CN106554365A - A kind of preparation technology of entecavir midbodies and its application - Google Patents
A kind of preparation technology of entecavir midbodies and its application Download PDFInfo
- Publication number
- CN106554365A CN106554365A CN201611005027.5A CN201611005027A CN106554365A CN 106554365 A CN106554365 A CN 106554365A CN 201611005027 A CN201611005027 A CN 201611005027A CN 106554365 A CN106554365 A CN 106554365A
- Authority
- CN
- China
- Prior art keywords
- preparation technology
- formula
- entecavir
- compound
- nhpi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000980 entecavir Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001451 organic peroxides Chemical class 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 230000004224 protection Effects 0.000 claims description 12
- BIISIZOQPWZPPS-UHFFFAOYSA-N 2-tert-butylperoxypropan-2-ylbenzene Chemical compound CC(C)(C)OOC(C)(C)C1=CC=CC=C1 BIISIZOQPWZPPS-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- -1 organic peroxide Compound Chemical class 0.000 claims description 4
- OKIRBHVFJGXOIS-UHFFFAOYSA-N 1,2-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC=C1C(C)C OKIRBHVFJGXOIS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000000864 peroxy group Chemical group O(O*)* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical group C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 7
- 208000002672 hepatitis B Diseases 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 4
- 0 *C[C@@]([C@](*)CC1)C1=O Chemical compound *C[C@@]([C@](*)CC1)C1=O 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YVOMYDHIQVMMTA-BYPYZUCNSA-N (3s)-3-hydroxyhexanedioic acid Chemical class OC(=O)C[C@@H](O)CCC(O)=O YVOMYDHIQVMMTA-BYPYZUCNSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- KRDXTHSSNCTAGY-UHFFFAOYSA-N 2-cyclohexylpyrrolidine Chemical compound C1CCNC1C1CCCCC1 KRDXTHSSNCTAGY-UHFFFAOYSA-N 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 238000006228 Dieckmann condensation reaction Methods 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010053961 Mitochondrial toxicity Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical group CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000006946 Rubottom oxidation reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 231100000296 mitochondrial toxicity Toxicity 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 125000005704 oxymethylene group Chemical group [H]C([H])([*:2])O[*:1] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the application of a kind of preparation technology of entecavir midbodies and the intermediate in Entecavir is prepared, the preparation technology includes：In the presence of NHPI, by the compound shown in formula S, haptoreaction obtains the compound shown in entecavir midbodies formula T in organic solvent with organic peroxide；The preparation technology of the entecavir midbodies that the present invention is provided, yield are greatly improved, and step is shorter, and cost is lower, and operation is easier, effectively reduces the workload in Entecavir preparation process, are adapted to industrialized production, have ensured the raw material supply of Entecavir.
Description
Technical field
The invention belongs to technical field of medicine synthesis, is related to preparation technology and its application of a kind of entecavir midbodies.
Background technology
Entecavir, its chemical name are 2- amino -9- [(1s, 3s, 4s) -4- hydroxyl -3- methylol -2- methylenes penta
Base] -1,9- hydrogen -6-H- purine-6-ones-hydrate, the compound researched and developed by Bristol-MyersSquibb companies, is
It is a kind of effective, the deoxyguanosine analog of Selective depression hepatitis B replication, for treating hepatitis B.
In vitro test shows that Entecavir is more more effective than other nucleoside analogs.Animal model and Human Clinical Study result show, grace
There is extremely strong suppression hepatitis B replication for card Wei, the effect of serum-virus DNA level is reduced, to resistance to Lamivudine
Mutant strain is still effective, and has no obvious bad reaction and mitochondrial toxicity.
A large amount of clinical testings show that it has directly to reverse transcriptase in liver cell and hepatitis B virus DNA polymerase
Inhibitory action, has strong anti-virus ability, while the selectivity ratios of the compound are higher, its cytotoxicity is anti-hepatitis virus
Activity 1/8000, can effectively treatment chronic hepatitis B and do not disturb influenza virus and inhibition of HIV.And due to its mechanism of action not
Together, the drug resistance that Long-Time Service is produced is low.
