CN105367567B - A kind of compound and its application in the western croak of Leo is prepared - Google Patents
A kind of compound and its application in the western croak of Leo is prepared Download PDFInfo
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- CN105367567B CN105367567B CN201510795116.3A CN201510795116A CN105367567B CN 105367567 B CN105367567 B CN 105367567B CN 201510795116 A CN201510795116 A CN 201510795116A CN 105367567 B CN105367567 B CN 105367567B
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- 0 CC(*)c1c(N)nc(-c2n[n](Cc(cccc3)c3F)c3ncccc23)nc1N Chemical compound CC(*)c1c(N)nc(-c2n[n](Cc(cccc3)c3F)c3ncccc23)nc1N 0.000 description 1
- LQCFFAGUCURQEC-UHFFFAOYSA-N NC(c1n[n](Cc(cccc2)c2F)c2ncccc12)=N Chemical compound NC(c1n[n](Cc(cccc2)c2F)c2ncccc12)=N LQCFFAGUCURQEC-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of diamines of 5 methylamino 2 [base of 1 (2 luorobenzyl) 1H pyrazolos [3,4 b] pyridine 3] pyrimidine of compound 4,6, it can be used as the intermediate of the western croak of Leo and its derivative.A kind of new method that the western croak of Leo is prepared using the intermediate is also disclosed, the western croak yield of obtained Leo and purity are high, effectively reduce the generation of side reaction, have saved production cost.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of compound 5- methylaminos -2- [1- (2- luorobenzyls) -1H-
Pyrazolo [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines, its as intermediate be used for prepare antithrombotic embolism class diseases medicine
The application of the western croak of Leo (Riociguat) and its derivative.
Technical background
The western croak of Leo, English name Riociguat, Chinese 4,6- diaminourea -2- [1- (2- luorobenzyls) 1H- pyrroles
Azoles simultaneously [3,4-b] pyridin-3-yl] -5- pyrimidine radicals (methyl) methyl carbamate or N- [4,6- diaminourea -2- [1- [(2-
Fluorophenyl) methyl] -1H- pyrazolos [3,4-B] pyridin-3-yl] -5- pyrimidine radicals]-N- methylene dicarbamates, its structural formula
Shown in formula I, No. CAS is 625115-55-1, and the compound is reported in WO03095451 at first, as soluble guanylate ring
The stimulant for changing enzyme is worked, and medicament can be used as to be used to prevent or treat angiocardiopathy, such as treating hypertension
And heart failure, stable and unstable angina pectoris.The medicine is developed by Beyer Co., Ltd, for treating chronic thromboembolic lung
Arterial hypertension (CTEPH), pulmonary hypertension (PAH), ratify to list by FDA within 2013.
The synthetic route of a western croak of Leo is disclosed in patent WO03095451 first, it is as follows,
Wherein need to react to obtain with methylchloroformate by No. 5 bit aminos in 4,5,6- Triaminopyrimidine compounds VI
Intermediate pyrimdinyl-amino formic acid esters VII, selective alkylation is finally carried out to obtain on carbamate using iodomethane etc.
The western croak I of object Leo.This route certainly exists selecting response due to three amino, alkylation simultaneously on pyrimidine ring be present
Sex chromosome mosaicism, cause non-targeted Aminomethylated or alkylated reaction, produce structure and physicochemical property is similar to the western croak of Leo
The final product that No. 4 positions and/or No. 6 bit aminos in impurity such as VI obtain after being reacted with methylchloroformate, to later-period purification
Or impurity removes and brings very big difficulty, it is difficult to reaches the quality requirement to bulk drug high-purity.
Patent CN102939289 reports a new process route and prepares the western croak of Leo, as follows：
The route is coupled by palladium and tin reagent, is restored nitro and is obtained the western triamido of croak key intermediate 4,5,6- of Leo
Pyrimidine compound VI, but still unavoidable No. 5 bit aminos that must pass through pyrimidine ring in VI as in WO03095451
Intermediate pyrimdinyl-amino formic acid esters is obtained with methylchloroformate reaction, the western croak of Leo is finally re-formed, has again resulted in above-mentioned
The problem of.Moreover, the route employs tin reagent, definitely used with caution in field of medicaments.
