CN106565769B - The synthesis technology of entecavir midbodies - Google Patents
The synthesis technology of entecavir midbodies Download PDFInfo
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- CN106565769B CN106565769B CN201610996190.6A CN201610996190A CN106565769B CN 106565769 B CN106565769 B CN 106565769B CN 201610996190 A CN201610996190 A CN 201610996190A CN 106565769 B CN106565769 B CN 106565769B
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- 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 System
- 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
Abstract
The invention discloses the synthesis technology of entecavir midbodies, 1) synthesis technology with boric acid, acetic anhydride in acetonitrile under zinc chloride catalysis by compound shown in formula A the following steps are included: be stirred to react to obtain boronate complex C；2) the boronate complex C that step 1) obtains is reacted with metal iodide, then reacts to obtain entecavir midbodies formula M compound represented with the chloro- purine of 2- amino -6- in the presence of palladium catalyst and alkali again.Method provided by the invention, it reacts to obtain the entecavir midbodies product of Formation keeping with the chloro- purine of 2- amino -6- by using (S) configuration by-product (compound shown in formula A), and good yield is achieved, new approach is provided for entecavir midbodies.
Description
Technical field
The invention belongs to technical field of organic synthesis, it is related among a kind of selective depression hepatitis type B virus Entecavir
The synthesis technology of body.
Background technique
Entecavir, its chemical name is 2- amino -9- [(1s, 3s, 4s) -4- hydroxyl -3- methylol -2- methylenes penta
Base] -1,9- hydrogen -6-H- purine-6-one-hydrate, which researched and developed by Bristol-Myers Squibb Co., as choosing
Selecting property inhibits the deoxyguanosine analog of hepatitis B replication, is mainly used for treating hepatitis B.Entecavir
Specific structure it is as follows:
Entecavir original grinds drug patent and has expired at present, although field of medicinal chemistry is for having carried out considerable grind
Study carefully, but since its structure is complicated, it is huge to synthesize difficulty for the reasons such as Stereocenter is more.
The synthetic method of Entecavir in the prior art is mostly chloro- by following key intermediate and 2- amino -6-
What purine was reacted, wherein X is oxygen atom or carbon atom, and Y is chlorine atom or hydroxyl, R1、R2It is separately this
Field commonly various hydroxyl protection bases or hydrogen atom.In general, intermediate hydroxyl configuration be limited to (R) configuration then with 2- ammonia
The chloro- purine compound of base -6- reacts generation configuration reversal by Mitsunobu and obtains (S)-N substitution product, further generates grace
For card Wei.Intermediate specific structure and to be related to reaction route as follows:
In the prior art, during preparing key intermediate, often along with by-product (S) configurational isomer
It generates.And in the prior art it has not been found that (S) configuration by-product to be directly directly used in the report for preparing Entecavir preparation.
Summary of the invention
For above-mentioned problems of the prior art, the present invention provides a kind of synthesis technology of entecavir midbodies,
This method is directly used in (S) configuration of compound (as shown in formula A) to be prepared Entecavir and achieves good yield.
To achieve the goals above, entecavir midbodies of the invention synthesis technology the following steps are included:
1) compound shown in formula A is stirred to react to obtain boron in acetonitrile under zinc chloride catalysis with boric acid, acetic anhydride
Acid esters complex compound C；
2) the boronate complex C that step 1) obtains is reacted with metal iodide, then again in palladium catalyst and alkali
In the presence of react to obtain entecavir midbodies formula M compound represented with the chloro- purine of 2- amino -6-；
The synthesis technology of entecavir midbodies provided by the invention is reacted in step 1) by monitoring, monitoring to formula
A compound represented end of reaction, reaction temperature can be 50~65 DEG C, and the reaction time was at 1~2 hour；Preferably, formula
A compound represented and the dosage molar ratio of zinc chloride, boric acid, acetic anhydride are 1:0.2~0.4:0.8~1.2:0.5~0.8.
Wherein, TBS is t-Butyldimethylsilyl.