At present, there are 3.5 hundred million～400,000,000 Hepatitis B Virus Infections in the whole world, wherein there is nearly 1,000,000 patient to die from every year
Cirrhosis and liver cancer that HBV infection causes.China there are about 1.2 hundred million HBV infection persons, accounts for the 1/3 of the world total, ranks first in the world
Position, chronic hepatitis B patient 30,000,000, and also this numeral is just in rising trend at present.Chronic hepatitis B virus infection is arrived
The method for also not having to cure completely till now, patient need long-term or in most cases need to carry out virus throughout one's life
Suppress.The clinical guidelines recommended therapy course for the treatment of is at least 1 year.The market share of nucleoside medicine in the medicine of chronic hepatitis B
Rate is more than 80%.And in nucleoside medicine, Entecavir relies on its significant curative effect and good anti-drug resistance, from 2007 years
Since, having substituted Lamivudine becomes the anti-hepatic-B virus medicine of a line.Entecavir is ground by Bristol-Myers Squibb Co. of the U.S.
System, on March 29th, 2005, approval was listed U.S. FDA.State food pharmaceuticals administration is obtained on November 15th, 2005 total
Office SFDA ratifies in Discussion on Chinese Listed.The drug patent expired in 2008, and pharmaceutical chemistry brainstrust is for its preparation method
Very many researchs are carried out, but due to entecavir compound prepared complex structure, has also been widely present in existing synthetic method
Step length, yield are low, high cost the problems such as.
CN102593956B discloses a kind of preparation technology of Entecavir, wherein, the technique discloses a kind of by ring
The method that oxygen compound open loop introduces chiral hydroxyl group, shown in concrete following route.The technique needs to urge using precious metal palladium
Agent and active magnesium metallic compound, high cost, condition are harsh.Further, since 2- positions replace the space bit of Oxymethylene
Inhibition effect so that the epoxide of target configuration generates more difficult, yield reduction, industrializes difficulty larger.The method must also
The transformation of compound hydroxyl configuration just must can be obtained into target compound using chiral reagent.
CN105037363B discloses a kind of entecavir compound prepared synthetic method, builds a house with (S) -3- hydroxyl adipic acids
Dimethyl ester is initiation material, protects into ketal, ester group and is reduced into hydroxyl by hydroxyl TBS protections, Dieckmann condensation reactions, ketone
Base, hydroxyl protection, deprotection, ketone are obtained intermediate T into silyl enol ether, Rubottom oxidation reactions, intermediate T Jing Wittg again
Reaction, Mitsunobu reactions etc. obtain Entecavir, although the method is there is provided a kind of method for being more suitable for industrialized production,
Yield is also improved, but, the method be particularly intermediate T production yet suffer from complex steps, reaction condition have high demands with
And the problem that yield is not high.Correlation step is as follows：
The content of the invention
In view of in the preparation technology of Entecavir, also there are the problems referred to above, it is special to propose the present invention.
The present invention provides a kind of preparation technology of entecavir midbodies (compound shown in formula T), and the preparation technology is anti-
Answer that step is shorter, yield is higher and it is easier to operate, be adapted to amplify mass production.
The present invention provides the preparation technology of entecavir midbodies, and the preparation technology includes：
In the presence of NHPI, by the compound shown in formula S, haptoreaction obtains grace in organic solvent with organic peroxide
For the compound shown in card Wei intermediate formula T；
Under preferable case, the more specifically process of the preparation technology is：By the compound shown in NHPI, formula S and have
Machine solvent is added in reactor, is cooled to -10～10 DEG C, and the solution containing organic peroxide is added dropwise, and drop finishes, keeping temperature
Stirring 2～5 hours, saturated ammonium chloride are quenched reaction, dichloromethane extraction, wash, and recrystallize to obtain compound shown in formula T, its
Middle organic solvent is tetrahydrofuran or ether or other ether solvents etc..
In the present invention, NHPI writing a Chinese character in simplified form for HP, its addition quickly can be caused above-mentioned anti-
Should, and coordinate the product for obtaining enantiomeric excess or even single configuration with organic peroxide.
In the present invention, it is preferred in the case of, the compound and NHPI, the consumption mol ratio of organic peroxide shown in formula S
For 1：0.05～0.25：1～3.Compound and NHPI, the consumption of organic peroxide in the case of further preferably, shown in formula S
Mol ratio is 1：0.05～0.15：1.2～2.Inventor puts into practice discovery in a large number, and organic peroxide consumption is more than shown in formula S
When the consumption of 2 equivalent of compound and HP is more than 0.15 equivalent, reaction is not preferably showed,
The workload of cost and post processing can be increased on the contrary.