The content of the invention
In order to solve that side reaction easily occurs present in the above-mentioned synthesis technique for preparing the western croak of Leo, be also easy to produce impurity, production
The problems such as product purification difficult, the invention provides a kind of new method for preparing the western croak of Leo, it can expeditiously produce height
The western croak of Leo of purity.
To achieve the above object, the present invention adopts the following technical scheme that：Change the synthetic route of prior art, there is provided brand-new
Midbody compound, so as to prepare the western croak of Leo of high-quality at lower cost.
Therefore, it is an object of the present invention to provide the compound 5- methylamino -2- [1- shown in a kind of formula II
(2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines：
It is an object of the present invention to provide a kind of method for preparing above-claimed cpd II, comprise the following steps：
Make the compound (5- substitutions -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] shown in formula III
Pyrimidine -4,6- diamines) and methylamine progress nucleophilic substitution, compound II is made,
The substituent of No. 5 positions is LG wherein on compound III pyrimidine ring, selected from halogen or sulfonic group RSO3-, it is described
Halogen is selected from fluorine, chlorine, bromine, iodine, and the R is C1-C6 alkyl or cycloalkyls, substitution or unsubstituted aromatic radical, the C1-C6
Alkyl or cycloalkyl is selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, different
Amyl group, neopentyl, n-hexyl, cyclopenta, cyclohexyl etc., the substitution or unsubstituted aromatic radical are selected from phenyl, benzyl, right
Methoxyphenyl, p-methylphenyl, 4- fluorophenyls, 4- bromophenyls, 4- iodophenyls, 4- trifluoromethyls, 2,5- dichlorophenyls,
The chloro- 4- fluorophenyls of 3- chlorphenyls, 3-, 4- 2-bromomethylphenyls, 3- cyano-phenyls, the bromo- 4- fluorophenyls of 2-, 2,4 dichloro benzene base, 5,
6,7,8- tetrahydrochysene -2- naphthyls, 4- tert-butyl-phenyls, 2,4,6- trimethylphenyls etc..
Preferably, LG is selected from bromine, iodine, methanesulfonic acid base CH3SO3-, now compound III is respectively：
The bromo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines；
The iodo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines；
5- methanesulfonic acid bases -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines.
The nucleophilic substitution can be carried out in the presence of a base, wherein described alkali is organic base or inorganic base, wherein
Inorganic base is one or two kinds of mixed above in potassium carbonate, sodium carbonate, cesium carbonate, saleratus, sodium acid carbonate, sodium hydride
Thing, described organic base be triethylamine, DBU (carbon -7- alkene of 1,8- diazabicylo 11), tri-n-butylamine, one kind in pyridine or
The two or more mixtures of person.
In above-mentioned prepare compound II method, base amount and compound III mol ratio are 1-5:1.
Alternatively, the nucleophilic substitution can also be without using alkali, now methylamine or intermediate III itself
Serve the effect of acid binding agent.
In above-mentioned nucleophilic substitution, methylamine and the mol ratio of pyrimidine ring intermediate compound III are 1-5:1.
Above-mentioned nucleophilic substitution temperature is 20-100 DEG C.
Above-claimed cpd III can be prepared by the method comprised the steps：
In organic solvent, by 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- carbonamidines shown in structural formula IV
(abbreviation amidine intermediate compound IV) and the malononitrile V of LG substitutions carry out ring-closure reaction in the case where alkali accelerator acts on, and compound III is made,
Wherein LG meaning is identical with above-mentioned restriction.
Route of synthesis is as follows：
Wherein, the organic solvent be selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), toluene, dimethylbenzene,
Dimethyl acetamide (DMAC), acetone (AC), 1-METHYLPYRROLIDONE (NMP), hexamethyl phosphoramide (HMPA), 4-methyl urea
(TMU), triethyl phosphate (TEP), trimethyl phosphate (TMP), ethyl acetate, isoamyl acetate and they are two or more
Mixture；Described alkali accelerator is sodium hydride, hydrofining, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, methanol
Sodium, caustic alcohol, sodium carbonate, potassium carbonate, cesium carbonate and their two or more mixtures.
