH) NH-(C3-C12Heteroaryl) ,-C (NH) NH-(C3-C12Saturated heterocyclyl) ,-C (NH) NH-(C3-C12Unsaturated heterocycle base) ,-S (O)-(C1-C12Alkyl) ,-S (O)-(C2-C8Thiazolinyl) ,-S (O)-(C2-C8Alkynyl) ,-S (O)-(C3-C12Cycloalkyl) ,-S (O)-(C6-C12Aryl) ,-S (O)-(C3-C12Heteroaryl) ,-S (O)-(C3-C12Saturated heterocyclyl) ,-S (O)-(C3-C12Unsaturated heterocycle base) ,-SO2NH2、-SO2NH-(C1-C12Alkyl) ,-SO2NH-(C2-C8Thiazolinyl) ,-SO2NH-(C2-C8Alkynyl) ,-SO2NH-(C3-C12Cycloalkyl) ,-SO2NH-(C6-C12Aryl) ,-SO2NH-(C3-C12Heteroaryl) ,-SO2NH-(C3-C12Saturated heterocyclyl) ,-SO2NH-(C3-C12Unsaturated heterocycle base) ,-NHSO2-(C1-C12Alkyl) ,-NHSO2-(C2-C8Thiazolinyl) ,-NHSO2-(C2-C8Alkynyl) ,-NHSO2-(C3-C12Cycloalkyl) ,-NHSO2-(C6-C12Aryl) ,-NHSO2-(C3-C12Heteroaryl) ,-NHSO2-(C3-C12Saturated heterocyclyl) ,-NHSO2-(C3-C12Unsaturated heterocycle base) ,-CH2NH2、-CH2SO2CH3、C6-C12Aryl, C6-C12The substituted C of aryl1-C12Alkyl, C3-C12Heteroaryl, C3-C12The substituted C of heteroaryl1-C12Alkyl, C3-C12Saturated heterocyclyl, C3-C12Unsaturated heterocycle base, C3-C12Cycloalkyl,1The substituted C of individual alkoxyl1-C12Alkyl, methoxymethoxy, methoxy ethoxy, sulfydryl ,-S-(C1-C12Alkyl) ,-S-(C2-C8Thiazolinyl) ,-S-(C2-C8Alkynyl) ,-S-(C3-C12Cycloalkyl) ,-S-(C6-C12Aryl) ,-S-(C3-C12Heteroaryl) ,-S-(C3-C12Saturated heterocyclyl) ,-S-(C3-C12Unsaturated heterocycle base) or methylthiomethyl；Wherein said aryl, heteroaryl, saturated heterocyclyl, unsaturated heterocycle base, alkyl, thiazolinyl, alkynyl, cycloalkyl, alkoxyl are unsubstituted or are further substituted with by one or more in above-mentioned substituent group.
Wherein, R1It is preferably H or benzyl.R2It is preferably H or benzyl.R3It is preferably F, Cl, Br, I or OH.R4It is preferably H.
Wherein, the method of described coupling reaction and condition can be all conventional method and the condition of this type of reaction of this area, following method specifically preferred according to the invention and condition: wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, it it is preferably aprotic solvent, it is more preferably one or more in toluene, dimethyl sulfoxide, DMF, oxolane and ether.The volume mass of described organic solvent and compound ii is 1 ~ 100ml/g than preferably, is more preferably 3 ~ 30ml/g.Described alkali can be the conventional alkaline of this type of reaction of this area, is preferably one or more in triethylamine, n-BuLi, potassium carbonate and potassium tert-butoxide.The consumption of described alkali is preferably 0.1 ~ 10 times of compound ii mole, is more preferably 1 ~ 5 times.Described palladium catalyst can be the palladium catalyst that this area is conventionally used for this type of reaction, is preferably one or more in tetrakis triphenylphosphine palladium (0), palladium (II) and two (triphenylphosphine) Palladous chloride. (II).The consumption of described palladium catalyst is preferably the 0.001% ~ 100% of compound ii mole, is more preferably 0.01% ~ 5%.The consumption of described compound III is preferably 0.1 ~ 3 times of compound ii mole, is more preferably 0.5 ~ 2 times.The temperature of described reaction is preferably-20 ~ 180 DEG C, is more preferably 0 ~ 120 DEG C；Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound ii can be prepared by following either method:
(1) R is worked as2For R2aTime, compound ii (R2For R2a) can be prepared by following either method: (i) in organic solvent, in the presence of base, by compound ii (R2For H) and R2aOTf、R2aCl or R2aBr reacts,.Wherein, OTf is trifluoro-methanesulfonyl oxy.Or, (ii) in organic solvent, in the presence of acid, by compound ii (R2For H) and R2aC(NH)CCl3Or 1-methyl-2-R2aYl pyridines reactant salt,.
Wherein, group R1、R2aAnd R5As defined above described.
Or, (2) work as R2During for H, compound ii (R2For H) can be prepared by following method: in organic solvent, compound V is reacted under the effect of tiron and reducing metal,；
Wherein, group R1And R5As defined above described.
In method (1), organic solvent that method is (i) described and compound ii (R2For H) volume mass be 1 ~ 1000ml/g than preferably, be more preferably 3 ~ 100ml/g.The consumption of the alkali that method is (i) described is preferably compound ii (R2For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 10 times.The R that method is (i) described2aOTf、R2aCl or R2aThe consumption of Br is preferably compound ii (R2For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 3 times.The temperature of the reaction that method is (i) described is preferably-78 ~ 100 DEG C；Till the time of the reaction that method is (i) described preferably completes with detection reaction.
In method (1), organic solvent that method is (ii) described and compound ii (R2For H) volume mass be 1 ~ 1000ml/g than preferably, be more preferably 3 ~ 100ml/g.The (ii) described acid of method can be this type of conventional acid reacted of this area, is preferably one or more in methanesulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid.The consumption of the acid that method is (ii) described is preferably compound ii (R2For H) 0.5 ~ 30 times of mole, it is more preferably 1 ~ 10 times.The R that method is (ii) described2aC(NH)CCl3Or 1-methyl-2-R2aThe consumption of yl pyridines salt is preferably compound ii (R2For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 10 times.The temperature of the reaction that method is (ii) described is preferably-20 ~ 180 DEG C, is more preferably 0 ~ 120 DEG C；Till the time of the reaction that method is (ii) described preferably completes with detection reaction.
