CN108276379A - The preparation method of EV71 viruses and CAV16 viral inhibitors aminopyridine imidazolone derivatives - Google Patents
The preparation method of EV71 viruses and CAV16 viral inhibitors aminopyridine imidazolone derivatives Download PDFInfo
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- CN108276379A CN108276379A CN201710007699.8A CN201710007699A CN108276379A CN 108276379 A CN108276379 A CN 108276379A CN 201710007699 A CN201710007699 A CN 201710007699A CN 108276379 A CN108276379 A CN 108276379A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
The present invention provides a kind of preparation method as EV71 viruses and the aminopyridine imidazolone derivatives of CAV16 viral inhibitors, the synthetic route of the preparation method includes the following steps：(1) is starting material with 4 bromine, 2 aminopyridine 1, forms two blocking groups (PG) on amino and obtains midbody compound 2；(2) midbody compounds 2 carry out coupling reaction with monoacylphosphine imidazolone 3, obtain midbody compound 4；(3) deacetylate obtains midbody compound 5 to midbody compounds 4 under alkaline condition；(4) for midbody compounds 5 under alkaline condition with 1, midbody compound 7 is obtained by the reaction in 5 dibromo, 3 methylpentane 6；(5) midbody compounds 7 slough protecting group and obtain midbody compound 8；(6) aminopyridine imidazolone derivatives are obtained by the reaction with compound 9 under alkaline condition in midbody compounds 8.
Description
Technical field
The present invention relates to the preparation methods of EV71 viruses and CAV16 viral inhibitors aminopyridine imidazolone derivatives.
Background technology
People's hand-foot-and-mouth disease (Hand-foot-mouth disease, HFMD) is global common transmittable disease, China always with
Being all the hotspot of people's hand-foot-and-mouth disease, the new cases quantity of China's hand-foot-and-mouth disease was at 2010,2011,2012 continuous 3 years
It occupies first of China's Notifiable disease, and has apparent ascendant trend, there is presently no the special efficacy antiviral agents for hand-foot-and-mouth disease
Object lists.
Human enterovirus 71 (EV71 viruses) and Coxsack A16 types virus (CAV16 viruses) are to draw in recent years in China
Play the main pathogens of hand-foot-and-mouth disease.Clinically, symptom caused by CAV16 is typically more slight, and the brothers caused by EV71
In stomatosis case, there are a small number of cases that serious central nervous system disease can occur, leads to the higher death rate.
EV71 and CAV16 belongs to Picornaviridae, enterovirus genus, and virion is in regular dodecahedron structure, entire disease
Malicious shell is made of 60 substances (protomer), each substance is by this four protein protomers of VP1, VP2, VP3 and VP4
Composition.EV71 and CAV16 are first combined with the specific receptor on host cell membrane, then pass through when infecting host cell
Host cell endocytosis is formed by endosome, enters inside host cell, in endosome, the disease of EV71 and CAV16
A series of structure change occurs for malicious particle, and forms a hole in the secondary shaft position of the positive 20 face structure of virion,
The RNA that viral capsid wraps up is discharged from the hole to cell cytosol, this process is known as the shell process of undressing of virus.
In the VP1 of EV71 and CAV16, there are a conservative hydrophobic pocket, this hydrophobic pocket is often a kind of in intact virus
The lipid molecule for coming from host cell occupies, therefore the inhibitor by designing specificity, is incorporated in the conserved hydrophobic mouth of VP1
In bag, the shell process of undressing of enterovirus can be inhibited, infect the process of host cell to further suppress it.In the present invention
The aminopyridine imidazolone derivatives being related to are the potent inhibitor of a kind of EV71 and CAV16, can be with EV71's and CAV16
Hydrophobic pocket specific binding in VP1, to inhibit the process of virus infection host cell, therefore such inhibitor can be used for
The drug for the treatment of hand-foot-and-mouth disease is prepared, therefore needs a kind of preparation method at present to meet research and development of such compound as drug
Production.