Wherein, ring-closure reaction temperature is 20-100 DEG C.
In above-mentioned ring-closure reaction, amidine intermediate compound IV and the malononitrile V of LG substitutions mol ratio are 1:1-5.
It is yet a further object of the present invention to provide a kind of above-claimed cpd II as intermediate for preparing the western croak of Leo
And its application of derivative, when for preparing the western croak of Leo, there is provided a kind of method for preparing the western croak of Leo, including following step
Suddenly：
Compound II is reacted with methylchloroformate, the western croak of Leo shown in Formulas I is made.Route of synthesis is as follows：
The synthetic reaction of the above-mentioned western croak of Leo is carried out at 20-100 DEG C of temperature.
The synthetic reaction of the above-mentioned western croak of Leo can be carried out in the presence of a base, wherein described alkali is organic base or inorganic
Alkali, wherein inorganic base are one or two kinds of in potassium carbonate, sodium carbonate, cesium carbonate, saleratus, sodium acid carbonate, sodium hydride
Thing mixed above, described organic base are one or two kinds of thing mixed above in triethylamine, DBU, tri-n-butylamine, pyridine.
In the above-mentioned method for preparing the western croak of Leo, base amount and compound II mol ratio are 1-5:1.
In the above-mentioned method for preparing the western croak of Leo, the mol ratio of methylchloroformate and compound II is 1-5:1.
In the western croak of Leo and its preparation method of derivative that the present invention designs, pass through on the pyrimidine ring of intermediate II 5
Number position introduces the methylamino for being more easy to participate in necleophilic reaction, solves selecting response sex chromosome mosaicism in the western croak building-up process of Leo, will not
Substantial amounts of accessory substance is caused to produce；Simultaneous reactions mild condition, avoid using highly basic hazardous agents.Moreover, reaction yield is higher,
Resulting good product purity, easily reaches the drug standards, so as to reduce production cost, has significant economic implications.
Brief description of the drawings
Fig. 1 is the nuclear magnetic resonance map of the western croak of Leo obtained by embodiment 7-8；
Fig. 2 is the mass spectrogram of the western croak of Leo obtained by embodiment 7-8.
Embodiment
Below in conjunction with specific embodiment and accompanying drawing, the invention will be further described.It should be understood that these embodiments are only used for
Illustrate the present invention rather than limitation the scope of the present invention.
Addition, content and the concentration of many kinds of substance is referred to herein, wherein described percentage composition, except special instruction
Outside, weight/mass percentage composition is all referred to.
In the embodiments herein, illustrated if do not made for reaction temperature or operation temperature, the temperature is led to
Often refer to room temperature.
In the present invention, term " compound shown in structural formula n ", " intermediate shown in structural formula n ", " compound n "
" intermediate n " represents identical meaning, and the compound for being n all referring to numbering, wherein n refers to numbering I, II, III, IV, V.Class
As, the western croak of Leo is referred to as the western croak I of Leo sometimes herein, they represent identical meaning.
Herein, for simplicity, compound III is referred to as " pyrimidine ring intermediate III " or " intermediate sometimes
III ", they represent identical compound；Similarly, intermediate compound IV is referred to as " amidine intermediate compound IV " sometimes, they represent phase
Same compound.
Substituent LG in compound V and compound III is not involved in anti-in compound IV and compound V ring-closure reaction
Should；But it is used as leaving group in methylamine and compound III nucleophilic substitution.LG is selected from halogen or sulfonic group RSO3-,
The halogen is selected from fluorine, chlorine, bromine, iodine；It is preferred that chlorine, bromine, iodine；More preferably bromine, iodine.The R is C1-C6 alkyl or cycloalkyls, taken
Generation or unsubstituted aromatic radical, the C1-C6 alkyl or cycloalkyls be selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopenta, cyclohexyl etc., it is described substitution or
Unsubstituted aromatic radical is selected from phenyl, benzyl, p-methoxyphenyl, p-methylphenyl, 4- fluorophenyls, 4- bromophenyls, 4- iodobenzenes
The chloro- 4- fluorophenyls of base, 4- trifluoromethyls, 2,5- dichlorophenyls, 3- chlorphenyls, 3-, 4- 2-bromomethylphenyls, 3- cyano group benzene
The bromo- 4- fluorophenyls of base, 2-, 2,4 dichloro benzene base, 5,6,7,8- tetrahydrochysene -2- naphthyls, 4- tert-butyl-phenyls, 2,4,6- trimethylbenzenes
Base etc., more preferably R are methyl.