In method (2), described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably aprotic solvent, is more preferably one or more in oxolane, ether, methyl tertiary butyl ether(MTBE), 2-methyltetrahydrofuran, toluene and dimethyl sulfoxide.The volume mass of described organic solvent and compound V is 1 ~ 1000ml/g than preferably, is more preferably 3 ~ 100ml/g.Described tiron can be the tiron that this area is conventionally used for this type of reaction, is preferably one or more in cyclopentadienyl titanium dichloride (IV), a chlorine titanocenes (III), tetraisopropoxy titanium (IV) and titanium tetrachloride (IV).The consumption of described tiron is preferably 0.0001 ~ 10 times of compound V mole；It is more preferably 0.05 ~ 5 times.Described reducing metal can be the reducing metal that this area is conventionally used for this type of reaction, is preferably one or more in zinc, ferrum and magnesium.The consumption of described reducing metal is preferably 0.8 ~ 100 times of compound V mole；It is more preferably 1 ~ 10 times.It is also preferred that the left reaction protonation ammonium salt in the presence of carry out, the ammonium salt of described protonation be preferably 2，4，6-trimethylpyridine hydrochlorate, 2,6-dimethyl pyrazole thiamine hydrochloride, pyridine hydrochloride, one or more in triethylamine hydrochloride and ammonium chloride.The consumption of the ammonium salt of described protonation is preferably 0.8 ~ 100 times of compound V mole；It is more preferably 1 ~ 10 times.The temperature of described reaction is preferably-50 ~ 180 DEG C, is more preferably-20 ~ 80 DEG C；Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound V can be prepared by following method: in organic solvent, under the effect of peroxide, compound VI is carried out epoxidation reaction,；
Wherein, group R1And R5As defined above described.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably dichloromethane and/or chloroform.The volume mass of described organic solvent and compound VI is 1 ~ 1000ml/g than preferably, is more preferably 3 ~ 100ml/g.Described peroxide can be the peroxide that this area is conventionally used for this type of reaction, is preferably one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide.The consumption of described peroxide is preferably 0.5 ~ 100 times of compound VI mole, is more preferably 1 ~ 10 times.It is also preferred that the left reaction is carried out in the presence of chiral catalyst, described chiral catalyst can be the catalyst that this area is conventionally used for this type of reaction, is preferably tetraisopropoxy titanium (IV) and diethyl tartrate. catalyst system and catalyzing.The consumption of described chiral catalyst is preferably the 0.01% ~ 100% of compound VI mole, is more preferably 0.05% ~ 10%.It is also preferred that the left reaction is carried out in the presence of an inorganic base, described inorganic base can be the inorganic base that this area is conventionally used for this type of reaction, is preferably sodium bicarbonate and/or disodium-hydrogen.The consumption of described inorganic base is preferably 0.5 ~ 100 times of compound VI mole, is more preferably 1 ~ 10 times.The temperature of described reaction is preferably-20 ~ 80 DEG C, is more preferably 0 ~ 60 DEG C.Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound VI can be prepared by following either method:
(1) R is worked as5For R5aTime, compound VI (R5For R5a) can be prepared by following either method: (i) in organic solvent, in the presence of base, by compound VI (R5For H) and R5aOTf、R5aCl or R5aBr reacts,.Or, (ii) in organic solvent, in the presence of acid, by compound VI (R5For H) and R5aC(NH)CCl3Or 1-methyl-2-R5aYl pyridines reactant salt,.
Wherein, group R1And R5aAs defined above described.
Or, (2) work as R5During for H, compound VI can be prepared by following either method:
(i) in organic solvent, by compound VII withReaction,.
Wherein, group R1As defined above described.
Or, (ii) in organic solvent, by compound VII withOrCarry out nucleophilic addition, obtain compound VII '；Compound VII ' carries out removing the reaction of silicon protection group again,.
Wherein, group R1As defined above described.
In method (1), organic solvent that method is (i) described and compound VI (R5For H) volume mass be 1 ~ 1000ml/g than preferably, be more preferably 3 ~ 100ml/g.The consumption of the alkali that method is (i) described is preferably compound VI (R5For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 10 times.The R that method is (i) described5aOTf、R5aCl or R5aThe consumption of Br is preferably compound VI (R5For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 3 times.The temperature of the reaction that method is (i) described is preferably-78 ~ 100 DEG C.Till the time of the reaction that method is (i) described preferably completes with detection reaction.
In method (1), organic solvent that method is (ii) described and compound VI (R5For H) volume mass be 1 ~ 1000ml/g than preferably, be more preferably 3 ~ 100ml/g.The (ii) described acid of method can be this type of conventional acid reacted of this area, is preferably one or more in methanesulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid.The consumption of the acid that method is (ii) described is preferably compound VI (R5For H) 0.5 ~ 30 times of mole, it is more preferably 1 ~ 10 times.The R that method is (ii) described5aC(NH)CCl3Or 1-methyl-2-R5aThe consumption of yl pyridines salt is preferably compound VI (R5For H) 0.5 ~ 100 times of mole, it is more preferably 1 ~ 10 times.The temperature of the reaction that method is (ii) described is preferably-20 ~ 180 DEG C, is more preferably 0 ~ 120 DEG C.Till the time of the reaction that method is (ii) described preferably completes with detection reaction.
In method (2), the (i) described organic solvent of method can be this type of Conventional solvents reacted of this area, it is preferably aprotic solvent, is more preferably one or more in oxolane, toluene, ether, methyl tertiary butyl ether(MTBE), dichloromethane and 2-methyltetrahydrofuran.The volume mass of the (i) described organic solvent of method and compound VII is 1 ~ 1000ml/g than preferably, is more preferably 3 ~ 100ml/g.Method is (i) describedConsumption be preferably 0.5 ~ 10 times of compound VII mole, be more preferably 0.8 ~ 5 times.Preferably, the (i) described reaction of method is carried out in the presence of chiral catalyst, described chiral catalyst can be the catalyst that this area is conventionally used for this type of reaction, it is preferably tetraisopropoxy titanium and S-dinaphthol or derivatives thereof catalyst system and catalyzing, trifluoromethanesulfonic acid zinc and N-methylephedrine or derivatives thereof catalyst system and catalyzing or trifluoromethanesulfonic acid zinc and (1R, 2R)-3-tert-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol catalysis system.The consumption of described chiral catalyst is preferably 0.001 ~ 3 times of compound VII mole, is more preferably 0.5% ~ 100%.The temperature of the reaction that method is (i) described is preferably-78 ~ 180 DEG C, is more preferably-60 ~ 60 DEG C.Till the time of the reaction that method is (i) described preferably completes with detection reaction.
In method (2), method is (i) describedCan be prepared with alkali reaction in organic solvent by acetylene.Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area.Described alkali can be the conventional alkaline of this type of reaction of this area, is preferably one or more in triethylamine, ethylmagnesium bromide, diethyl zinc and n-BuLi.The consumption of described alkali is preferably 0.5 ~ 10 times of acetylene mole, is more preferably 0.8 ~ 3 times.The temperature of described reaction is preferably-78 ~ 100 DEG C, is more preferably-78 ~ 60 DEG C.
In method (2), organic solvent in the nucleophilic addition that method is (ii) described can be the Conventional solvents of this type of reaction of this area, it is preferably aprotic solvent, is more preferably one or more in oxolane, toluene, ether, methyl tertiary butyl ether(MTBE) and dichloromethane.Method is (ii) described OrConsumption be preferably 0.5 ~ 10 times of compound VII mole, be more preferably 0.8 ~ 5 times.Preferably, the (ii) described nucleophilic addition of method is carried out in the presence of chiral catalyst, described chiral catalyst can be the catalyst that this area is conventionally used for this type of reaction, it is preferably tetraisopropoxy titanium and S-dinaphthol or derivatives thereof catalyst system and catalyzing, trifluoromethanesulfonic acid zinc and N-methylephedrine or derivatives thereof catalyst system and catalyzing or trifluoromethanesulfonic acid zinc and (1R, 2R)-3-tert-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol catalysis system.The consumption of described chiral catalyst is preferably the 0.1% ~ 100% of compound VII mole, is more preferably 0.5% ~ 50% times.The temperature of the nucleophilic addition that method is (ii) described is preferably-78 ~ 80 DEG C, is more preferably-78 ~ 60 DEG C.Till the time of the nucleophilic addition that method is (ii) described preferably completes with detection reaction.
Method (ii) in, describedOrCan be respectively by Me3SiC≡CH、Et3SiC ≡ CH orPrepare with alkali reaction in organic solvent.Described alkali can be the conventional alkaline of this type of reaction of this area, is preferably one or more in triethylamine, ethylmagnesium bromide, diethyl zinc and n-BuLi.The consumption of described alkali is preferably Me3SiC≡CH、Et3SiC ≡ CH or0.5 ~ 10 times of mole, is more preferably 0.8 ~ 3 times.The temperature of described reaction is preferably-78 ~ 100 DEG C, is more preferably-78 ~ 60 DEG C.