The synthesis technology of entecavir midbodies provided by the invention, the reaction process of step 2) may include: by step
1) the boronate complex C and metal iodide obtained is stirred 2~4 hours for 30~40 DEG C in tetrahydrofuran, filtering, in filtrate
55~65 DEG C of reactions of palladium catalyst and alkali and the chloro- purine of 2- amino -6- are added and obtain change shown in entecavir midbodies formula M
Close object.It is above-mentioned huge for reaction influence with the temperature of the chloro- purine of 2- amino -6- reacted, when the temperature is excessively high, such as higher than
70 DEG C, monitoring discovery to chiral cyclopentanone autoimmunity syndrome product.
Step 2) is actually the reaction in two stages, and the first stage, boronate complex C was reacted with iodide, without spy
Different post-processing then carries out coupling reaction with the chloro- purine of 2- amino -6-.Under preferable case, compound shown in formula A, metal iodine
Compound, the molar ratio of the dosage of palladium catalyst, alkali, the chloro- purine of 2- amino -6- are 1:1~2:0.05~0.3:2~5:1~2.
In further preferred situation, the use of compound shown in formula A, metal iodide, palladium catalyst, alkali, the chloro- purine of 2- amino -6-
The molar ratio of amount is 1:1~1.2:0.05~0.1:3~4:1~1.5.For the present invention, inventor thinks reaction product
The reason of Formation keeping may be because two stages of reaction process are the results for recurring to overturn twice.Inventor is rear
Continuous test discovery, the complex compound that step 1) obtains directly with 2- amino -6- purine compound haptoreaction, react pole be not easy into
Row, and Formation keeping person is (on the basis of initial starting material configuration) in the majority in final product.
In the present invention, the metal iodide can be one in sodium iodide, potassium iodide, cuprous iodide and iron iodide
Kind is a variety of.
In the present invention, the palladium catalyst is one of palladium chloride, palladium acetate and tetra-triphenylphosphine palladium or a variety of, excellent
It is selected as palladium acetate.In the present invention, the alkali can be inorganic base or organic base commonly used in the art, under preferable case,
The alkali is sodium carbonate, potassium carbonate or cesium carbonate.
Each step reaction of the invention can carry out post-reaction treatment according to the means of this field routine, such as wash, filter,
Crystallization etc..It can be monitored according to conventional means during every step, such as LCMS, GCMS, TLC etc..
The entecavir midbodies that the present invention obtains, namely such as formula M compound represented, pass through carbonyl methylenation (example
As Wittg react), eliminating hydroxide protecting group, chlorine atom hydrolysis be easily obtained antiviral drug of Entecavir, these steps
It can easily be realized by reference to the method for the prior art.
The preparation method of entecavir midbodies provided by the invention, it is (shown in formula A by using (S) configuration by-product
Compound) it reacts to obtain the entecavir midbodies product of Formation keeping with the chloro- purine of 2- amino -6-, and achieve good
Yield, new approach is provided for entecavir midbodies.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection scope.
Embodiment 1
The synthesis technology of entecavir midbodies
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 2.7g (20mmol),
Boric acid 7.4g (120mmol), acetic anhydride 6.1g (60mmol) and 100ml acetonitrile, are warming up to 50 DEG C, are stirred to react 2 hours, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, potassium iodide is then added
19.9g (120mmol) is simultaneously warming up to 40 DEG C of stirrings 2 hours, filters while hot, palladium acetate 2.2g (10mmol) and carbon are added in filtrate
Sour potassium 41.5g (300mmol) and the chloro- purine 20.3g (120mmol) of 2- amino -6- are warming up to 60 DEG C and react 12 hours, decompression
Concentration, washing, petroleum ether are recrystallized to give entecavir midbodies formula M compound represented 38.2g, yield 72.6%.