First technology has found that a kind of aminopyridine imidazolone derivatives (general structure is as shown in Equation 1) have extremely strong suppression
The ability of EV71 and CAV16 processed have the ability of potential treatment hand-foot-and-mouth disease, can be used as a kind of new E V71's and CAV16
VP1 inhibitor and applied to prepare treatment hand-foot-and-mouth disease drug.
There are two types of the synthetic methods of such pyridine imidazolone derivatives disclosed in currently available technology：
Chinese patent CN104744433A (data of publication of application：On July 1st, 2015) a kind of preparation method is disclosed (see figure
1)：Protection amino is reacted as raw material with dimethyl dicarbonate butyl ester using the bromo- 4-aminopyridines of 2- and obtain intermediate A, then pass through palladium
Intermediate C is obtained by the reaction with intermediate B in catalyzed coupling reaction, and finally deprotection obtains 1- (2- ammonia under conditions of trifluoroacetic acid
Yl pyridines -4- bases) -3- (5- (4- ((ethyoxyl imines) methyl) phenoxy group) -3- methyl amyls)-imidazoline -2- ketone, i.e. chemical combination
Object a.
The synthetic method of this patent disclosure has the following problems：
(1) the preparation methods have used palladium chtalyst coupling, but coupling yield is very low (being less than 30%), causes to be prepared into
This is high.
(2) synthesis step of the intermediate B involved in reactions is more and yield is low.
(3) protecting group on trifluoroacetic acid removing amino has been used in reactions, this can cause O- ethyls oxime in product simultaneously
The fracture of key hydrolyzes, and yield is caused to reduce.
Chinese patent (application number 201610315888.7) discloses a kind of preparation method (see Fig. 2)：With the bromo- 4- amino of 2-
Pyridine is that midbody compound D is obtained by the reaction with 2- chloroethyl isocyanates in starting material, and compound D cyclizations later obtain centre
Bromine on pyridine ring is become azido group, then in stannous chloride also original work by body compound E under sodium azide effect later
Under, azido group becomes amino, obtains compound H, and target compound a is obtained by the reaction in compound H and compound I later.
The synthetic method of this patent disclosure has the following problems：
(1) the preparation methods have used 2- chloroethyl isocyanates, and the toxicity of compound is very big, are easy to environment and behaviour
It causes damages as personnel.
(2) sodium azide has been used in reactions, the compound is explosive, restricted to production is further amplified.
(3) stannous chloride has been used in the reduction of reaction process kind azido group, and step reaction will produce a large amount of waste residues, right
Environment has larger pressure, and the heavy metal for be easy to causeing metallic tin in final product is remaining.
Invention content
In order to overcome the above problem in the prior art, the present invention provides a kind of as EV71 viruses and CAV16 viruses
The preparation method of the aminopyridine imidazolone derivatives of inhibitor, before this method can overcome in patent report in synthetic route
There are the shortcomings that, have the characteristics that easy to operate, high income, it is environmental-friendly and meet industry amplification require.
The present invention provides a kind of as the aminopyridine imidazolone derivatives of EV71 viruses and CAV16 viral inhibitors
The synthetic route of preparation method, the preparation method includes the following steps：(1) is starting material with bromo- 2 amino-pyridines of 4- 1,
Two blocking groups (PG) are formed on amino and obtain midbody compound 2, and reaction temperature is 0-60 DEG C, reaction time 3-
24h；(2) midbody compounds 2 carry out coupling reaction with monoacylphosphine imidazolone 3, obtain midbody compound 4, reaction temperature
It is 50-110 DEG C, reaction time 3-24h；(3) deacetylate obtains intermediate to midbody compounds 4 under alkaline condition
Compound 5, reaction temperature are 10-60 DEG C, reaction time 1-10h；(4) midbody compounds 5 are under alkaline condition with 1,5-
Midbody compound 7 is obtained by the reaction in two bromo- 3- methyl-pentanes 6, and reaction temperature is 0-60 DEG C, reaction time 1-10h；(5).