Method (ii) in, the method for the reaction of described removing silicon protection group and condition can be all this type of conventional method reacted and condition of this area.Following method specifically preferred according to the invention and condition: method (a), by compound VII ' in proton solvent, react in the presence of an inorganic base,.Or, method (b), in solvent, the reagent of compound VII ' with fluoride ion is reacted,.
In method (a), described proton solvent is preferably one or more in methanol, second alcohol and water, and described proton solvent is 1 ~ 1000ml/g with the volume mass of compound VII ' than preferably, is more preferably 3 ~ 30ml/g.Described inorganic base is preferably one or more in potassium carbonate, sodium carbonate and sodium hydroxide.The consumption of described inorganic base is preferably 0.1 ~ 10 times of compound VII ' mole, is more preferably 0.5 ~ 5 times.The temperature of described reaction is preferably-20 ~ 100 DEG C, is more preferably 0 ~ 60 DEG C.Till the time of described reaction preferably completes with detection reaction.
In method (b), described solvent is 1 ~ 1000ml/g with the volume mass of compound VII ' than preferably, is more preferably 3 ~ 100ml/g.The reagent of described fluoride ion can be the reagent that this area is conventionally used for removing the fluoride ion of silicon protection group; it is preferably one or more in potassium fluoride, tetrabutyl ammonium fluoride and Methanaminium, N,N,N-trimethyl-, fluoride; the consumption of the reagent of described fluoride ion is preferably 0.8 ~ 100 times of compound VII ' mole, is more preferably 1 ~ 10 times.The temperature of described reaction is preferably-78 ~ 100 DEG C, is more preferably-20 ~ 60 DEG C.Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound VII can be prepared by following method: compound VIII is carried out oxidation reaction；
Wherein, described oxidation reaction can be the reaction that this area is conventionally used for being melted into hydroxyl oxygen carbonyl.Following oxidation reaction specifically preferred according to the invention: Swern oxidation reaction, Corey-Kim oxidation reaction, Dess-Martin oxidation reaction or carry out oxidation reaction by sodium hypochlorite and 2,2,6,6-tetramethyl piperidine combination of oxides.
In the present invention, work as R1For CH2R8Time, described compound VIII (R1For CH2R8) can be prepared by following method: in organic solvent, compound Ⅹ is reacted with reducing agent,；
Wherein, R8It is the aryl of 6 to 12 carbon, the aryl of 6 to 12 carbon being replaced, the heteroaryl of 3 to 12 carbon or the heteroaryl of 3 to 12 carbon being replaced.
Wherein, described " being replaced " is as defined above described.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably aprotic solvent, is more preferably one or more in dichloromethane, toluene and normal hexane.The volume mass of described organic solvent and compound Ⅹ is 1 ~ 1000ml/g than preferably, is more preferably 3 ~ 100ml/g.Described reducing agent can be the reagent that this area is conventionally used for being reduced to acetal ether, is preferably diisobutyl aluminium hydride and/or lithium aluminium hydride reduction.The consumption of described reducing agent is preferably 0.5 ~ 100 times of compound Ⅹ mole, is more preferably 0.8 ~ 10 times.It is also preferred that the left reaction is carried out in the presence of a lewis acid, described lewis acid is preferably one or more in aluminum chloride, lithium chloride and boron trifluoride.Described lewis acidic consumption is preferably 0.5 ~ 100 times of compound Ⅹ mole, is more preferably 0.8 ~ 10 times.The temperature of described reaction is preferably-78 ~ 180 DEG C, is more preferably-20 ~ 100 DEG C.Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound Ⅹ can be prepared by following method: in aprotic solvent, by compound Ⅹ ' and CH2=PPh3Or Tebbe reagent reacts,；
Wherein, group R8As defined above described.
Wherein, described aprotic solvent is preferably one or more in oxolane, 2-methyltetrahydrofuran and dichloromethane.Described aprotic solvent is 1 ~ 1000ml/g with the volume mass of compound Ⅹ ' than preferably, is more preferably 3 ~ 100ml/g.Described CH2=PPh3Or the consumption of Tebbe reagent is preferably 0.5 ~ 100 times of compound Ⅹ ' mole, it is more preferably 0.8 ~ 10 times.The temperature of described reaction is preferably-60 ~ 180 DEG C, is more preferably-30 ~ 100 DEG C.Till the time of described reaction preferably completes with detection reaction.
In the present invention, described compound Ⅹ ' can be prepared by following method: compound Ⅺ is carried out oxidation reaction,；
Wherein, group R8As defined above described.
Wherein, described oxidation reaction can be the reaction that this area is conventionally used for being melted into hydroxyl oxygen carbonyl.Following oxidation reaction specifically preferred according to the invention: Swern oxidation reaction, Corey-Kim oxidation reaction, Dess-Martin oxidation reaction or carry out oxidation reaction by sodium hypochlorite/2,2,6,6-tetramethyl piperidine combination of oxides.
In the present invention, described compound Ⅺ can be prepared by following method: in aprotic solvent, in the presence of acid, by compound Ⅺ ' and R8CHO reacts,；
Wherein, group R8As defined above described.
Wherein, described aprotic solvent is preferably one or more in benzene,toluene,xylene and normal hexane.Described aprotic solvent is 1 ~ 1000ml/g with the volume mass of compound Ⅺ ' than preferably, is more preferably 3 ~ 100ml/g.Described R8The consumption of CHO is preferably 0.5 ~ 100 times of compound Ⅺ ' mole, is more preferably 0.8 ~ 10 times.Described acid can be the acid that this area is conventionally used for this type of reaction, is preferably nonvolatile acid, is more preferably one or more in methanesulfonic acid, p-methyl benzenesulfonic acid, sulphuric acid, pyridinium p-toluenesulfonate and camphorsulfonic acid.The consumption of described acid is preferably 0.0001 ~ 2 times of compound Ⅺ ' mole, is more preferably that the temperature of 0.001 ~ 1 times of described reaction is preferably 0 ~ 180 DEG C, is more preferably 25 ~ 120 DEG C.Till the time of described reaction preferably completes with detection reaction.
The invention further relates to the midbody compound preparing formula IV compound as shown in formula V or VI.
Wherein, group R1And R5As defined above described.
Without prejudice to the field on the basis of common sense, each preferred feature above-mentioned in the present invention can combination in any, obtain the preferred embodiments of the invention.
In the present invention, term " alkyl " represents have appointment carbon number purpose side chain and the radical of saturated aliphatic alkyl of straight chain.Such as, at " C1-C10Alkyl " defined in for be included in straight chain or branched structure the group with 1,2,3,4,5,6,7,8,9 or 10 carbon atoms.Such as, " C1-C10Alkyl " specifically include methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc..
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, multi-ring or bridge joint carbocyclic ring substituent group.Such as, the ring with 3-20 carbon atom can be expressed as C3-C20Cycloalkyl；The ring with 5-15 carbon atom can be expressed as C5-C15Cycloalkyl；The ring with 3-8 carbon atom can be expressed as C3-C8Cycloalkyl, etc..nullThis term includes but not limited to cyclopropyl、Cyclobutyl、Cyclopenta、Cyclohexyl、Suberyl、Ring octyl group、1H-indenyl、2,3-indanyl、1,2,3,4-tetrahydro-naphthalenyl、5,6,7,8-tetrahydro-naphthalenyl、8,9-dihydro-7H-benzo ring heptene-6-base、6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl、5,6,7,8,9,10-hexahydro-benzo ring octenyl、Fluorenyl、Bicyclo-[2.2.1] heptyl、Bicyclo-[2.2.1] heptenyl、Bicyclo-[2.2.2] octyl group、Bicyclo-[3.1.1] heptyl、Bicyclo-[3.2.1] octyl group、Bicyclo-[2.2.2] octenyl、Bicyclo-[3.2.1] octenyl、Adamantyl、Octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalene base etc..Cycloalkyl can be connected on central element through any carbon atom, and can be further substituted with it.