In a kind of embodiment, the organic solvent for above-claimed cpd IV and compound V ring-closure reaction can
Be it is any can dissolve amidine intermediate compound IV and intermediate V but be not involved in chemical reaction organic solvent or mixed solvent.Example
Such as, the organic solvent is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), toluene, dimethylbenzene, dimethylacetamide
Amine (DMAC), acetone (AC), 1-METHYLPYRROLIDONE (NMP), hexamethyl phosphoramide (HMPA), 4-methyl urea (TMU), phosphoric acid
Triethyl (TEP), trimethyl phosphate (TMP), ethyl acetate, isoamyl acetate and their two or more mixtures；It is more excellent
Organic solvent is selected to be selected from DMF, DMSO, toluene, ethyl acetate and their two or more mixtures.
Preferably, the ring-closure reaction for above-claimed cpd IV and compound V is carried out in the presence of alkali accelerator,
Alkali accelerator be selected from sodium hydride, hydrofining, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, caustic alcohol,
Sodium carbonate, potassium carbonate, cesium carbonate and their two or more mixtures；More preferably sodium tert-butoxide, potassium tert-butoxide, sodium methoxide,
Caustic alcohol, sodium carbonate, potassium carbonate.
Preferably, the reaction temperature of above-claimed cpd IV and compound V ring-closure reaction is 20-100 DEG C.Reaction temperature
Lower limit is 20 DEG C, preferably 22,25,28,30,32,35 or 40 DEG C；Be limited to 100 DEG C thereon, preferably 95,90,85,80,75,
70th, 65 or 60 DEG C.If reaction temperature is less than 20 DEG C, reaction speed is excessively slow, or reaction is incomplete, influences production efficiency；
On the other hand, if reaction temperature is more than 100 DEG C, reaction speed is too fast, it is possible to causes the generation of impurity, influences intermediate
III purity and yield.
Preferably, in above-mentioned ring-closure reaction, amidine intermediate compound IV and the malononitrile V of LG substitutions mol ratio are 1:1-5.That is LG
Substituted malononitrile V relative usage will be equal to or higher than the dosage of amidine intermediate compound IV, because the cost of amidine intermediate compound IV
Higher than the malononitrile V of LG substitutions, the principle based on chemical balance, economically consider, the malononitrile V of LG substitutions dosage is not
Less than amidine intermediate compound IV.For example amidine intermediate compound IV and the malononitrile V of LG substitutions mol ratio can be 1:1、1:1.5、1:2、1:
2.5、1:3、1:3.5、1:4、1:4.5 or 1:5.Those skilled in the art can be true by testing according to specifically used reagent
It is fixed.
In a kind of embodiment, the nucleophilic substitution between methylamine and compound III is under the catalysis of alkali
Carry out, described alkali be organic base or inorganic base, wherein inorganic base be potassium carbonate, sodium carbonate, cesium carbonate, saleratus,
One or two kinds of thing mixed above in sodium acid carbonate, sodium hydride；Described organic base is triethylamine, DBU, tri-n-butylamine, pyrrole
One or two kinds of thing mixed above in pyridine.
When using alkali as catalyst, base amount and compound III mol ratio are 1-5:1, for example can be 1:1、
1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.5:1 or 5:1.Those skilled in the art can be according to specifically used examination
Agent is determined by experiment.
In another embodiment, the nucleophilic substitution between methylamine and compound III need not use volume
The alkali of outer addition is as catalyst, because methylamine and compound III may serve as acid binding agent in itself.