Midbody compound 7 sloughs protecting group and obtains midbody compound 8, and reaction temperature is 10-60 DEG C, reaction time 1-10h；
(6) aminopyridine imidazolone derivatives are obtained by the reaction with compound 9 under alkaline condition in midbody compounds 8, and reaction temperature is
40-90 DEG C, reaction time 12-24h.
In the above preparation method, wherein compound 2 isThe blocking group is tertbutyloxycarbonyl, second
Acyl group, benzyl or to methoxy-benzyl.
In the above preparation method, wherein compound 4 isUsed in coupling reaction in step (2)
Metallic catalyst is tetra-triphenylphosphine palladium, two (triphenylphosphine) palladium bichlorides, tris(dibenzylideneacetone) dipalladium, [1,1 '-bis- (two
Phenylphosphine) ferrocene] it is palladium chloride, palladium, palladium chloride, cuprous iodide, one or more in copper acetate.
In the above preparation method, wherein alkali used in step (3), (4) and (6) be sodium hydroxide, potassium hydroxide,
One or more in sodium hydride, cesium carbonate, potassium carbonate, compound 5 isCompound 7 is
In the above preparation method, wherein protecting group in step (5) removing condition be alkaline condition, acid condition or
Oxidizing condition, when for alkaline condition, alkali used is in sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, potassium carbonate
One or more, when for acid condition, acid used is trifluoroacetic acid, hydrochloric acid, one or more in hydrobromic acid, when for oxygen
When change condition, oxidant used is one or both of ammonium ceric nitrate, dichloro dicyano quinone.
In the above preparation method, wherein used solvent is tetrahydrofuran, N, N- dimethyl formyls in reaction process
It is one or more in amine, ethyl alcohol, methanol, acetonitrile, dichloromethane, toluene.
In the above preparation method, wherein compound 9 isR3Including：
In the above preparation method, wherein the blocking group is benzyl, to methoxy-benzyl, the reaction in step (1)
Temperature is 0-40 DEG C, reaction time 12-18h.
In the above preparation method, wherein compound 8 is
The present invention also provides the aminopyridine imidazolone derivatives prepared by method made above to prepare treatment hand
Purposes in the drug of sufficient stomatosis.
Description of the drawings
Fig. 1 shows a kind of process of synthetic method of pyridine imidazolone derivatives.
Fig. 2 shows the processes of another synthetic method of pyridine imidazolone derivatives.
Fig. 3 shows the process of the synthetic method of aminopyridine imidazolone derivatives according to an embodiment of the invention.
Fig. 4 shows the building-up process of compound a.
Fig. 5 shows the hydrogen nuclear magnetic spectrogram of compound 5.
Fig. 6 shows the hydrogen nuclear magnetic spectrogram of compound 8.
Specific implementation mode
The following examples can make those skilled in the art that the present invention be more fully understood, but not limit in any way
The present invention.
Synthetic route according to the present invention is as shown in Figure 3.Synthetic route includes the following steps：
(1) is starting material with bromo- 2 amino-pyridines of 4- 1, forms two protecting groups on amino and obtains intermediate compound
Object 2 (PG=protecting groups), reaction temperature can be 0-60 DEG C, and the reaction time can be 3-24h, and blocking group can be tertiary fourth oxygen
Carbonyl, acetyl group, benzyl, to methoxy-benzyl etc..
(2) midbody compounds 2 carry out coupling reaction with monoacylphosphine imidazolone 3, obtain midbody compound 4, are coupled
Metallic catalyst used can be tetra-triphenylphosphine palladium, two (triphenylphosphine) palladium bichlorides, tris(dibenzylideneacetone) dipalladium, [1,
1 '-bis- (diphenylphosphine) ferrocene] palladium catalysts such as palladium chloride, palladium, palladium chloride can also be cuprous iodide, vinegar
The copper salt catalysts such as sour copper, reaction temperature can be 50-110 DEG C, and the reaction time can be 3-24h.