1HNMR(400MHz,d6- DMSO): δ 7.89 (s, 1H), 6.68 (brs, 2H), 4.42 (t, 1H), 3.53 (d, 2H),
3.29(m,1H),2.17-2.09(m,3H),1.04(s,18H),0.37(s,12H)。
Embodiment 2
The synthesis technology of entecavir midbodies
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 2.7g (20mmol),
Boric acid 6.2g (100mmol), acetic anhydride 7.2g (70mmol) and 100ml acetonitrile, are warming up to 60 DEG C, are stirred to react 2 hours, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, potassium iodide is then added
21.6g (130mmol) is simultaneously warming up to 30 DEG C of stirrings 2 hours, filters while hot, palladium catalyst palladium acetate 1.8g is added in filtrate
The chloro- purine 22g (130mmol) of (8mmol) and cesium carbonate 97.7g (300mmol) and 2- amino -6- is warming up to 55 DEG C of reactions 10
Hour, it is concentrated under reduced pressure, washing, petroleum ether is recrystallized to give entecavir midbodies formula M compound represented 38.6g, yield
73.4%.
Embodiment 3
The synthesis technology of entecavir midbodies
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 5.5g (40mmol),
Boric acid 4.9g (80mmol), acetic anhydride 5.1g (50mmol) and 100ml acetonitrile, are warming up to 65 DEG C, are stirred to react 2 hours, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, sodium iodide is then added
22.5g (150mmol) is simultaneously warming up to 35 DEG C of stirrings 2 hours, filters while hot, tetra-triphenylphosphine palladium 9.2g is added in filtrate
The chloro- purine 25.4g (150mmol) of (8mmol) and potassium carbonate 55.3g (400mmol) and 2- amino -6- is warming up to 60 DEG C of reactions
It 11 hours, is concentrated under reduced pressure, washing, petroleum ether is recrystallized to give entecavir midbodies formula M compound represented 37.8g, yield
71.8%.
Embodiment 4
The synthesis technology of entecavir midbodies
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 4.1g (30mmol),
Boric acid 7.4g (120mmol), acetic anhydride 5.1g (50mmol) and 100ml acetonitrile, are warming up to 50 DEG C, are stirred to react 1 hour, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, cuprous iodide is then added
19g (100mmol) is simultaneously warming up to 45 DEG C of stirrings 1 hour, filters while hot, palladium acetate 3.4g (15mmol) and carbonic acid are added in filtrate
The chloro- purine 20.3g (120mmol) of potassium 69.1g (500mmol) and 2- amino -6- is warming up to 65 DEG C and reacts 10 hours, depressurizes dense
Contracting, washing, rapid column chromatography obtain entecavir midbodies formula M compound represented 29.3g, yield 55.7%.
Embodiment 5
The synthesis technology of entecavir midbodies
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 2.7g (20mmol),
Boric acid 6.2g (100mmol), acetic anhydride 8.2g (80mmol) and 100ml acetonitrile, are warming up to 60 DEG C, are stirred to react 2 hours, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, potassium iodide is then added
33.2g (200mmol) is simultaneously warming up to 30 DEG C of stirrings 2 hours, filters while hot, palladium chloride 4.4g (25mmol) and carbon are added in filtrate
Sour caesium 65.2g (200mmol) and the chloro- purine 16.9g (100mmol) of 2- amino -6- are warming up to 55 DEG C and react 12 hours, decompression
Concentration, washing, petroleum ether are recrystallized to give entecavir midbodies formula M compound represented 27.9g, yield 53.1%.
Comparative example
1) in 250ml flask, be added compound 37.5g (100mmol) shown in formula A, zinc chloride 2.7g (20mmol),
Boric acid 7.4g (120mmol), acetic anhydride 6.1g (60mmol) and 100ml acetonitrile, are warming up to 50 DEG C, are stirred to react 2 hours, cold
But it to room temperature, pours into 100ml water, ethyl acetate extraction, washing three times, is concentrated to get boronate complex C；
2) the boronate complex C that step 1) obtains is added in 150ml tetrahydrofuran, palladium acetate 2.2g is then added
The chloro- purine 20.3g (120mmol) of (10mmol) and potassium carbonate 41.5g (300mmol) and 2- amino -6- is warming up to 60 DEG C instead
It answers 12 hours, is concentrated under reduced pressure, washing, column chromatographic purifying obtains entecavir midbodies formula M compound represented 4.4g, yield
8.3%.