Term " alkoxyl " represents that described carbon number purpose is ring-type or acyclic alkyl groups by having of connecing of oxygen bridging.Thus, " alkoxyl " comprises the definition of above alkyl and cycloalkyl.
Term " aryl " represents any stable monocycle or the bicyclic carbocyclic that may be up to 7 atoms in each ring, and at least one of which ring is aromatic rings.The example of above-mentioned aryl unit includes phenyl, naphthyl, tetralyl, indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl.It is two ring substituents at aryl substituent, and one of them ring is in the case of non-aromatic ring, carry out with the aromatic ring that connects through of central element.
Term " heteroaryl " represents stable monocycle or the bicyclo-that may be up to 7 atoms in each ring, and at least one of which ring is aromatic rings and contains 1-4 the hetero atom selected from O, N and S.Heteroaryl within the range defined herein includes but not limited to: acridinyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline." heteroaryl " it should also be understood that the N-oxide derivative being to include any nitrogen-containing hetero aryl.Wherein heteroaryl substituent be two ring substituents and ring be non-aromatic ring or do not comprise heteroatomic in the case of, it will be understood that connect and by aromatic ring or carry out by comprising the hetero atom of ring respectively.
Term " straight chained alkyl " means to include having the radical of saturated aliphatic alkyl specifying carbon number purpose straight chain.Such as, containing the straight chained alkyl of 1 ~ 8 carbon, for being included in linear chain structure the group with 1,2,3,4,5,6,7 or 8 carbon atoms.Such as, methyl, ethyl, n-pro-pyl, normal-butyl, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc..
Term " direct-connected thiazolinyl " refers to containing specifying number carbon atom, and the straight-chain alkyl containing at least one carbon-carbon double bond, and wherein carbon-carbon double bond is connected with parent.Preferably there is a carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds can be there are.Thus, " containing the direct-connected thiazolinyl of 2 ~ 8 carbon ", include but not limited to vinyl, acrylic and cyclobutenyl etc..
Term " straight-chain alkynyl " refers to containing specifying number carbon atom, and the straight-chain alkyl containing at least one triple carbon-carbon bonds, and wherein triple carbon-carbon bonds is connected with parent.Wherein can there are up to three triple carbon-carbon bonds.Thus, acetenyl, propinyl and butynyl etc. are included but not limited to " containing the direct-connected alkynyl of 2 ~ 8 carbon ".
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, multi-ring or bridge joint carbocyclic ring substituent group.nullThis term includes but not limited to cyclopropyl、Cyclobutyl、Cyclopenta、Cyclohexyl、Suberyl、Ring octyl group、1H-indenyl、2,3-indanyl、1,2,3,4-tetrahydro-naphthalenyl、5,6,7,8-tetrahydro-naphthalenyl、8,9-dihydro-7H-benzo ring heptene-6-base、6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl、5,6,7,8,9,10-hexahydro-benzo ring octenyl、Fluorenyl、Bicyclo-[2.2.1] heptyl、Bicyclo-[2.2.1] heptenyl、Bicyclo-[2.2.2] octyl group、Bicyclo-[3.1.1] heptyl、Bicyclo-[3.2.1] octyl group、Bicyclo-[2.2.2] octenyl、Bicyclo-[3.2.1] octenyl、Adamantyl、Octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalene base etc..Naphthenic substituent can be connected on central element through any suitable carbon atom.
Term " saturated heterocyclyl " represents containing 1 ~ 4 heteroatomic 4 ~ 10 yuan of carba ring group without unsaturated bond (such as carbon-carbon double bond or three keys) selected from O, N and S, and includes bicyclic groups.Other example of " saturated heterocyclyl " includes but not limited to following: morpholinyl, piperazinyl, piperidyl etc..Saturated heterocyclyl can be attached through carbon atom or hetero atom.
Term " unsaturated heterocycle base " represents containing 1 ~ 4 hetero atom selected from O, N and S, and 4 ~ 10 yuan of non-aromatic carba ring groups containing unsaturated bond (such as carbon-carbon double bond or three keys), and includes bicyclic groups.Unsaturated heterocycle base can be attached through carbon atom or hetero atom.
Term " hydroxyl of protection " represents that the hydrogen in hydroxyl is conventionally used for the group protecting the group of hydroxyl to be replaced by this area.Hydroxyl protecting group such as methyl, the tert-butyl group, benzyl, trityl group, methoxy, dimethyl silyl, THP trtrahydropyranyl, t-Butyldimethylsilyl or the acyl group etc. that described this area is conventional.
Term " amino of protection " represents that one or two hydrogen in amino is conventionally used for the group protecting the group of amino to be replaced by this area.
Heretofore described raw material or reagent are in addition to special instruction, the most commercially.
The actively progressive effect of the present invention is: the preparation method cheaper starting materials of the present invention easy, preparation method easy, efficiently, be suitable to industrialized production, the synthesis for Entecavir class medicine provides a new approach.
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not intended to be limited thereto.
Raw material used in embodiment or reagent are in addition to special instruction, the most commercially.
Room temperature described in embodiment refers both to 20 ~ 35 DEG C.
Embodiment 1
Step 1a
S-1,2,4-butantriols (15g, 0.14mol) and benzaldehyde (22ml, 0.15mol) are dissolved in benzene (300mL), add 4-toluene sulfonic acide (270mg, 1.4mmol), are heated to reflux point water to no longer there being moisture to steam, about 3 hours.Use saturated sodium bicarbonate solution cancellation, separatory, collect organic facies, be evaporated, obtain pale red grease, silica gel column chromatography purification, obtain white crystal 20g, yield 73%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.48 (m, 2H), 7.36 (m, 3H), 5.54 (s, 1H), 4.30 (ddd, 1H), 3.97 (m, 2H), 3.68 (m, 2H), 2.12 (m, 1H), 1.91 (m, 1H), 1.43 (ddd, 1H).
Step 1b
In dichloromethane (32mL) solution of the oxalyl chloride (2.44g, 28.8mmol) at-70 DEG C, it is slowly added dropwise dichloromethane (4mL) solution of dimethyl sulfoxide (3.05mL).After completion of dropwise addition, reactant liquor stirs 1 hour at-70 DEG C, is slowly added dropwise dichloromethane (3mL) solution of the product (2.7g, 13.9mmol) of step 1a.After dropping, reactant liquor continues to stir 1 hour at-70 DEG C, it is slowly added dropwise triethylamine (10.2mL), after reactant liquor is slowly raised to-20 DEG C, add saturated ammonium chloride solution, separatory, the pale yellow oil obtained after organic facies solvent evaporated is after too short silicagel column filters, it is evaporated filtrate, the colorless oil obtained is dissolved in oxolane (20mL), it is slowly added into iodide triphenyl phasphine (8.14g, 21.6mmol) and potassium tert-butoxide (1.94,17.3mmol) in the mixed liquor of oxolane (120mL).Reactant liquor is stirred at room temperature 16 hours, filters.Filtrate is dissolved in 50ml dichloromethane after being evaporated, and instills petroleum ether (150mL).After filtering precipitation, filtrate is evaporated, is filtrated to get colorless oil as product 1.3g, yield 48% through too short silicagel column.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.51 (m, 2H), 7.37 (m, 3H), 5.94 (ddd, 1H), 5.57 (s, 1H), 5.33 (d, 1H), 5.17 (d, 1H), 4.38 (m, 1H), 4.29 (dd, 1H), 4.00 (dt, 1H), 1.93 (dq, 1H), 1.60 (dq, 1H).