In the present invention, inventor is also had found using the peroxide of different structure for the selectivity of product configuration affects
Larger, under preferable case, the organic peroxide is cumyl peroxide and/or t-butylcumylperoxide.This
Under part, it is capable of the target compound for obtaining single configuration of high selectivity.Under preferable case, organic peroxide such as peroxidating
Diisopropylbenzene (DIPB) or t-butylcumylperoxide are instilled in reaction system in the form of its solution, for example, instill peroxidating diisopropyl
The tetrahydrofuran solution of diethyl ether solution or cumyl peroxide of benzene, the diethyl ether solution of t-butylcumylperoxide or peroxide
Change the tetrahydrofuran solution of tert-butyl cumyl peroxide.
In the present invention, in order to prevent the impact to reacting such as moisture and oxygen in external environment, under preferable case, make
Standby technique is carried out under nitrogen protection.The reaction of the present invention can carry out post-reaction treatment, example according to the conventional means in this area
Such as washing, filtration, crystallization etc..Can be monitored according to conventional means during per step, such as LCMS, GCMS, TLC
Deng.In the case of not having other specified otherwises, the room temperature for being used in the present invention refers to 23 ± 2 DEG C.
The present invention also provides a kind of preparation technology of Entecavir, the grace that wherein technique is prepared by above-mentioned preparation technology
It is initiation material for card Wei intermediate (compound shown in formula T), by intermediate T, Jing Wittg reactions, Mitsunobu are anti-again
Answer, dehydroxylation protection group and hydrolysis obtain Entecavir, these steps may be referred to method of the prior art to be carried out, for example
Related operating method in CN105037363B, is hereby incorporated and is expressly incorporated herein.
Three-dimensional hydroxyl, using one-step method, is directly introduced ring by the preparation technology of the entecavir midbodies that the present invention is provided
Pentane ring, yield are greatly improved, and selectively obtain R anomeric products, obtain target mesh without the need for chiral resolution or purifying
Mark compound, operation are easier, effectively reduce the workload in Entecavir preparation process.Entecavir midbodies formula T
The yield of shown compound is significantly improved, and has ensured the raw materials requirement of Entecavir.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present invention
Protection domain.
Embodiment 1
Under nitrogen protection, by compound 35.9g (100mmol) and 100ml shown in NHPI 0.81g (5mmol), formula S
Anhydrous tetrahydro furan is added in 250ml reactors, stirs and be cooled to 5 DEG C, and the second of cumyl peroxide is then added dropwise
The tetrahydrofuran solution (containing cumyl peroxide 40.56g) of ethereal solution or cumyl peroxide, drop are finished, keeping temperature
Stirring 3 hours, monitors that reaction terminates, and adds saturated ammonium chloride that reaction, dichloromethane extraction, washing three is quenched in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether recrystallize to obtain compound 32.37g shown in formula T, receive
Rate 86.40%.
1HNMR(400MHz,CDCl3)δ5.51(brs,1H),4.40-4.35(m,2H),3.51(d,1H),3.28(m,
1H),2.79-2.75(m,1H),2.19-1.98(m,1H),1.82(d,1H),0.98(s,9H),0.96(s,9H),0.12(m,
12H)。
Embodiment 2
Under nitrogen protection, by the compound 35.9g (100mmol) shown in NHPI 1.63g (10mmol), formula S and
100ml anhydrous tetrahydro furans are added in 250ml reactors, stir and be cooled to 0 DEG C, and cumyl peroxide is then added dropwise
Diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 54.07g), drop finishes, and keeping temperature stirring is 2 little
When, monitoring that reaction terminates, in ice bath, add saturated ammonium chloride that reaction is quenched, dichloromethane extraction is washed three times, is associated with
Machine phase, anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether recrystallize to obtain compound 32.32g shown in formula T, yield 86.27%.
Embodiment 3
Under nitrogen protection, by the compound 35.9g (100mmol) shown in NHPI 2.45g (15mmol), formula S and
100ml anhydrous tetrahydro furans are added in 500ml reactors, stir and be cooled to 0 DEG C, tert-butyl peroxide are then added dropwise different
The diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 25.0g) of propyl benzene, drop are finished, keeping temperature stirring
4 hours, monitor that reaction terminates, in ice bath, add saturated ammonium chloride that reaction is quenched, dichloromethane extraction is washed three times, closed
And organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether recrystallize to obtain compound 31.89g shown in formula T, yield
85.12%.
Embodiment 4
Under nitrogen protection, by the compound 35.9g (100mmol) shown in NHPI 3.26g (20mmol), formula S and
100ml anhydrous tetrahydro furans are added in 250ml reactors, stir and be cooled to -10 DEG C, and peroxidating diisopropyl is then added dropwise
The tetrahydrofuran solution (containing cumyl peroxide or t-butylcumylperoxide 27.04g) of benzene, drop are finished, keeping temperature
Stirring 5 hours, monitors that reaction terminates, and adds saturated ammonium chloride that reaction, dichloromethane extraction, washing three is quenched in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether recrystallize to obtain compound 30.51g shown in formula T, receive
Rate 81.43%.