(3) deacetylate obtains midbody compound 5 to midbody compounds 4 under alkaline condition, and alkali used can be
Sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, potassium carbonate etc., reaction temperature can be 10-60 DEG C, and the reaction time can be
1-10h。
(4) intermediate is obtained by the reaction with 1,5-, bis- bromo- 3- methyl-pentanes 6 under alkaline condition in midbody compounds 5
Object 7 is closed, alkali used can be sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, potassium carbonate etc., and reaction temperature can be 0-60
DEG C, the reaction time can be 1-10h.
(5) midbody compounds 7 slough protecting group and obtain midbody compound 8, and it can be alkalinity that protecting group, which removes condition,
Condition, or acid condition or oxidizing condition, alkali used can be sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate,
Potassium carbonate etc., acid used can be trifluoroacetic acid, hydrochloric acid, hydrobromic acid etc., and oxidant used can be ammonium ceric nitrate, dichloro dicyan
Base quinone etc., reaction temperature can be 10-60 DEG C, and the reaction time can be 1-10h.
(6) desired inhibitor molecule is obtained by the reaction in midbody compounds 8 with compound 9 under alkaline condition, and alkali used can
Think that sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, potassium carbonate etc., reaction temperature can be 40-90 DEG C, the reaction time can
Think 12-24h.
(7) solvent used in reaction process can be tetrahydrofuran, N,N-dimethylformamide, ethyl alcohol, methanol,
Acetonitrile, dichloromethane, toluene etc..
The preferably following reaction condition of reaction process：
(1) is starting material with bromo- 2 amino-pyridines of 4- 1, forms two protecting groups on amino and obtains intermediate compound
Object 2 (PG=protecting groups), the preferred benzyl of blocking group, to methoxy-benzyl, preferred 0-40 DEG C of reaction temperature, the reaction time is preferred
12-18h。
(2) midbody compounds 2 carry out coupling reaction with monoacylphosphine imidazolone 3, obtain midbody compound 4, are catalyzed
The preferred tris(dibenzylideneacetone) dipalladium of agent, palladium, preferred 70-100 DEG C of reaction temperature, reaction time preferred 12-18h.
(3) deacetylate obtains midbody compound 5, the preferred hydrogen of alkali used to midbody compounds 4 under alkaline condition
Sodium oxide molybdena, cesium carbonate, preferred 15-40 DEG C of reaction temperature, reaction time preferred 1-5h.
(4) intermediate is obtained by the reaction with 1,5-, bis- bromo- 3- methyl-pentanes 6 under alkaline condition in midbody compounds 5
Close object 7, the preferred sodium hydride of alkali used, cesium carbonate, preferred 0-40 DEG C of reaction temperature, reaction time preferred 1-5h.
(5) midbody compounds 7 slough protecting group and obtain midbody compound 8, and the preferred trifluoroacetic acid of acid used is used
The preferred sodium hydride of alkali, preferred 15-40 DEG C of reaction temperature, reaction time preferred 1-5h.
(6) desired inhibitor molecule is obtained by the reaction in midbody compounds 8 with compound 9 under alkaline condition, and alkali used is excellent
Select potassium carbonate, sodium hydride, preferred 50-80 DEG C of reaction temperature, reaction time preferred 15-20h.
Selected chemicals a's of the present invention synthesizes to be illustrated to the synthetic route of the present invention, but is not intended to limit this
The application of invention preparation method.It will be understood by those skilled in the art that other similar compounds may be used it is similar with compound a
Method is synthesized.
The synthetic method of compound a is as shown in figure 4, operating procedure is as follows：
1. the compound 1 of 72g is dissolved in the dimethylformamide (DMF) of 3L, system is cooled to 0 DEG C, later by 80g's
NaH is added in reaction system, charging finish architecture heat preservation reaction 0.5h, backward reaction system in dropwise addition 300g to methoxy
Base benzyl chloride (PMBCl), clear-cutting forestland is to reacting at room temperature overnight after the subsequent continuous insulation reaction 0.5h of completion of dropwise addition.After reaction plus
H2Reaction is quenched in O, and a large amount of solids, filtering, a large amount of H of filter cake are precipitated in system2O mashing washings, filtration drying obtains 172g yellow later
Solid, i.e. midbody compound 2, yield 90%.