Step 1c
Step 1b product (1.3g at-20 DEG C, in dichloromethane (30mL) solution 6.91mmol), it is slowly added to diisobutyl aluminium hydride (1.0M hexane solution, 14mL), after stirring 30 minutes at-20 DEG C, being slowly added to the saturated solution of sodium potassium tartrate tetrahydrate, mixed liquor is stirred at room temperature to clarification.Separatory, the colorless oil obtained after organic facies solvent evaporated, through silica gel column chromatography purification, obtains colorless oil as product 1.1g, yield 85%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.34 (m, 5H), 5.80 (ddd, 1H), 5.29 (dd, 1H), 5.26 (s, 1H), 4.63 (d, 1H), 4.37 (d, 1H), 4.03 (m, 1H), 3.77 (m, 2H), 2.36 (m, 1H), 1.85 (m, 2H).
Step 1d
In dichloromethane (28ml) solution of the product (1.1g, 5.73mmol) of step 1c, add sodium bicarbonate (730mg, 8.5mmol) and Dess-Martin reagent (2.5g, 5.73mmol).The reactant liquor obtained adds hypo solution cancellation after being stirred at room temperature 45 minutes, and dichloromethane extracts, and merges organic facies, and anhydrous sodium sulfate is dried.Filtering, concentrating under reduced pressure, silicagel column filters, and obtains colorless oil 912mg, yield 83%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 9.76 (s, 1H), 7.31 (m, 5H), 5.81 (m, 1H), 5.32 (m, 2H), 4.62 (d, 1H), 4.40 (d, 1H), 4.33 (m, 1H), 2.74 (m, 1H), 2.56 (m, 1H).
Step 1e
In the tetrahydrofuran solution (6.72ml, 1M) of ethylmagnesium bromide, it is slowly added to trimethylsilyl acetylene (1mL), stirs 45 minutes under room temperature.At-78 DEG C, join in the 20ml dichloromethane solution of step 1d product (912mg, 4.8mmol).Reactant liquor is slowly increased to room temperature, stirs 16 hours, adds aqueous ammonium chloride solution cancellation, and dichloromethane extracts, and merges organic facies, and anhydrous sodium sulfate is dried.Filtering, concentrating under reduced pressure, silicagel column filters, and obtains colorless oil 654mg, yield 48%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.31 (m, 5H), 5.79 (m, 1H), 5.30 (d, 1H), 5.27 (s, 1H), 4.61 (d, 1H), 4.59 (m, 1H), 4.35 (d, 1H), 4.05 (m, 1H), 2.88 (d, 1H), 2.13 (m, 1H), 1.89 (m, 1H), 0.15 (s, 9H).
Step 1f
Being joined by potassium carbonate (300mg) in methanol (20mL) solution of step 1e product (654mg, 2.27mmol), the reactant liquor obtained stirs 16 hours at room temperature.Being evaporated organic facies, residual liquid stirs split-phase in water and dichloromethane, and aqueous phase dichloromethane extracts, and merges organic facies, and anhydrous sodium sulfate is dried.Filter, concentrating under reduced pressure, the crude product obtained is dissolved in pyridine (5mL), add acetic anhydride (1.5mL) and 4-dimethylaminopyridine (27mg), stir 3 hours under room temperature.It is evaporated organic facies, residual liquid is dissolved in dichloromethane, wash with dilute hydrochloric acid (0.5M), add anhydrous sodium sulfate and be dried.Filtering, concentrating under reduced pressure, short silicagel column filters, and obtains oily liquids 532mg, yield 93%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.33 (m, 5H), 5.76 (ddd, 1H), 5.54 (m, 1H), 5.29 (d, 1H), 5.26 (s, 1H), 4.60 (d, 1H), 4.36 (d, 1H), 4.01 (m, 1H), 2.43 (s, 1H), 2.19 (m, 1H), 2.04 (s, 3H), 1.95 (m, 1H).
Step 1g
In step 1f product (131mg, adding m-chlorobenzoic acid (414mg, 70% purity) in dichloromethane (10mL) solution 0.48mmol), the reactant liquor obtained is stirred at room temperature 48 hours, add sodium hydrate aqueous solution (1M) cancellation, separatory, organic facies anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, short silicagel column filters, and obtains colourless oil liquid 132mg, yield 95%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.29 (m, 5H, m), 5.48 (m, 1H, m), 4.79 (d, 0.5H, d), 4.61 (d, 0.5H), 4.46 (q, 1H, q), 3.49 (m, 0.5H, m), 3.29 (m, 0.5H, m), 3.00 (m, 0.5H, m), 2.89 (m, 0.5H), 2.72 (m, 1H, m), 2.68 (m, 0.5H, m), 2.48 (m, 0.5H), 2.39 (d, 1H, d), 2.03 (m, 1H, m), 1.98 (s, 3H, s), 1.89 (m, 1H).
Step 1h-1
Under nitrogen protection; in step 1g product (120mg; tetrahydrofuran solution (12mL) 0.43mmol) is sequentially added into zinc powder (84mg; 1.3mmol), cyclopentadienyl titanium dichloride (VI) (12mg; 0.084mmol) He 2; 6-dimethyl pyrazole thiamine hydrochloride (180mg, 0.22mmol), at room temperature stirring 15 hours.Filtering, obtain filtrate, solvent evaporated, the residual liquid obtained is dissolved in 150ml dichloromethane, washs with 10% aqueous solution of malic acid and saturated sodium bicarbonate aqueous solution successively, anhydrous sodium sulfate is dried.Filtering, concentrating under reduced pressure, silicagel column filters, and obtains colorless oil as product 90mg, yield 75%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.32 (s, 5H, s), 5.39 (t, 1H, t), 5.24 (d, 1H, d), 5.12 (d, 1H), 4.55 (dd, 2H, dd), 3.88 (q, 1H, q), 3.69 (m, 2H, m), 2.85 (br, 1H, br), 2.53 (q, 1H, p), 2.11 (br, 1H), 2.05 (3H, s), 1.75 (q, 1H).
Step 1h-2
Under nitrogen protection; in step 1g product (120mg; tetrahydrofuran solution (12mL) 0.43mmol) is sequentially added into zinc powder (84mg; 1.3mmol), cyclopentadienyl titanium dichloride (VI) (12mg; 0.084mmol) with 2，4，6-trimethylpyridine hydrochlorate (200mg; 0.22mmol), stir 15 hours at room temperature.Filtering, remove insoluble matter, be evaporated filtrate, the residual liquid obtained is dissolved in 150ml dichloromethane, washs with 10% aqueous solution of malic acid and saturated sodium bicarbonate aqueous solution successively, anhydrous sodium sulfate is dried.Filtering, concentrating under reduced pressure, silicagel column filters, and obtains colorless oil 62mg, yield 53%.
The rapid 1h-1 of its Structural Identification data syn-chronization.
Step 1i
Under room temperature, in dichloroethanes (100ml) solution of step 1h-1 product (200mg, 0.72mmol), add 1-methyl-2-benzyloxypyridine fluoroform sulphonate (1.15g, 2.82mmol) and magnesium oxide (300mg, 7.5mmol), it is warming up to 88 DEG C, reacts 12 hours.It is cooled to room temperature, concentrating under reduced pressure, residue over silica gel column chromatography purification, obtains pure product 230mg, yield 67%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.32 (m, 10H), 5.45 (t, 1H), 5.24 (d, 1H), 5.19 (d, 1H), 4.51 (m, 4H), 3.91 (q, 1H), 3.54 (m, 2H), 2.95 (br, 1H), 2.51 (br, 1H), 2.05 (s, 3H), 1.82 (q, 1H).