Claims (9)
1. the synthesis technology of entecavir midbodies, which is characterized in that the synthesis technology the following steps are included:
1) compound shown in formula A is stirred to react to obtain borate in acetonitrile under zinc chloride catalysis with boric acid, acetic anhydride
Complex compound C；
2) the boronate complex C that step 1) obtains is reacted with metal iodide, is then existed again in palladium catalyst and alkali
It is lower to react to obtain entecavir midbodies formula M compound represented with the chloro- purine of 2- amino -6-；
2. synthesis technology as described in claim 1, which is characterized in that in step 1), reaction temperature is 50~65 DEG C, formula A institute
The dosage molar ratio of the compound shown and zinc chloride, boric acid, acetic anhydride is 1:0.2~0.4:0.8~1.2:0.5~0.8.
3. synthesis technology as claimed in claim 2, which is characterized in that the reaction process of step 2) includes: to obtain step 1)
Boronate complex C and metal iodide stirred 2~4 hours for 30~40 DEG C in tetrahydrofuran, palladium is added in filtrate in filtering
Catalyst and alkali and 55~65 DEG C of the chloro- purine of 2- amino -6- reactions obtain entecavir midbodies formula M compound represented.
4. synthesis technology as claimed in claim 1 or 3, which is characterized in that compound shown in formula A, metal iodide, palladium are urged
Agent, the molar ratio of the dosage of alkali, the chloro- purine of 2- amino -6- are 1:1~2:0.05~0.3:2~5:1~2.
5. synthesis technology as claimed in claim 4, which is characterized in that compound shown in formula A, metal iodide, palladium chtalyst
Agent, alkali, the chloro- purine of 2- amino -6- dosage molar ratio be 1:1~1.2:0.05~0.1:3~4:1~1.5.
6. synthesis technology as claimed in claim 4, which is characterized in that the metal iodide is sodium iodide, potassium iodide, iodate
One of cuprous and iron iodide is a variety of.
7. synthesis technology as described in claim 1, which is characterized in that the palladium catalyst is palladium chloride, palladium acetate and four or three
One of Phenylphosphine palladium is a variety of.
8. synthesis technology as claimed in claim 7, which is characterized in that the palladium catalyst is palladium acetate.
9. synthesis technology as described in claim 1, which is characterized in that the alkali is sodium carbonate, potassium carbonate or cesium carbonate.
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| CN101182322A (en) * | 2007-12-06 | 2008-05-21 | 福建广生堂药业有限公司 | Method for preparing antiviral drug of Entecavir |
| CN101235034A (en) * | 2008-02-28 | 2008-08-06 | 陆锦康 | Method for synthesizing entecavir |
| CN101410120A (en) * | 2003-04-25 | 2009-04-15 | 吉里德科学公司 | Anti-inflammatory phosphonate compounds |
| CN102596956A (en) * | 2009-10-12 | 2012-07-18 | 韩美控股株式会社 | Novel method for preparing entecavir and intermediate used therein |
| 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 |
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- 2016-11-12 CN CN201610996190.6A patent/CN106565769B/en active Active
Patent Citations (5)
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| CN101410120A (en) * | 2003-04-25 | 2009-04-15 | 吉里德科学公司 | Anti-inflammatory phosphonate compounds |
| CN101182322A (en) * | 2007-12-06 | 2008-05-21 | 福建广生堂药业有限公司 | Method for preparing antiviral drug of Entecavir |
| CN101235034A (en) * | 2008-02-28 | 2008-08-06 | 陆锦康 | Method for synthesizing entecavir |
| CN102596956A (en) * | 2009-10-12 | 2012-07-18 | 韩美控股株式会社 | Novel method for preparing entecavir and intermediate used therein |
| 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 |
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