Embodiment 5
Under nitrogen protection, by the compound 35.9g (100mmol) shown in NHPI 4.08g (25mmol), formula S and
100ml anhydrous tetrahydro furans are added in 500ml reactors, stir and be cooled to -5 DEG C, and tert-butyl peroxide is then added dropwise
The diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 62.49g) of isopropylbenzene, drop are finished, keeping temperature
Stirring 3 hours, monitors that reaction terminates, and adds saturated ammonium chloride that reaction, dichloromethane extraction, washing three is quenched in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether recrystallize to obtain compound 31.75g shown in formula T, receive
Rate 84.75%.
Comparative example
Under nitrogen protection, the compound 35.9g (100mmol) and 100ml anhydrous tetrahydro furans shown in formula S is added to
In 250ml reactors, 5 DEG C are stirred and are cooled to, diethyl ether solution or the peroxidating two that cumyl peroxide is then added dropwise is different
The tetrahydrofuran solution (containing cumyl peroxide 40.56g) of propyl benzene, drop are finished, and keeping temperature is stirred 5 hours, monitor anti-
Answer raw material (compound shown in formula S) no longer to change, in ice bath, add saturated ammonium chloride that reaction is quenched, dichloromethane is extracted,
Washing three times, merges organic phase, and anhydrous sodium sulfate drying, reduced pressure concentration, column chromatography obtain the compound 12.25g shown in formula T, receives
Rate 32.70%.
1HNMR(400MHz,CDCl3)δ5.51(brs,1H),4.40-4.35(m,2H),3.51(d,1H),3.28(m,
1H),2.79-2.75(m,1H),2.19-1.98(m,1H),1.82(d,1H),0.98(s,9H),0.96(s,9H),0.12(m,
12H)。
Claims (7)
1. a kind of preparation technology of entecavir midbodies, it is characterised in that the preparation technology includes：
In the presence of NHPI, by the compound shown in formula S, haptoreaction obtains entecavir in organic solvent with organic peroxide
Compound shown in Wei intermediate formula T；
2. preparation technology according to claim 1, it is characterised in that the more specifically process of the preparation technology is：Will
Compound and organic solvent shown in NHPI, formula S is added in reactor, is cooled to -10～10 DEG C, is added dropwise containing organic mistake
The solution of oxide, drop are finished, and keeping temperature is stirred 2～5 hours, and saturated ammonium chloride is quenched reaction, and dichloromethane extraction is washed,
Compound shown in formula T is recrystallized to obtain, wherein organic solvent is tetrahydrofuran or ether or other ether solvents etc..
3. preparation technology according to claim 1 and 2, it is characterised in that the compound shown in formula S and NHPI, organic mistake
The consumption mol ratio of oxide is 1：0.05～0.25：1～3.
4. preparation technology according to claim 3, it is characterised in that the compound shown in formula S and NHPI, organic peroxy
The consumption mol ratio of thing is 1：0.05～0.15：1.2～2.
5. the preparation technology according to claim 1-4, it is characterised in that the organic peroxide is peroxidating diisopropyl
Benzene and/or t-butylcumylperoxide.
6. the preparation technology according to claim 1-5, it is characterised in that preparation technology is carried out under nitrogen protection.