Step 1j
Under room temperature, Feldalat NM (200mg) is joined in methanol (5ml) solution of step 1i product (230mg, 0.63mmol), stir 2 hours under room temperature.Concentrating under reduced pressure, crude product obtains pure product 205mg, yield 93% through silica gel column chromatography purification.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.35 (m, 10H), 5.45 (s, 1H), 5.18 (s, 1H), 4.55 (s, 2H), 4.51 (q, 2H), 4.41 (m, 1H), 4.08 (m, 1H), 3.52 (q, 1H), 3.30 (t, 1H), 3.10 (br, 1H), 2.48 (d, 1H), 1.90-2.15 (m, 2H).
Step 1k
In oxolane (3mL) solution of step 1j product (40mg, 0.13mmol), it is sequentially added into triphenylphosphine (68mg, 0.26mmol), the chloro-2-aminopurine of 6-(44mg, 0.26mmol) with diethyl azodiformate (45mg, 0.26mmol), stirring 16 hours at room temperature.It is evaporated organic solvent, residual liquid is redissolved in the mixed liquor of trifluoroacetic acid (8mL) and water (2mL), stir 8 hours under room temperature.It is evaporated all solvents, after residue by silicagel column chromatography purification, obtains white solid 25mg, yield 45%.
Its Structural Identification data are as follows:
ESI-MSm/z:458.1 [M+H]+。
Step 1l
At-78 DEG C, dichloromethane (1ml) solution of step 1k product (25mg, 0.059mmol) adds the dichloromethane solution (0.3mL, 1M) of boron chloride, stir 30 minutes at-20 DEG C, add methanol (1mL) cancellation reaction.After all of volatile material is taken away by nitrogen stream, residue being dissolved in water, aqueous phase is the most neutral with sodium hydrate aqueous solution (1M) regulation after extracting with ether.After boiling off the water of half, the white suspension thing obtained is collected by filtration, and obtains white solid 11mg, yield 73% after drying.
Its Structural Identification data are as follows:
1HNMR(d6-DMSO): 10.81 (s, 1H), 7.65 (s, 1H), 6.70 (br, 2H), 5.35 (t, 1H), 5.09 (s, 1H), 4.93 (d, 1H), 4.55 (s, 1H), 4.23 (s, 1H), 3.53 (t, 2H), 2.52 (m, 2H), 2.20 (m, 1H), 2.05 (m, 1H).
Embodiment 2
Step 2a
4-toluene sulfonic acide (172mg, 1mmol) is joined S-1, in toluene (150mL) solution of 2,4-butantriols (10.6g, 0.1mol) and anisaldehyde (20.4g, 0.15mol), is heated to reflux point water to no longer there being moisture to steam.Add saturated sodium bicarbonate solution cancellation reaction, separatory, by organic facies solvent evaporated, obtain dark red oil, silica gel column chromatography purification, obtain pale yellow oil 13.7g, yield 62%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.42 (d, 2H), 6.90 (d, 2H), 5.50 (s, 1H), 4.31 (dd, 1H), 3.98 (m, 2H), 3.80 (s, 3H), 3.66 (m, 2H), 1.92 (dq, 1H), 1.44 (d, 1H).
Step 2b
At-70 DEG C, dichloromethane (150mL) solution of oxalyl chloride (11g, 87mmol) is slowly added dropwise dichloromethane (10mL) solution of dimethyl sulfoxide (10.5g).Completion of dropwise addition, stirs reactant liquor 1 hour at-70 DEG C, is slowly added dropwise dichloromethane (20mL) solution of step 2a product (10g, 44.6mmol).Drip complete, continue to stir 1 hour at-70 DEG C, be slowly added dropwise triethylamine (32mL), after reactant liquor is slowly raised to 0 DEG C, add saturated ammonium chloride solution.By organic facies solvent evaporated, the pale yellow oil obtained is after too short silicagel column filters, it is evaporated filtrate, the colorless oil obtained is dissolved in oxolane (20mL), it is slowly added into iodate potassio triphen to see (48g, 120mmol) and potassium tert-butoxide (12.3g, 110mmol) oxolane (120mL) mixed liquor in.Reactant liquor filters after being stirred at room temperature 16 hours.It is dissolved in after filtrate solvent evaporated in 50ml dichloromethane, instills petroleum ether (150mL).After being filtered to remove precipitation, filtrate is evaporated, is filtrated to get colorless oil 7.2g, yield 73% through too short silicagel column.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.44 (d, 2H), 6.88 (d, 2H), 5.94 (m, 1H), 5.55 (s, 1H), 5.33 (d, 1H), 5.16 (d, 1H), 4.36 (m, 1H), 4.27 (m, 1H), 3.98 (dt, 1H), 3.79 (s, 3H), 1.92 (dq, 1H), 1.58 (d, 1H).
Step 2c
At-20 DEG C, diisobutyl aluminium hydride (1.0M hexane solution, 45mL) it is slowly added in dichloromethane (75mL) solution of the product (5g, 22.7mmol) of step 2b, stir 30 minutes at-20 DEG C, being slowly added to the saturated solution of sodium potassium tartrate tetrahydrate, mixed liquor is stirred at room temperature to clarification, by organic facies solvent evaporated, obtain colorless oil, silica gel column chromatography purification, obtains colorless oil 4.2g, yield 84%.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 7.34 (d, 2H), 6.98 (d, 2H), 5.90 (m, 1H), 5.37 (m, 1H), 5.34 (s, 1H), 4.65 (d, 1H), 4.39 (d, 1H), 4.10 (m, 1H), 3.90 (s, 3H), 3.84 (m, 2H), 1.95 (m, 1H), 1.87 (m, 1H).
Step 2d
In step 2c product (500mg, dichloromethane (20mL) solution 2.25mmol) adds sodium bicarbonate solid (238mg, 2.25mmol) with Dess-Martin oxidant (977mg, 2.25mmol), it is stirred at room temperature 1 hour, add saturated sodium thiosulfate solution cancellation, after stirring to clarify, separatory, organic facies is boiled off solvent, the residual liquid obtained obtains colorless oil compound 430mg, yield 86% through silica gel column chromatography purification.
Its Structural Identification data are as follows:
1HNMR(CDCl3): 9.73 (s, 1H), 7.24 (m, 2H), 6.87 (d, 2H), 5.80 (m, 1H), 5.34 (m, 2H), 4.55 (d, 1H), 4.33 (d, 1H), 4.31 (m, 1H), 3.80 (s, 3H), 2.70 (m, 1H), 2.55 (m, 1H).
Claims (24)
1. the preparation method of class purine derivative as shown in formula IV, it comprises the steps of in organic solvent, alkali, palladium catalyst effect under, compound ii and compound III are carried out coupling reaction；
Wherein, R1For H or benzyl；R2For H or benzyl；R3For halogen；R4For H；R5For H or R5a；R5aFor OC (O) R5a’、OC(O)OR5a’Or OSO2R5a’；Wherein, R5a’Independently be the straight chained alkyl containing 1 to 8 carbon；
Described compound ii is prepared by following either method:
(1) R is worked as2For R2aTime, compound ii is prepared by following either method: in (i) organic solvent, in the presence of base, by R2For compound ii during H and R2aOTf、R2aCl or R2aBr reacts, wherein, OTf is trifluoro-methanesulfonyl oxy；Or, in (ii) organic solvent, in the presence of acid, by R2For compound ii during H and R2aC(NH)CCl3Or 1-methyl-2-R2aYl pyridines salt reacts,；
R2aFor benzyl；
Or, (2) work as R2During for H, compound ii is prepared by following method: in organic solvent, is reacted by compound V under the effect of tiron and reducing metal；
Described palladium catalyst is one or more in tetrakis triphenylphosphine palladium (0), palladium (II) and two (triphenylphosphine) Palladous chloride. (II)；The consumption of described palladium catalyst is the 0.001%～100% of compound ii mole.
2. preparation method as claimed in claim 1, it is characterised in that: described organic solvent is one or more in toluene, dimethyl sulfoxide, DMF, oxolane and ether.
3. preparation method as claimed in claim 1, it is characterised in that: described alkali is one or more in triethylamine, n-BuLi, potassium carbonate and potassium tert-butoxide；The consumption of described alkali is 0.1～10 times of compound ii mole.
4. preparation method as claimed in claim 1, it is characterised in that: the consumption of described compound III is 0.1～3 times of compound ii mole.
5. preparation method as claimed in claim 1, it is characterised in that: the temperature of described reaction is-20～180 DEG C；Till the time of described reaction completes with detection reaction.
6. preparation method as claimed in claim 1, it is characterised in that:
In described method (1), the consumption of the alkali described in method (i) is R2For the mole of compound ii during H 0.5～100 times；R described in method (i)2aOTf、R2aCl or R2aThe consumption of Br is R2For the mole of compound ii during H 0.5～100 times；The temperature of the reaction described in method (i) is-78～100 DEG C；Till the time of the reaction described in method (i) completes with detection reaction；
In described method (1), the acid described in method (ii) is one or more in methanesulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid；The consumption of the acid described in method (ii) is R2For the mole of compound ii during H 0.5～30 times；R described in method (ii)2aC(NH)CCl3Or 1-methyl-2-R2aThe consumption of yl pyridines salt is R2For the mole of compound ii during H 0.5～100 times；The temperature of the reaction described in method (ii) is-20～180 DEG C；Till the time of the reaction described in method (ii) completes with detection reaction；
In described method (2), described organic solvent is one or more in oxolane, ether, methyl tertiary butyl ether(MTBE), 2-methyltetrahydrofuran, toluene and dimethyl sulfoxide；Described tiron is one or more in cyclopentadienyl titanium dichloride (IV), a chlorine titanocenes (III), tetraisopropoxy titanium (IV) and titanium tetrachloride (IV)；The consumption of described tiron is 0.0001～10 times of compound V mole；Described reducing metal is one or more in zinc, ferrum and magnesium；The consumption of described reducing metal is 0.8～100 times of compound V mole；The temperature of described reaction is-50～180 DEG C；Till the time of described reaction completes with detection reaction.
7. preparation method as claimed in claim 1, it is characterized in that: the reaction described in method (2) is carried out in the presence of the ammonium salt of protonation, the ammonium salt of described protonation is 2,4,6-trimethylpyridine hydrochlorate, 2,6-dimethyl pyrazole thiamine hydrochloride, pyridine hydrochloride, one or more in triethylamine hydrochloride and ammonium chloride；The consumption of the ammonium salt of described protonation is 0.8～100 times of compound V mole.
8. preparation method as claimed in claim 1, it is characterised in that: described compound V is prepared by following either method:
(1) in organic solvent, under the effect of peroxide, compound VI is carried out epoxidation reaction,；
(2) in organic solvent, in the presence of chiral catalyst and peroxide, compound VI is carried out epoxidation reaction,；
(3) in organic solvent, in the presence of chiral catalyst, peroxide and inorganic base, compound VI is carried out epoxidation reaction,；
Or in (4) organic solvent, in the presence of peroxide and inorganic base, compound VI is carried out epoxidation reaction,；
Wherein, group R1And R5Definition as claimed in claim 1.
9. preparation method as claimed in claim 8, it is characterised in that:
Organic solvent described in method (1) is dichloromethane and/or chloroform；Peroxide described in method (1) is one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide；The consumption of the peroxide described in method (1) is 0.5～100 times of compound VI mole；The temperature of the reaction described in method (1) is-20～80 DEG C；Till the time of the reaction described in method (1) completes with detection reaction；
Organic solvent described in method (2) is dichloromethane and/or chloroform；Peroxide described in method (2) is one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide；The consumption of the peroxide described in method (2) is 0.5～100 times of compound VI mole；Chiral catalyst described in method (2) is tetraisopropoxy titanium (IV) and diethyl tartrate. catalyst system and catalyzing；The consumption of the chiral catalyst described in method (2) is the 0.01%～100% of compound VI mole；The temperature of the reaction described in method (2) is-20～80 DEG C；Till the time of the reaction described in method (2) completes with detection reaction；
Organic solvent described in method (3) is dichloromethane and/or chloroform；Peroxide described in method (3) is one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide；The consumption of the peroxide described in method (3) is 0.5～100 times of compound VI mole；Chiral catalyst described in method (3) is tetraisopropoxy titanium (IV) and diethyl tartrate. catalyst system and catalyzing；The consumption of the chiral catalyst described in method (3) is the 0.01%～100% of compound VI mole；Inorganic base described in method (3) is sodium bicarbonate and/or disodium-hydrogen；The consumption of the inorganic base described in method (3) is 0.5～100 times of compound VI mole；The temperature of the reaction described in method (3) is-20～80 DEG C；Till the time of the reaction described in method (3) completes with detection reaction；
Organic solvent described in method (4) is dichloromethane and/or chloroform；Peroxide described in method (4) is one or more in hydrogen peroxide, metachloroperbenzoic acid and tertbutanol peroxide；The consumption of the peroxide described in method (4) is 0.5～100 times of compound VI mole；Inorganic base described in method (4) is sodium bicarbonate and/or disodium-hydrogen；The consumption of the inorganic base described in method (4) is 0.5～100 times of compound VI mole；The temperature of the reaction described in method (4) is-20～80 DEG C；Till the time of the reaction described in method (4) completes with detection reaction.
10. preparation method as claimed in claim 8 or 9, it is characterised in that: described compound VI is prepared by following either method:
(1) R is worked as5For R5aTime, compound VI is prepared by following either method: in (i) organic solvent, in the presence of base, by R5For the compound VI and R during H5aOTf、R5aCl or R5aBr reacts,；Or, in (ii) organic solvent, in the presence of acid, by R5For the compound VI and R during H5aC(NH)CCl3Or 1-methyl-2-R5aYl pyridines reactant salt,；
Wherein, group R1And R5aDefinition as claimed in claim 1；
Or, (2) work as R5During for H, compound VI is prepared by following either method:
In (i) organic solvent, by compound VII withReaction,；
Wherein, group R1Definition as claimed in claim 1；
Or, in (ii) organic solvent, by compound VII withCarry out nucleophilic addition, obtain compound VII '；Compound VII ' carries out removing the reaction of silicon protection group again,；
Wherein, group R1Definition as claimed in claim 1.
11. preparation methoies as claimed in claim 10, it is characterised in that:
In method (1), the consumption of the alkali described in method (i) is R5For the mole of the compound VI during H 0.5～100 times；R described in method (i)5aOTf、R5aCl or R5aThe consumption of Br is R5For the mole of the compound VI during H 0.5～100 times；The temperature of the reaction described in method (i) is-78～100 DEG C；Till the time of the reaction described in method (i) completes with detection reaction；
In method (1), the acid described in method (ii) is one or more in methanesulfonic acid, p-methyl benzenesulfonic acid and hydrochloric acid；The consumption of the acid described in method (ii) is R5For the mole of the compound VI during H 0.5～30 times；R described in method (ii)5aC(NH)CCl3Or 1-methyl-2-R5aThe consumption of yl pyridines salt is R5For the mole of the compound VI during H 0.5～100 times；The temperature of the reaction described in method (ii) is-20～180 DEG C；Till the time of the reaction described in method (ii) completes with detection reaction；
In method (2), described in method (i)0.5～10 times that consumption is compound VII mole；The temperature of the reaction described in method (i) is-78～180 DEG C；Till the time of the reaction described in method (i) completes with detection reaction；
In method (2), the organic solvent of the nucleophilic addition described in method (ii) is one or more in oxolane, toluene, ether, methyl tertiary butyl ether(MTBE) and dichloromethane；In nucleophilic addition described in method (ii)0.5～10 times that consumption is compound VII mole；The temperature of the nucleophilic addition described in method (ii) is-78～80 DEG C；Till the time of the nucleophilic addition described in method (ii) completes with detection reaction；The reaction of the removing silicon protection group described in method (ii) comprises the following steps: method (a), by compound VII ' in proton solvent, react in the presence of an inorganic base,；Or, method (b), in solvent, the reagent of compound VII ' with fluoride ion is reacted,.