Preferably, in the present invention prepares the method for the western croak of Leo, the mol ratio of compound III and methylamine is 1:1-5.I.e.
The relative usage of methylamine will be equal to or higher than compound III dosage, because compound III cost is higher than methylamine, base
In the principle of chemical balance, economically consider, the dosage of methylamine is not less than compound III.Such as compound III and first
The mol ratio of amine can be 1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5 or 1:5.Those skilled in the art
It can be determined by experiment.
Nucleophilic substitution between methylamine and compound III is carried out at a temperature of 20-100 DEG C.Under reaction temperature
It is limited to 20 DEG C, preferably 22,25,28,30,32,35 or 40 DEG C；Be limited to 100 DEG C thereon, preferably 95,90,85,80,75,
70th, 65 or 60 DEG C.If reaction temperature is less than 20 DEG C, reaction speed is excessively slow, or reaction is incomplete, influences production efficiency；
On the other hand, if reaction temperature is more than 100 DEG C, reaction speed is too fast, it is possible to causes the generation of impurity, influences compound
II purity and yield.
In a kind of embodiment, the reaction of compound II and methylchloroformate can be carried out in the presence of a base, its
Described in alkali be organic base or inorganic base, wherein inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, saleratus, bicarbonate
One or two kinds of thing mixed above in sodium, sodium hydride, described organic base are in triethylamine, DBU, tri-n-butylamine, pyridine
One or two kinds of thing mixed above.Base amount and compound II mol ratio are 1-5:1, for example can be 1:1、1.5:1、2:
1、2.5:1、3:1、3.5:1、4:1、4.5:1 or 5:1.Those skilled in the art can be determined by experiment.
The reaction of above-claimed cpd II and methylchloroformate is carried out at 20-100 DEG C of temperature.The lower limit of reaction temperature is 20
DEG C, preferably 22,25,28,30,32,35 or 40 DEG C；100 DEG C are limited to thereon, preferably 95,90,85,80,75,70,65 or 60
℃.If reaction temperature is less than 20 DEG C, reaction speed is excessively slow, or reaction is incomplete, influences production efficiency；On the other hand,
If for reaction temperature more than 100 DEG C, reaction speed is too fast, it is possible to causes the generation of impurity, influences the purity of the western croak of Leo
And yield.
In the reaction of above-claimed cpd II and methylchloroformate, the mol ratio of methylchloroformate and compound II is 1-5:1.
I.e. the relative usage of methylchloroformate will be equal to or higher than compound II dosage, because compound II cost is higher than chlorine
Methyl formate, the principle based on chemical balance, economically considers, the dosage of methylchloroformate is not less than compound II.Than
Such as, the mol ratio of methylchloroformate and compound II can be 1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.5:1
Or 5:1.Those skilled in the art can be determined by experiment.
The western croak yield of Leo and purity obtained by the synthesis technique that the present invention designs is very high, effectively reduces side reaction
Generation, improve medicine quality, reduce production cost.
Embodiment
First, reagent
Reagent：2- bromo malononitrile, 2- methanesulfonic acid bases malononitrile, 2- iodos malononitrile, 1- (2- luorobenzyls) -1H- pyrazoles
And [3,4-b] pyridine -3- carbonamidines, methylamine, methylchloroformate, it is that chemistry is pure, can be used directly or as needed through simple
Purifying；Solvent methanol, toluene, DMF, DMSO etc. and other reagents are that analysis is pure, are directly used；Potassium tert-butoxide, sodium methoxide,
Potassium carbonate, triethylamine are that analysis is pure, and these reagents are purchased from China Medicine (Group) Shanghai Chemical Reagent Co.,.
2nd, detection method
1HNMR NMRs use BRUKER-400MHz.
Mass spectrograph is LC-MS instrument (LCMS), model：Agilent 6120B, detector：DAD, mobile phase A are water,
Mobile phase B is 1% aqueous formic acid.Testing conditions：
| Time (min) | A | B | Flow velocity (ml/min) | Pressure (bar) |
| 0 | 80 | 20 | 1.0 | 400 |
| 30 | 20 | 80 | 1.0 | 400 |
| 31 | 10 | 90 | 1.0 | 400 |
| 40 | 10 | 90 | 1.0 | 400 |
Embodiment 1
The bromo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines (compounds
III, LG are bromine) preparation
1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- carbonamidines (compound IV) are added in 100 milliliters of there-necked flasks
(2.7g, 10mmol), sodium methoxide (0.7g, 15mmol) and toluene 35mL, be stirred at room temperature lower addition 2- bromos malononitrile (1.43g,
10mmol), with nitrogen displacement three times, heating reflux reaction 5 hours, are then cooled to room temperature, there is solid precipitation, filtering, filter cake
Washed with cold toluene (20mL).Obtain 3.39g yellow solids, the bromo- 2- of as 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-
B] pyridin-3-yl] pyrimidine -4,6- diamines, yield 82%.
1H NMR(DMSO-d6)：δ=8.92 (dd, 1H), 8.76 (dd, 1H), 7.63 (m, 2H), 7.54 (m, 2H), 7.10
(m, 1H), 6.76 (brs, 4H), 5.68 (s, 2H).
Embodiment 2
5- methanesulfonic acid bases -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines (is changed
Compound III, LG are methanesulfonic acid base) preparation
In 100 milliliters of there-necked flasks add 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- carbonamidines (IV) (2.7g,
10mmol), potassium tert-butoxide (1.68g, 15mmol) and 35mL DMFs, lower addition 2- methanesulfonic acids are stirred at room temperature
Base malononitrile (1.6g, 10mmol), with nitrogen displacement three times, 80 DEG C are heated to, stirring reaction 5 hours, is cooled to room temperature, had solid
Body is separated out, and filtering, filter cake is washed with cold toluene (20mL).Obtain 3.65g yellow solids, as 5- methanesulfonic acids base -2- [1- (2-
Luorobenzyl) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines, yield 85%.
1H NMR(DMSO-d6)：δ=8.92 (dd, 1H), 8.72 (dd, 1H), 7.64 (m, 2H), 7.54 (m, 2H), 7.10
(m, 1H), 6.94 (brs, 4H), 5.68 (s, 2H), 3.59 (s, 3H).
Embodiment 3
The iodo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines (compounds
III, LG are iodine) preparation
In 100 milliliters of there-necked flasks add 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- carbonamidines (IV) (2.7g,
10mmol), potassium carbonate (0.7g, 15mmol) and 30mL dimethyl sulfoxide (DMSO)s, be stirred at room temperature lower addition 2- iodos malononitrile (1.91g,
10mmol), with nitrogen displacement three times, reaction 48 hours is stirred at room temperature, adds 30mL water, there is solid precipitation, filter cake toluene
(20mL) is washed, and obtains 3.13g yellow solids, the iodo- 2- of as 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3-
Base] pyrimidine -4,6- diamines, yield 68%.
1H NMR(DMSO-d6)：δ=8.92 (dd, 1H), 8.76 (dd, 1H), 7.63 (m, 2H), 7.54 (m, 2H), 7.10
(m, 1H), 6.76 (brs, 4H), 5.72 (s, 2H).
Embodiment 4
Compound II (5- methylaminos -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6-
Diamines) preparation
In 100 milliliters of reaction bulbs, obtained intermediate compound III (2.07g, 5mmol) and 30mL are added in embodiment 1
DMF, be slowly added to potassium carbonate (1.38g, 10mmol), after dissolving is stirred at room temperature, by methylamine (0.155g,
5mmol) it is dissolved in 10mL DMFs, is slowly dropped in reaction system, drop finishes and continues stirring reaction at room temperature
6 hours, after reaction terminates, carry out 400 mesh silica gel column chromatography (mobile phases：Dichloromethane：Methanol=10:1) product, is collected, is obtained
To 1.62g compound II, yield 89%.
1H NMR(DMSO-d6)：δ=8.84 (dd, 1H), 8.72 (dd, 1H), 7.64 (m, 2H), 7.52 (m, 2H), 7.10
(m, 1H), 6.42 (brs, 4H), 6.02 (brs, 1H), 5.52 (s, 2H), 2.82 (s, 3H).