2. the compound 3 of the compound 2 of 171g and 56g is placed in 5L toluene, the Cs of 200g is added later2CO3、10g
Tris(dibenzylideneacetone) dipalladium [Pd2 (dba)3] and the bis- diphenylphosphine -9,9- dimethyl oxa-s of 4,5- of 16g fear
(Xantphos), system is warming up to 80 DEG C of reaction 15h later.After the reaction was complete, system is cooled to room temperature and is filtered, filter cake is used
A large amount of ethyl acetate (EA) elution, filtrate is with a large amount of H2O is washed twice, later combined ethyl acetate (EA) phase, by combined EA phases
It is washed once with a large amount of saturated salts again, is concentrated to give 259g brown oils, i.e. 4 crude product of compound later, crude product is tied again
Crystalline substance operation：259g brown oils are heated to 60 DEG C with the EA of 400mL, the petroleum ether of 250mL is slowly added into system
(PE), a large amount of yellow solids are precipitated in system, are naturally cooling to 25 DEG C, and filtering collects filtration cakes torrefaction and obtains 105g yellow solids, i.e., in
Intermediate compounds therefor 4, yield 54%.
3. the compound 4 of 105g is added in the MeOH of 1L, after by the K of 100g2CO3It is added in system, reacts at room temperature
3h.After the reaction was complete, a large amount of water are added into system, after stirring 30min, system are directly filtered, filter cake is beaten with a large amount of water
Slurry is collected by filtration filter cake and does to obtain 90.4g khaki solids, i.e. midbody compound 5, and yield 92%, Fig. 5 shows compound
5 hydrogen nuclear magnetic spectrogram.
4. the compound 6 of the compound 5 of 45g and 30g is added in the DMF of 1L, system is cooled to 0 DEG C, backward
The NaH of 8g is added in system, after charging, clear-cutting forestland is to reacting at room temperature 3h.After reaction, it is added into reaction system
The water of 1L, system are extracted with a large amount of EA, collect organic phase, with organic phase of washing of 1L, then the saturated salt washing one with 1L
Secondary organic phase collects organic phase later, and anhydrous magnesium sulfate drying is added, and 82g brown oils are done to obtain in organic phase concentration later, i.e.,
The crude product of midbody compound 7 is directly used in subsequent reactions, crude yield 67% without further purification.
5. the crude product of the midbody compound 7 of 82g is dissolved in the dichloromethane (DCM) of 1L, after the TFA of 400mL is added
Enter into system, reacts at room temperature 3h.After the reaction was complete, trifluoroacetic acid (TFA) is removed completely with Rotary Evaporators, it later will be dense
System saturation NaHCO after contracting3Adjust pH=7, backward system in be added 1L EA dissolving, extraction liquid separation, collection EA phases use
The saturated brine of 1L washs, and after collection EA phases are dried with anhydrous magnesium sulfate, is concentrated to give 72g clear yellow viscous objects, is tied again to it
Crystalline substance operation：The EA that 100mL is added into system is heated to 60 DEG C, is slowly added to the methyl tertiary butyl ether(MTBE) of 75mL thereto
(MTBE), rear clear-cutting forestland later filters the solid of precipitation to room temperature, collects filtration cakes torrefaction and obtains 13.9g off-white powders,
That is midbody compound 8, yield 50%, Fig. 6 show the hydrogen nuclear magnetic spectrogram of compound 8.
6. the compound 9 of the compound 8 of 13g and 8g is added in the acetonitrile of 100mL, the K of 20g is added later2CO3,
It is warming up to 65 DEG C of reactions for 24 hours, directly filters system after the reaction was complete, filter cake is eluted with the DCM of 100mL, is collected filtrate and is used in combination
The saturated salt washing of 100mL is primary, backward filtrate in anhydrous magnesium sulfate be added dry, filtrate is concentrated to give 19g yellow later
Solid carries out recrystallization operation with EA to it, and the solid that crystallization is precipitated is heated to 60 DEG C of mashing washings with ethyl alcohol, is collected by filtration
Filter cake obtains 8.5g white solids, i.e. compound a, yield 53% after dry.