12. preparation methoies as claimed in claim 10, it is characterised in that:
In method (2), reaction described in method (i) is carried out in the presence of chiral catalyst, described chiral catalyst is tetraisopropoxy titanium and S-dinaphthol or derivatives thereof catalyst system and catalyzing, trifluoromethanesulfonic acid zinc and N-methylephedrine or derivatives thereof catalyst system and catalyzing, or trifluoromethanesulfonic acid zinc and (1R, 2R)-3-tert-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol catalysis system；The consumption of described chiral catalyst is 0.001～3 times of compound VII mole；
In method (2), nucleophilic addition described in method (ii) is carried out in the presence of chiral catalyst, described chiral catalyst is tetraisopropoxy titanium and S-dinaphthol or derivatives thereof catalyst system and catalyzing, trifluoromethanesulfonic acid zinc and N-methylephedrine or derivatives thereof catalyst system and catalyzing, or trifluoromethanesulfonic acid zinc and (1R, 2R)-3-tert-butoxy-2-dimethylamino-1-phenyl propyl-1-alcohol catalysis system；The consumption of described chiral catalyst is the 0.1%～100% of compound VII mole.
13. preparation methoies as claimed in claim 10, it is characterised in that:
In method (2), described in method (i)Prepared with alkali reaction in organic solvent by acetylene；Wherein, described alkali is one or more in triethylamine, ethylmagnesium bromide, diethyl zinc and n-BuLi；The consumption of described alkali is 0.5～10 times of acetylene mole；The temperature of described reaction is-78～100 DEG C；
In method (2), described in method (ii)Respectively by Me3SiC≡CH、Et3SiC ≡ CH orPrepare with alkali reaction in organic solvent；Described alkali is one or more in triethylamine, ethylmagnesium bromide, diethyl zinc and n-BuLi；The consumption of described alkali is Me3SiC≡CH、Et3SiC ≡ CH or0.5～10 times of mole；The temperature of described reaction is-78～100 DEG C.
14. preparation methoies as claimed in claim 11, it is characterised in that: in the reaction of the removing silicon protection group described in method (ii), the proton solvent described in method (a) is one or more in methanol, second alcohol and water；Inorganic base described in method (a) is one or more in potassium carbonate, sodium carbonate and sodium hydroxide；The consumption of the inorganic base described in method (a) is 0.1～10 times of compound VII ' mole；The temperature of the reaction described in method (a) is-20～100 DEG C；Till the time of the reaction described in method (a) completes with detection reaction；The reagent of the fluoride ion described in method (b) is one or more in potassium fluoride, tetrabutyl ammonium fluoride and Methanaminium, N,N,N-trimethyl-, fluoride；The consumption of the reagent of the fluoride ion described in method (b) is 0.8～100 times of compound VII ' mole；The temperature of the reaction described in method (b) is-78～100 DEG C；Till the time of the reaction described in method (b) completes with detection reaction.
15. preparation methoies as claimed in claim 10, it is characterised in that: described compound VII is prepared by following method: compound VIII is carried out oxidation reaction；
Wherein, group R1Definition as claimed in claim 1.
16. preparation methoies as claimed in claim 15, it is characterized in that: described oxidation reaction is Swern oxidation reaction, Corey-Kim oxidation reaction, Dess-Martin oxidation reaction or with sodium hypochlorite and 2,2,6,6-tetramethyl piperidine combination of oxides carry out oxidation reaction.
17. preparation methoies as described in claim 15 or 16, it is characterised in that: work as R1For CH2R8Time, described compound VIII is prepared by following either method:
(1), in organic solvent, compound Ⅹ is reacted with reducing agent,；
Or in (2) organic solvent, in the presence of a lewis acid, compound Ⅹ is reacted with reducing agent,；
Wherein, R8It is the aryl of 6 to 12 carbon, the aryl of 6 to 12 carbon being replaced, the heteroaryl of 3 to 12 carbon or the heteroaryl of 3 to 12 carbon being replaced；
Wherein, described " being replaced " definition is as claimed in claim 1.
18. preparation methoies as claimed in claim 17, it is characterised in that:
Organic solvent described in method (1) is one or more in dichloromethane, toluene and normal hexane；Reducing agent described in method (1) is diisobutyl aluminium hydride and/or lithium aluminium hydride reduction；The consumption of the reducing agent described in method (1) is 0.5～100 times of compound Ⅹ mole；The temperature of the reaction described in method (1) is-78～180 DEG C；Till the time of the reaction described in method (1) completes with detection reaction；
Organic solvent described in method (2) is one or more in dichloromethane, toluene and normal hexane；Reducing agent described in method (2) is diisobutyl aluminium hydride and/or lithium aluminium hydride reduction；The consumption of the reducing agent described in method (2) is 0.5～100 times of compound Ⅹ mole；Lewis acid described in method (2) is one or more in aluminum chloride, lithium chloride and boron trifluoride；Lewis acidic consumption described in method (2) is 0.5～100 times of compound Ⅹ mole；The temperature of the reaction described in method (2) is-78～180 DEG C；Till the time of the reaction described in method (2) completes with detection reaction；
19. preparation methoies as claimed in claim 17, it is characterised in that: described compound Ⅹ is prepared by following method: in aprotic solvent, by compound Ⅹ ' and CH2=PPh3Or Tebbe reagent reacts,；
Wherein, group R8Definition as claimed in claim 17.
20. preparation methoies as claimed in claim 19, it is characterised in that: described aprotic solvent is one or more in oxolane, 2-methyltetrahydrofuran and dichloromethane；Described CH2=PPh3Or 0.5～100 times that the consumption of Tebbe reagent is compound Ⅹ ' mole；The temperature of described reaction is-60～180 DEG C；Till the time of described reaction completes with detection reaction.
21. preparation methoies as described in claim 19 or 20, it is characterised in that: described compound Ⅹ ' is prepared by following method: compound Ⅺ is carried out oxidation reaction,；
Wherein, group R8Definition as claimed in claim 17.
22. preparation methoies as claimed in claim 21, it is characterized in that: described oxidation reaction is Swern oxidation reaction, Corey-Kim oxidation reaction, Dess-Martin oxidation reaction or with sodium hypochlorite/2,2,6,6-tetramethyl piperidine combination of oxides carry out oxidation reaction.
23. preparation methoies as claimed in claim 21, it is characterised in that: described compound Ⅺ is prepared by following method: in aprotic solvent, in the presence of acid, by compound Ⅺ ' and R8CHO reacts,；
Wherein, group R8Definition as claimed in claim 17.
24. preparation methoies as claimed in claim 23, it is characterised in that: described aprotic solvent is one or more in benzene,toluene,xylene and normal hexane；Described R8The consumption of CHO is 0.5～100 times of compound Ⅺ ' mole；Described acid is one or more in methanesulfonic acid, p-methyl benzenesulfonic acid, sulphuric acid, pyridinium p-toluenesulfonate and camphorsulfonic acid；0.0001～2 times that consumption is compound Ⅺ ' mole of described acid；The temperature of described reaction is 0～180 DEG C；Till the time of described reaction completes with detection reaction.
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