Embodiment 5
Compound II preparation
In 100 milliliters of reaction bulbs, the compound III (2.15g, 5mmol) and 30mL N, N- prepared is added in embodiment 2
Dimethylformamide, 0 DEG C of stirring is cooled to, methylamine (0.31g, 10mmol) is dissolved in 10mL DMFs, delayed
Slowly it is added drop-wise in reaction system, drop finishes stirring reaction 5 hours at room temperature, after reaction terminates, carries out 400 mesh silica gel column chromatographies (stream
Dynamic phase：Dichloromethane：Methanol=10：1) target product, is collected, obtains 1.64g compound II, yield 90%.
Embodiment 6
Compound II preparation
In 100 milliliters of reaction bulbs, the compound III (2.31g, 5mmol) and 30mL N, N- prepared is added in embodiment 3
Dimethylformamide, triethylamine (0.51g, 5mmol) is slowly added to, after dissolving is stirred at room temperature, by methylamine (0.155g, 5mmol)
It is dissolved in 10mL DMFs, is slowly dropped in reaction system, it is small drips complete maintenance room temperature continuation stirring reaction 3
When, after reaction terminates, carry out 400 mesh silica gel column chromatography (mobile phases：Dichloromethane：Methanol=10:1) target product, is collected, is obtained
To 1.64g compound II, yield 90%.
Embodiment 7
The western croak I of Leo preparation
In 100 milliliters of reaction bulbs, the compound II (3.64g, 10mmol) and potassium carbonate that will be prepared in embodiment 4-6
(1.38g, 10mmol) is placed in 30mL dimethyl sulfoxide (DMSO)s, is at room temperature slowly dropped to methylchloroformate (0.31g, 10mmol)
In reaction system, it is heated to 50 DEG C and continues stirring reaction 5 hours, after reaction terminates, reaction system is poured into 50mL cold water, there is Huang
Color solid separates out, and filters to obtain the western croak I of 3.38g Leos, yield 80%.
MS:423(M+H)
1H NMR (400MHz, DMSO-d6) δ 9.06 (dd, J=8.1,1.6Hz, 1H), 8.60 (dd, J=4.5,1.8Hz,
1H), 7.41-7.30 (m, 2H), 7.29-7.18 (m, 1H), 7.11 (dd, J=8.5,6.4Hz, 2H), 6.39 (d, J=8.2Hz,
4H),5.81(s,2H),3.66(s,0.75H),3.54(s,2.25H),3.01(s,3H)
Embodiment 8
The western croak I of Leo preparation
With reference to embodiment 7, in 100 milliliters of reaction bulbs, by compound II (3.64g, 10mmol) and triethylamine (1.2g,
12mmol) it is placed in 30mL dimethyl sulfoxide (DMSO)s, methylchloroformate (0.31g, 10mmol) is slowly dropped to reactant at room temperature
In system, it is heated to 80 DEG C and continues stirring reaction 3 hours, after reaction terminates, reaction system is poured into 50mL cold water, there is yellow solid
Separate out, filter to obtain the western croak I of 3.58g Leos, yield 85%.
Claims (10)
1. shown in a kind of formula II compound 5- methylaminos -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -
3- yls] pyrimidine -4,6- diamines method, comprise the following steps：
The compound shown in formula III is carried out nucleophilic substitution with methylamine, compound II is made：
Wherein LG is selected from halogen or sulfonic group RSO3-, the halogen be selected from fluorine, chlorine, bromine, iodine, the R be selected from methyl, ethyl,
N-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopenta,
Cyclohexyl, phenyl, benzyl, p-methoxyphenyl, p-methylphenyl, 4- fluorophenyls, 4- bromophenyls, 4- iodophenyls, 4- fluoroforms
The chloro- 4- fluorophenyls of base phenyl, 2,5- dichlorophenyls, 3- chlorphenyls, 3-, 4- 2-bromomethylphenyls, 3- cyano-phenyls, the bromo- 4- fluorine of 2-
Phenyl, 2,4 dichloro benzene base, 5,6,7,8- tetrahydrochysene -2- naphthyls, 4- tert-butyl-phenyls, 2,4,6- trimethylphenyls.
2. the method as described in claim 1, it is characterised in that compound III is
The bromo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines；
The iodo- 2- of 5- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines；Or
5- methanesulfonic acid bases -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,6- diamines.
3. according to the method for claim 1, it is characterised in that the reaction temperature of the nucleophilic substitution is 20-120
℃。
4. according to the method for claim 1, it is characterised in that the nucleophilic substitution is carried out in the presence of a base, wherein
Described alkali is organic base or inorganic base, and wherein inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, saleratus, bicarbonate
One or two kinds of thing mixed above in sodium, sodium hydride, described organic base are triethylamine, 1,8- diazabicylos 11
One or two kinds of thing mixed above in carbon -7- alkene, tri-n-butylamine, pyridine.
5. according to the method for claim 4, it is characterised in that the mol ratio of the alkali and compound III is 1-5:1.
6. according to the method for claim 1, it is characterised in that the nucleophilic substitution is without using alkali.
7. according to the method for claim 6, it is characterised in that the mol ratio of the methylamine and compound III is 1-5:1.
8. the method as described in claim 1, it is characterised in that compound III is prepared by the method comprised the following steps：
In organic solvent, by 1- (2- luorobenzyls) -1H- pyrazolos [3, the 4-b] pyridine -3- carbonamidines shown in formula IV and Formula V institute
The malononitrile for the LG substitutions shown carries out ring-closure reaction in the case where alkali accelerator acts on, and is made compound II, wherein LG be selected from halogen or
Person's sulfonic group RSO3-, the halogen is selected from fluorine, chlorine, bromine, iodine, and the R is selected from methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopenta, cyclohexyl, phenyl, benzyl,
P-methoxyphenyl, p-methylphenyl, 4- fluorophenyls, 4- bromophenyls, 4- iodophenyls, 4- trifluoromethyls, 2,5- dichloro-benzenes
The chloro- 4- fluorophenyls of base, 3- chlorphenyls, 3-, 4- 2-bromomethylphenyls, 3- cyano-phenyls, the bromo- 4- fluorophenyls of 2-, 2,4 dichloro benzene base,
5,6,7,8- tetrahydrochysene -2- naphthyls, 4- tert-butyl-phenyls, 2,4,6- trimethylphenyls, route of synthesis are as follows：
Wherein, the organic solvent is selected from dimethylformamide, dimethyl sulfoxide (DMSO), toluene, dimethylbenzene, dimethyl acetamide, third
Ketone, 1-METHYLPYRROLIDONE, hexamethyl phosphoramide, 4-methyl urea, triethyl phosphate, trimethyl phosphate, ethyl acetate, acetic acid
Isopentyl ester and their two or more mixtures；Described alkali accelerator is selected from sodium hydride, hydrofining, sodium hydroxide, hydrogen-oxygen
Change potassium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, caustic alcohol, sodium carbonate, potassium carbonate, cesium carbonate and they are two or more
Mixture.
9. according to the method for claim 8, it is characterised in that the ring-closure reaction temperature is 20-100 DEG C.
10. according to the method for claim 8, it is characterised in that 1- (2- luorobenzyls) -1H- pyrazolos shown in formula IV [3,
4-b] mol ratios of malononitrile of LG substitutions shown in pyridine -3- carbonamidines and Formula V is 1:1-5.
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| US20060167016A1 (en) * | 2002-07-18 | 2006-07-27 | Achim Feurer | 2,5-disubstituted pyrimidine derivatives |
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| CN103113300A (en) * | 2013-03-06 | 2013-05-22 | 广西中医药大学 | Preparation method and application of compound with antitumor activity |
| CN104130143B (en) * | 2014-08-06 | 2017-02-15 | 江苏鼎龙科技有限公司 | Method for preparing 3-methylamino-4-nitrophenoxyethanol |
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| CN104086545A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride |
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