It will be understood by those skilled in the art that above example is only exemplary embodiment, in the spirit without departing substantially from the present invention
In the case of range, a variety of variations can be carried out, replaced and changed.
Claims (10)
1. a kind of preparation method as EV71 viruses and the aminopyridine imidazolone derivatives of CAV16 viral inhibitors, described
The synthetic route of preparation method includes the following steps：
(1) it is starting material with bromo- 2 amino-pyridines of 4- 1, forms two blocking groups (PG) on amino and obtain intermediate
Object 2 is closed, reaction temperature is 0-60 DEG C, reaction time 3-24h；
(2) midbody compound 2 carries out coupling reaction with monoacylphosphine imidazolone 3, obtains midbody compound 4, reaction temperature
It is 50-110 DEG C, reaction time 3-24h；
(3) deacetylate obtains midbody compound 5, reaction temperature 10-60 to midbody compound 4 under alkaline condition
DEG C, reaction time 1-10h；
(4) midbody compound 7 is obtained by the reaction with 1,5-, bis- bromo- 3- methyl-pentanes 6 under alkaline condition in midbody compound 5,
Reaction temperature is 0-60 DEG C, reaction time 1-10h；
(5) midbody compound 7 sloughs protecting group and obtains midbody compound 8, and reaction temperature is 10-60 DEG C, and the reaction time is
1-10h；
(6) aminopyridine imidazolone derivatives, reaction temperature is obtained by the reaction in midbody compound 8 with compound 9 under alkaline condition
Degree is 40-90 DEG C, reaction time 12-24h.
2. preparation method according to claim 1, wherein compound 2 isThe blocking group is tertiary fourth
Oxygen carbonyl, acetyl group, benzyl or to methoxy-benzyl.
3. preparation method according to claim 2, wherein compound 4 isCoupling in step (2) is anti-
Answer metallic catalyst used be tetra-triphenylphosphine palladium, two (triphenylphosphine) palladium bichlorides, tris(dibenzylideneacetone) dipalladium, [1,
1 '-bis- (diphenylphosphine) ferrocene] it is palladium chloride, palladium, palladium chloride, cuprous iodide, one or more in copper acetate.
4. preparation method according to claim 2, wherein alkali used in step (3), (4) and (6) be sodium hydroxide,
One or more in potassium hydroxide, sodium hydride, cesium carbonate, potassium carbonate, compound 5 isCompound 7 is
5. preparation method according to claim 1, wherein the protecting group removing condition in step (5) is alkaline condition, acid
Property condition or oxidizing condition, when for alkaline condition, alkali used is sodium hydroxide, potassium hydroxide, sodium hydride, cesium carbonate, carbon
One or more in sour potassium, when for acid condition, acid used is trifluoroacetic acid, hydrochloric acid, one kind in hydrobromic acid or more
Kind, when for oxidizing condition, oxidant used is one or both of ammonium ceric nitrate, dichloro dicyano quinone.
6. preparation method according to claim 1, wherein used solvent is tetrahydrofuran, N, N- in reaction process
It is one or more in dimethylformamide, ethyl alcohol, methanol, acetonitrile, dichloromethane, toluene.
7. preparation method according to claim 1, wherein compound 9 isR3Including：
8. preparation method according to claim 1, wherein the blocking group is benzyl, to methoxy-benzyl, step
(1) reaction temperature in is 0-40 DEG C, reaction time 12-18h.
9. preparation method according to claim 1, wherein compound 8 is
10. prepared by aminopyridine imidazolone derivatives prepared by the preparation method according to any one of claim 1-9
Treat the purposes in the drug of hand-foot-and-mouth disease.
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2017
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Application publication date: 20180713 |