7. application of the entecavir midbodies that prepared by the preparation technology described in claim 1-6 in Entecavir is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611005027.5A CN106554365B (en) | 2016-11-12 | 2016-11-12 | A kind of preparation process and its application of entecavir midbodies |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611005027.5A CN106554365B (en) | 2016-11-12 | 2016-11-12 | A kind of preparation process and its application of entecavir midbodies |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106554365A true CN106554365A (en) | 2017-04-05 |
| CN106554365B CN106554365B (en) | 2019-01-08 |
Family
ID=58443960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611005027.5A Expired - Fee Related CN106554365B (en) | 2016-11-12 | 2016-11-12 | A kind of preparation process and its application of entecavir midbodies |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106554365B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108976231A (en) * | 2018-10-26 | 2018-12-11 | 东莞理工学院 | The novel synthesis of therapeutic agent for hepatitis B Entecavir |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680037A (en) * | 2004-04-07 | 2005-10-12 | 中国科学院大连化学物理研究所 | Nonmetal composite catalytic system consisting of organic matter and use thereof |
| CN102264739A (en) * | 2008-12-26 | 2011-11-30 | 韩美控股株式会社 | Novel intermediate and process for preparing entecavir using same |
| CN102333750A (en) * | 2009-02-26 | 2012-01-25 | 埃克森美孚化学专利公司 | Process for producing phenol |
| CN105037363A (en) * | 2015-07-13 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Novel synthetic method for entecavir compound |
-
2016
- 2016-11-12 CN CN201611005027.5A patent/CN106554365B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680037A (en) * | 2004-04-07 | 2005-10-12 | 中国科学院大连化学物理研究所 | Nonmetal composite catalytic system consisting of organic matter and use thereof |
| CN102264739A (en) * | 2008-12-26 | 2011-11-30 | 韩美控股株式会社 | Novel intermediate and process for preparing entecavir using same |
| CN102333750A (en) * | 2009-02-26 | 2012-01-25 | 埃克森美孚化学专利公司 | Process for producing phenol |
| CN105037363A (en) * | 2015-07-13 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Novel synthetic method for entecavir compound |
Non-Patent Citations (2)
| Title |
|---|
| 沈国兵等: "恩替卡韦合成路线图解", 《中国医药工业杂志》 * |
| 王建伟等: "恩替卡韦关键中间体的合成工艺改进", 《浙江工业大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108976231A (en) * | 2018-10-26 | 2018-12-11 | 东莞理工学院 | The novel synthesis of therapeutic agent for hepatitis B Entecavir |
| CN108976231B (en) * | 2018-10-26 | 2019-12-24 | 东莞理工学院 | Method for synthesizing entecavir as hepatitis B treating medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106554365B (en) | 2019-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103275063B (en) | Method for preparing halofuginone hydrobromide | |
| Tamura et al. | Bioisostere of valtrate, anti-HIV principle by inhibition for nuclear export of Rev | |
| CN109438432B (en) | Preparation method of emtricitabine | |
| CN103922936A (en) | Method for preparing caffeic acid ester derivatives | |
| JPH04506669A (en) | Antimalarial homologs of artemisinin | |
| CN106946972B (en) | A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof | |
| CN106554365A (en) | A kind of preparation technology of entecavir midbodies and its application | |
| CN101148450A (en) | Preparation method of nucleoside compound | |
| CN101139287B (en) | Method for synthesizing alkannin dimethyl ether derivative | |
| CN109438431A (en) | A kind of preparation method of Lamivudine | |
| CN103058941B (en) | Rupestonic acid is containing heterocyclic esters derivative and its production and use | |
| CN104628803A (en) | Total synthesis method for rape pollen alkali A and caper alkali B and analogues thereof | |
| CN106946775B (en) | Compound and application thereof in preparation of anti-hepatitis C virus medicine | |
| CN106977543A (en) | The preparation technology of improved Suo Feibuwei intermediates | |
| CN106749255B (en) | A kind of preparation method of antiviral medicinal entecavir intermediate | |
| Kertesz et al. | Application of bakers' yeast-mediated reductions of bicyclo [4.2. 0] oct-2-en-7-ones to the enantioselective synthesis of prostacyclin analogs | |
| CN106749248B (en) | A kind of preparation method of antiviral drug of Entecavir | |
| CN108484566A (en) | A kind of preparation method of ticagrelor key intermediate | |
| CN106699701B (en) | The preparation method of 1-O- methyl -2,3- dideoxy-L- arabinofuranose | |
| CN106749382B (en) | The preparation method of entecavir midbodies | |
| CN107353256A (en) | The method of the triazole compounds of 4 acetyl group of one pot process 1,2,3 | |
| CN108129367B (en) | Construction method for constructing chiral sulfinyl imine alpha-site chiral quaternary carbon, product and application thereof | |
| CN102241648B (en) | Anti-multidrug resistance taxane derivatives and its preparation method and application | |
| CN103073472B (en) | The preparation method of the azacycloparaffin of 2 trifluoromethyl, 1 benzyloxycarbonyl group 1 | |
| CN104211748B (en) | 6 hydroxyl dideoxy guanine nucleoside phosphate preparation and uses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20181123 Address after: No. 786 Yazhong Road, Nanhu District, Jiaxing City, Zhejiang Province, 314000 Applicant after: Jiaxing Minshi Machinery Co., Ltd. Address before: 266520 1 residential 1708, Changjiang East Road, Huangdao District, Qingdao, Shandong, 1708 Applicant before: Chen Da bio tech ltd, Qingdao |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190108 Termination date: 20191112 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |