CN101723885A - Improved method for preparing diaminopyridine - Google Patents
Improved method for preparing diaminopyridine Download PDFInfo
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- CN101723885A CN101723885A CN200910133004A CN200910133004A CN101723885A CN 101723885 A CN101723885 A CN 101723885A CN 200910133004 A CN200910133004 A CN 200910133004A CN 200910133004 A CN200910133004 A CN 200910133004A CN 101723885 A CN101723885 A CN 101723885A
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- Prior art keywords
- pyridine
- diamino
- salt
- derivative
- diamino pyridine
- 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.)
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Links
- 238000000034 method Methods 0.000 title claims abstract description 53
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 26
- 229910021529 ammonia Inorganic materials 0.000 claims description 14
- 239000000376 reactant Substances 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000005576 amination reaction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- WIVXEZIMDUGYRW-UHFFFAOYSA-L copper(i) sulfate Chemical group [Cu+].[Cu+].[O-]S([O-])(=O)=O WIVXEZIMDUGYRW-UHFFFAOYSA-L 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- YNLZQSXUZWRKPF-UHFFFAOYSA-N (2-nitropyridin-3-yl)hydrazine Chemical compound NNC1=CC=CN=C1[N+]([O-])=O YNLZQSXUZWRKPF-UHFFFAOYSA-N 0.000 description 2
- SLCKILPMRGVCQV-UHFFFAOYSA-N 2-n-benzylpyridine-2,3-diamine Chemical compound NC1=CC=CN=C1NCC1=CC=CC=C1 SLCKILPMRGVCQV-UHFFFAOYSA-N 0.000 description 2
- GZBKVUGZEAJYHH-UHFFFAOYSA-N 2-nitropyridin-3-amine Chemical compound NC1=CC=CN=C1[N+]([O-])=O GZBKVUGZEAJYHH-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- -1 diamino-pyridine compound Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 1
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 1
- QOOCOFOGYRQPPN-UHFFFAOYSA-N 5-bromo-3-nitropyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1[N+]([O-])=O QOOCOFOGYRQPPN-UHFFFAOYSA-N 0.000 description 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical class C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical group C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- IPAWNHSNBYASJG-UHFFFAOYSA-N n-benzyl-2-nitropyridin-3-amine Chemical compound [O-][N+](=O)C1=NC=CC=C1NCC1=CC=CC=C1 IPAWNHSNBYASJG-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 150000003139 primary aliphatic amines Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention relates to an improved method for preparing diaminopyridine. The disclosed improved method enables the preparation of 2,3-diaminopyridine with high purity and high yield, derivatives and salts thereof by large scale industrial production.
Description
Technical field
The present invention relates generally to the improved method of preparation diamino-pyridine.More specifically, the invention provides improved and cost effective means and have highly purified 2,3 diamino pyridine, its derivative or its salt to be used for the large-scale industry manufacturing.
Background technology
The diamino-pyridine compound is used to prepare multiple pharmaceutically important compound as intermediate, as 2, and 3-diamino-5-picoline, it is imidazo [1, the 2-a] pyridine compounds that is used to prepare as medicine for ulcer.And 2,3 diamino pyridine is used to prepare the Inotropic medicine of imidazoles [4,5-b] pyridine (inotropic agents).They also are used for synthetic having the substituent cephem antibiotics of imidazo [4,5-b] picolyl as intermediate, also can be used as the part in the organometallic complex.Therefore, for satisfying the growing needs of this compound, prior art discloses several different methods with preparation 2,3 diamino pyridine and its derivative.
JP5339236 discloses preparation 2, the method of 3-diamino-pyridine, it is included under the existence of palladium catalyst and with hydrogen 2-amino-3-nitro-5-haloperidid is carried out dehalogenation and reduction in alcohol or water, and further mixes with the mineral acid of selecting and separate as hydrochlorate.
Leese and Rydon are at J.Chem.Soc., and 1954,4039 have reported the preparation of 2,3 diamino pyridine, comprise and use Pd-SrCO
3Catalytic reduction 2-amino-3-nitro-5-bromopyridine also extracts with ether.
Some prior aries disclose by hydrogenation 3-amino-2-nitropyridine and have prepared the method for 2,3 diamino pyridine.JP 2003012647 discloses that hydrogenation 3-amino-2-nitropyridine prepares the method for 2,3 diamino pyridine in the presence of the Pd-C catalyzer.
EP159112 discloses the method for preparing diamino-pyridine, and it is by using Ni catalyzer hydrogenation diazanyl nitropyridine in Ruan.And this diazanyl nitropyridine is by preparing with hydrazine hydrazineization (hydrazination) 2-chloro-3-nitropyridine.
EP156495 discloses hydrogenation simultaneously and suitable (benzylamino) nitropyridine of hydrogenolysis in the presence of Pd catalyzer and solvent.
German patent DE 667219 discloses the method for preparing pyridine derivate, and wherein 2-chloro-3-amino (or alkylamino)-pyridine is being with or without catalyzer (CuSO for example
4Under the situation of (or) acid binding agent) and NH
3Or primary aliphatic amine or aromatic amine heat together, to obtain corresponding diaminopyridine derivatives.
People such as Schickh are at Ber.Dtsch.Chem.Ges., and 1936,69B, 2593-605; Reported the preparation of several 3-aminopyrazole derivatives.This research paper discloses a kind of by prepare 2, the method for 3-diamino or 2-alkylamino-3-aminopyridine with ammonia or corresponding alkylamine processing 2-chloro-3-aminopyridine in the presence of mantoquita.This product is used extracted with diethyl ether in apparatus,Soxhlet's (soxhlet apparatus), and uses the benzene recrystallization.When handling the 3-aminopyridine, obtain 2-chloro-3-aminopyridine with the chlorine of new system, and follow a small amount of 2,6-dichloropyridine and 2,4,5,6-4 chloro pyridine.
Reported the pyridine compounds of a kind of three one step process with WO 2004069802 disclosed PCT applications with 2-amino-3-replacement of preparation formula (IV).This method comprise with the 3-of formula (III) replace-2-haloperidid compound reacts with ammonia in the presence of copper catalyst
(R=has the electron donating group with catalyzer coordinate character; The X=halogen), remove copper by handling from reaction mixture then with sulfide, and from the salt of reaction liquid (not comprising copper) preparation compound IV, subsequently by separate the pyridine (IV) that 2-amino-3-replaces with alkaline purification.
JP 2005170848 discloses another kind of preparation 2, the method of 3-diamino-pyridine compound, it is by in the presence of acid or copper catalyst, the reaction of 3-amino-2-haloperidid and benzyl amine derivatives uses hydrogen at hydrogenation 3-amino-2-(benzylamino) pyridine derivate in the presence of palladium catalyst to obtain 3-amino-2-(benzylamino) pyridine derivate then.
The prior art disclosed method comprises the diaminopyridine derivatives that preparation is impure, and it needs multistep to extract and to separate required derivative.And prior art does not disclose the product that any purification technique has high purity and high yield with acquisition.And method described in the prior art relates to uses deleterious and industrial inappropriate catalyzer and solvent, thereby makes them be not suitable for scale operation.
Owing to above-mentioned shortcoming of the prior art and to preparing 2, the demand that the 3-diamino-pyridine increases, the method that needs a kind of commerce of exploitation and practicality economically is to be used for 2,3 diamino pyridine or derivatives thereof or its salt that the large-scale industry manufacturing has high purity and high yield.
Therefore the invention provides the scheme that solves above-mentioned prior art problem, the present invention uses improved method to prepare diamino-pyridine, its derivative or its salt.
Summary of the invention
Main purpose of the present invention provides the method for preparing 2,3 diamino pyridine, its derivative or its salt, and wherein this method makes and can make highly purified 2,3 diamino pyridine, its derivative or its salt with technical scale.
Another purpose of the present invention provides the method for preparing 2,3 diamino pyridine, its derivative or its salt, and wherein this method is used minimum reactions steps, is viable commercial.
Another purpose of the present invention provides the method for preparing 2,3 diamino pyridine, its derivative or its salt, and wherein this method comprises the single extraction step of the solvent that uses environmental sound.
The present invention is above-mentioned further to be obtained and is supported according to following embodiment with other purpose.Yet the scope of the invention is not limited to embodiment hereinafter described.
According to an embodiment of the invention, provide the commercial run of 2,3 diamino pyridine, its derivative or its salt of improved preparation formula (I), wherein this method is included in the following and ammonia pressure 1-5kg/cm of existence of Cu catalyzer
2Use 3-amino-2-haloperidid, its derivative or its salt of ammoniacal liquor amination formula (II) down, and at 100-150 ℃ the temperature range and the pressure 18-25kg/cm of spontaneous generation
2Under heat this reactant to form thick 2,3 diamino pyridine.
According to another embodiment of the invention, 2 of improved preparation formula (I) is provided, the large-scale industry method of 3-diamino-pyridine, its derivative or its salt, wherein this method comprises organic solvent extraction thick 2 from reactant in one step of using environmental sound, the 3-diamino-pyridine, to obtain the 2,3 diamino pyridine of highly purified formula (I).
According to another embodiment of the invention, provide the method for 2,3 diamino pyridine, its derivative or its salt of a kind of preparation formula (I), this method is included in the following and ammonia pressure 1-5kg/cm of existence of catalyzer
2Down, 3-amino-2-haloperidid, its derivative or its salt with ammoniacal liquor amination formula (II), heat this reactant 7-10 hour to form thick 2 100-150 ℃ temperature range, the 3-diamino-pyridine, and in one step, with an organic solvent from reactant, extract 2, the 3-diamino-pyridine is with the 2,3 diamino pyridine of the formula (I) that obtains purified form.
Embodiment
This specification sheets is supported claims, and claims particularly point out and the content (it is considered to the present invention) that clearly requires to be protected, can expect that the present invention is by reading following detailed description and studying contained embodiment and can more easily understand.
Embodiment disclosed by the invention relates to the method for 2,3 diamino pyridine, its derivative or its salt of a kind of preparation formula (I).Method of the present invention is owing to using suitable solvent and the effective raw material of cost of industry to be better than prior art.In addition, this method has been eliminated undesirable treatment step, thereby makes this method viable commercial and be suitable for making pure 2,3 diamino pyridine (I), its derivative and its salt with the large-scale industry of less time.
According to the preferred embodiment of the invention, the improved method that is used for 2,3 diamino pyridine, its derivative or its salt of the formula (I) that industrial production has high purity and high yield is provided, it is applicable to scale operation.
Wherein R is hydrogen or C
1-C
3The straight or branched alkyl.
The method according to this invention, 2,3 diamino pyridine or its salt of formula (I) expression, 3-amino-2-haloperidid, its derivative or its salt by amination formula (II) prepare,
Wherein R is hydrogen or C
1-C
3The straight or branched alkyl, and wherein X is a halogen, it is selected from chlorine or bromine.
Described method is included under the existence of copper (Cu) catalyzer and under the ammonia pressure, and with 3-amino-2-haloperidid, its derivative or its salt of ammoniacal liquor amination formula (II), wherein employed ammonia pressure is 1-5kg/cm
2, preferred 2-4kg/cm
2, and wherein, but used ammonia is (recyclable) of recirculation in the method.
According to the present invention, the catalyzer that uses in this method is copper catalyst, and it is selected from cuprous sulfate, cuprous chloride, cupric chloride, cupric bromide, and preferably sulfuric acid is cuprous.
This reactant is at the pressure 18-25kg/cm of spontaneous generation
2Down, temperature range 100-150 ℃, more preferably be 115-140 ℃ of heating 7-10 hour, to obtain thick 2,3 diamino pyridine in temperature range.
The method according to this invention, the thick 2,3 diamino pyridine of extraction, its derivative or its salt carry out in one step from reactant, thus preparation purity is greater than 99.5% 2,3 diamino pyridine, its derivative or its salt.Described extraction uses the organic solvent of environmental sound to carry out, and it is selected from the Class III solvent according to the ICH guide, but is not limited to ethyl acetate, butylacetate, acetate diisopropyl ester and butanols, ethyl acetate.Used solvent separates by layer, and reuses in the method.
The present invention sets forth with further reference to following examples, but is not in order to limit the scope of the invention by any way.
Embodiment-1
Synthesizing of 2,3 diamino pyridine
With 2-chloro-3-aminopyridine (23gm); CuSO
45H
2O (9.2gm) and ammonia solution (25%; 230ml) be added in 0.4 liter of autoclave.This solution is stirred and applies 3kg/cm at 25-30 ℃
2Ammonia pressure.The gained material is heated to 130 ℃ gradually, and in this temperature at pressure 18-24kg/cm
2Under kept 8 hours.After reaction is finished, reaction mixture is slowly cooled to envrionment temperature simultaneously excessive ammonia is discharged, washing (scrubbed) and recirculation.At 50-55 ℃ product is extracted from reactant with ethyl acetate (190ml) then.At the envrionment temperature collected organic layer and distill the ethyl acetate that 60-70% adds, this material is cooled to about 5-8 ℃ then.Filter the filter cake of gained and wash with ethyl acetate.50 to 60 ℃ of these materials of drying obtained the 2,3 diamino pyridine (56% productive rate) of 11gm after 8 hours under vacuum; 112 to 114 ℃ of fusing points; HPLC purity is 99.5%.Ethyl acetate is placed on one side to be used for recirculation.By mass spectrum and
1H NMR confirms this product.
ms：m/e109(M+)；
1H?NMR(DMSO-D6)δ7.26ppm(d，6H，1H)，δ6.66ppm(t，4H，1H)，δ6.36ppm(d，5H，1H)，δ5.32ppm(s，2H，NH
2)，δ4.63ppm(s，2H，NH
2)
Embodiment-2
Synthetic 2, the 3-diamino-pyridine
With 2-chloro-3-aminopyridine (23gm); CuSO
45H
2O (9.2gm) and ammonia solution (25%; 230ml) be added in 0.4 liter of autoclave.This solution is stirred and applies 1.5kg/cm at 25-30 ℃
2Ammonia pressure.The gained material is heated to 130 ℃ gradually, and in this temperature at pressure 18-24kg/cm
2Under kept 8 hours.After reaction is finished, reaction mixture is slowly cooled to envrionment temperature, simultaneously excessive ammonia is discharged, washing and recirculation.At 50-55 ℃ product is extracted from reactant with ethyl acetate (190ml) then.At the envrionment temperature collected organic layer and distill the ethyl acetate that 60-70% adds, this material is cooled to about 5-8 ℃ then.Filter the filter cake of gained and wash with ethyl acetate.50 to 60 ℃ of these materials of drying are after 8 hours under vacuum, obtain～2,3 diamino pyridine (52% productive rate) of 10gm; 112 to 114 ℃ of fusing points; HPLC purity is 99.5%.Ethyl acetate is placed on one side to be used for recirculation.
Although with reference to some preferred embodiment detailed description, should understanding, the present invention the invention is not restricted to this specific embodiment.According to open (it is described and puts into practice preferred forms of the present invention at present) of the present invention, those skilled in the art can carry out many modifications and variations and not depart from scope of the present invention and essence.The present invention is easy to change accordingly in its practice in the spirit and scope of claims.
Claims (10)
1. the method for the 2,3 diamino pyridine of preparation formula (I), its derivative or its salt,
This method comprises:
In the presence of catalyzer and ammonia pressure be 1-5kg/cm
2Use 3-amino-2-haloperidid, its derivative or its salt of ammoniacal liquor amination formula (II) down;
Heat this reactant 7-10 hour to form the crude product 2,3 diamino pyridine 100-150 ℃ temperature range; With
In one step, with an organic solvent from reactant, extract 2,3 diamino pyridine, with 2,3 diamino pyridine, its derivative or its salt of the formula (I) that obtains purified form,
Wherein, R is hydrogen or C
1-C
3The straight or branched alkyl and,
Wherein X is a halogen, and it is selected from chlorine or bromine.
2. according to the process of claim 1 wherein that described catalyzer is a copper catalyst, it is selected from cuprous sulfate, cuprous chloride, cupric chloride, cupric bromide, and preferably sulfuric acid is cuprous.
3. according to the process of claim 1 wherein that described ammonia pressure is 2-4kg/cm
2
4. according to the process of claim 1 wherein that described temperature range is 115-140 ℃.
5. according to the process of claim 1 wherein that the organic solvent that uses is selected from ethyl acetate, butylacetate, acetate diisopropyl ester and butanols.
6. according to the method for claim 5, wherein said organic solvent is an ethyl acetate.
7. according to the process of claim 1 wherein that but described ammonia is for recirculation.
8. according to the process of claim 1 wherein that but described organic solvent is for recirculation.
9. make pure 2,3 diamino pyridine according to the process of claim 1 wherein that described method is applicable to less time large-scale industry.
10. according to the method for claim 9, wherein said 2,3 diamino pyridine has the purity greater than 99.5%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2434DE2008 | 2008-10-24 | ||
| IN2434/DEL/2008 | 2008-10-24 |
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|---|---|
| CN101723885A true CN101723885A (en) | 2010-06-09 |
| CN101723885B CN101723885B (en) | 2013-02-13 |
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| CN2009101330046A Expired - Fee Related CN101723885B (en) | 2008-10-24 | 2009-03-31 | Improved method for preparing diaminopyridine |
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| CN (1) | CN101723885B (en) |
| DE (1) | DE102009022830B4 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993090A (en) * | 2012-10-11 | 2013-03-27 | 南通市华峰化工有限责任公司 | Method for synthesizing 2,6-diamino pyridine |
| CN102993089A (en) * | 2012-10-11 | 2013-03-27 | 南通市华峰化工有限责任公司 | Method for synthesizing aminopyridine |
| CN103420904A (en) * | 2012-05-16 | 2013-12-04 | 苏州爱斯鹏药物研发有限责任公司 | Method for preparing 2,4-diaminopyridine |
| CN103664762A (en) * | 2013-12-06 | 2014-03-26 | 常熟市联创化学有限公司 | Method for preparing 2,3-diamino pyridine |
| CN106243021A (en) * | 2016-07-28 | 2016-12-21 | 南京红太阳生物化学有限责任公司 | A kind of method of synthesis 4 aminopyridines |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE667219C (en) | 1936-08-22 | 1938-11-07 | Schering Ag | Process for the preparation of pyridine compounds containing basic groups in the 2- and 3-positions |
| IL74375A (en) | 1984-02-21 | 1988-02-29 | Lilly Co Eli | Process for preparing diaminopyridines via hydrogenation of nitrobenzylamino-pyridines |
| IL74373A0 (en) | 1984-02-21 | 1985-05-31 | Lilly Co Eli | Process for the preparation of diaminopyridines |
| JP3088561B2 (en) | 1992-06-05 | 2000-09-18 | 日本合成化学工業株式会社 | Method for producing 2,3-diaminopyridines |
| JP2003012647A (en) | 2000-10-04 | 2003-01-15 | Shionogi & Co Ltd | Method for producing 2,3-diaminopyridine |
| WO2004069802A1 (en) | 2003-02-06 | 2004-08-19 | Shionogi & Co., Ltd. | Process for producing 2-amino-3-substituted pyridine |
| JP2005170848A (en) | 2003-12-11 | 2005-06-30 | Koei Chem Co Ltd | Method for producing 2,3-diaminopyridines |
-
2009
- 2009-03-31 CN CN2009101330046A patent/CN101723885B/en not_active Expired - Fee Related
- 2009-05-27 DE DE102009022830A patent/DE102009022830B4/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420904A (en) * | 2012-05-16 | 2013-12-04 | 苏州爱斯鹏药物研发有限责任公司 | Method for preparing 2,4-diaminopyridine |
| CN102993090A (en) * | 2012-10-11 | 2013-03-27 | 南通市华峰化工有限责任公司 | Method for synthesizing 2,6-diamino pyridine |
| CN102993089A (en) * | 2012-10-11 | 2013-03-27 | 南通市华峰化工有限责任公司 | Method for synthesizing aminopyridine |
| CN102993089B (en) * | 2012-10-11 | 2014-07-16 | 南通市华峰化工有限责任公司 | Method for synthesizing aminopyridine |
| CN103664762A (en) * | 2013-12-06 | 2014-03-26 | 常熟市联创化学有限公司 | Method for preparing 2,3-diamino pyridine |
| CN106243021A (en) * | 2016-07-28 | 2016-12-21 | 南京红太阳生物化学有限责任公司 | A kind of method of synthesis 4 aminopyridines |
Also Published As
| Publication number | Publication date |
|---|---|
| DE102009022830B4 (en) | 2013-07-04 |
| CN101723885B (en) | 2013-02-13 |
| DE102009022830A1 (en) | 2010-04-29 |
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