CN101723885B - Improved method for preparing diaminopyridine - Google Patents
Improved method for preparing diaminopyridine Download PDFInfo
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- CN101723885B CN101723885B CN2009101330046A CN200910133004A CN101723885B CN 101723885 B CN101723885 B CN 101723885B CN 2009101330046 A CN2009101330046 A CN 2009101330046A CN 200910133004 A CN200910133004 A CN 200910133004A CN 101723885 B CN101723885 B CN 101723885B
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- Prior art keywords
- pyridine
- salt
- diamino
- formula
- diamino pyridine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 54
- 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 28
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group 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
- 239000003054 catalyst Substances 0.000 claims description 8
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 238000005576 amination reaction Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 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
- WIVXEZIMDUGYRW-UHFFFAOYSA-L copper(i) sulfate Chemical group [Cu+].[Cu+].[O-]S([O-])(=O)=O WIVXEZIMDUGYRW-UHFFFAOYSA-L 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000002269 spontaneous effect Effects 0.000 claims description 3
- 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
- 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
- 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
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- 239000000284 extract Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000012423 maintenance 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
- 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
- AITFREYTVOPXOT-UHFFFAOYSA-N 5-methylpyridine-2,3-diamine Chemical compound CC1=CN=C(N)C(N)=C1 AITFREYTVOPXOT-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
- 230000015572 biosynthetic process Effects 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
- 238000005194 fractionation Methods 0.000 description 1
- NOVHEGOWZNFVGT-UHFFFAOYSA-N hydrazine Chemical compound NN.NN NOVHEGOWZNFVGT-UHFFFAOYSA-N 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 compound 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 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
- 238000011160 research Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003786 synthesis reaction 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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 Innovative 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
For the preparation of multiple pharmaceutically important compound, such as 2,3-diamino-5-picoline, it is for the preparation of imidazo [1, the 2-a] pyridine compounds as medicine for ulcer to the diamino-pyridine compound as intermediate.And 2,3 diamino pyridine is for the preparation of the Inotropic medicine of imidazoles [4,5-b] pyridine (inotropic agents).They also as intermediate for the synthesis of having the substituent cephem antibiotics of imidazo [4,5-b] picolyl, 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 hydrazine (hydrazination) 2-chloro-3-nitropyridine.
EP156495 discloses simultaneously hydrogenation and suitable (benzylamino) nitropyridine of hydrogenolysis in the presence of the Pd catalysts and solvents.
German patent DE 667219 discloses the method for preparing pyridine derivate, and wherein amino (or alkylamino)-pyridine of 2-chloro-3-is being with or without catalyzer (CuSO for example
4In the situation of (or) acid binding agent) with NH
3Or primary aliphatic amine or aromatic amine heat together, to obtain corresponding diaminopyridine derivatives.
The people such as Schickh are at Ber.Dtsch.Chem.Ges., 1936,69B, 2593-605; Reported the preparation of several 3-aminopyrazole derivatives.This research paper discloses a kind of by process the method that the 2-chlorine-3-aminopyridine prepares 2,3-diamino or 2-alkylamino-3-aminopyridine with ammonia or corresponding alkylamine 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 processing the 3-aminopyridine with the chlorine of new system, obtain the 2-chlorine-3-aminopyridine, and follow a small amount of 2,6-dichloropyridine and 2,4,5,6-4 chloro pyridine.
Reported that with WO 2004069802 disclosed PCT applications a kind of three one step process are with the pyridine compounds that 2-amino-3-replaces of preparation formula (IV).The 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 the character of catalyzer coordination; The X=halogen), then by removing copper with sulfide removal from reaction mixture, and from the salt of reaction liquid (not comprising copper) preparation compound IV, the pyridine (IV) that replaces by separate 2-amino-3-with alkaline purification subsequently.
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, then 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.
The disclosed method of prior art comprises the diaminopyridine derivatives that preparation is impure, and it needs multistep with the required derivative of extraction and fractionation.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 harmful and the inappropriate catalysts and solvents of industry, thereby so that they are 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, 2,3 diamino pyridine or derivatives thereof or its salt of method to have high purity and high yield for the large-scale industry manufacturing that needs a kind of commerce of exploitation and economically practicality.
Therefore the invention provides the scheme that solves above-mentioned prior art problem, the present invention uses Innovative 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 the method is so that 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 the 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 the 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 the method is included under the existence of Cu catalyzer and ammonia pressure 1-5kg/cm
2Lower 3-amino with ammoniacal liquor amination formula (II)-2-haloperidid, its derivative or its salt, and at 100-150 ℃ temperature range and the pressure 18-25kg/cm of spontaneous generation
2Lower this reactant of heating is 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 the 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), the method is included under the existence of catalyzer and ammonia pressure 1-5kg/cm
2Lower, with the 3-amino of ammoniacal liquor amination formula (II)-2-haloperidid, its derivative or its salt, 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 protect, 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, the method has been eliminated undesirable treatment step, thus so that the 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 method for 2,3 diamino pyridine, its derivative or its salt of the improved formula (I) that has high purity and high yield for industrial production 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, the 3-amino by amination formula (II)-2-haloperidid, its derivative or its salt prepare,
Wherein R is hydrogen or C
1-C
3The straight or branched alkyl, and wherein X is halogen, it is selected from chlorine or bromine.
Described method is included in copper (Cu) catalyzer and exists under lower and the ammonia pressure, the 3-amino of usefulness ammoniacal liquor amination formula (II)-2-haloperidid, its derivative or its salt, and 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 the 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
2Lower, temperature range 100-150 ℃, more preferably be 115-140 ℃ of heating 7-10 hour in temperature range, to obtain thick 2,3 diamino pyridine.
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, acetic acid 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-chlorine-3-aminopyridine (23gm); CuSO
45H
2O (9.2gm) and ammonia solution (25%; 230m1) 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
2Lower maintenance 8 hours.After reaction is finished, reaction mixture is slowly cooled to envrionment temperature simultaneously excessive ammonia is discharged, washing (scrubbed) and recirculation.Then at 50-55 ℃ product is extracted from reactant with ethyl acetate (190ml).At the envrionment temperature collected organic layer and distill the ethyl acetate that 60-70% adds, then this material is cooled to approximately 5-8 ℃.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 2,3 diamino pyridine
With 2-chlorine-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
2Lower maintenance 8 hours.After reaction is finished, reaction mixture is slowly cooled to envrionment temperature, simultaneously excessive ammonia is discharged, washing and recirculation.Then at 50-55 ℃ product is extracted from reactant with ethyl acetate (190ml).At the envrionment temperature collected organic layer and distill the ethyl acetate that 60-70% adds, then this material is cooled to approximately 5-8 ℃.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 at present preferred forms of the present invention) 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 2,3 diamino pyridine of preparation formula (I) or the method for its salt,
The method comprises:
In the presence of catalyzer and ammonia pressure be 1-5kg/cm
2Descend the 3-amino of usefulness ammoniacal liquor amination formula (II)-2-haloperidid or its salt;
Pressure 18-25kg/cm in 100-150 ℃ temperature range and spontaneous generation
2Lower this reactant of heating 7-10 hour is to form crude product 2,3 diamino pyridine or its salt; With
Extraction 2,3 diamino pyridine or its salt from reactant with an organic solvent in one step is with 2 of the formula (I) that obtains purified form, 3-diamino-pyridine or its salt, the 2,3 diamino pyridine of wherein said purified form or its salt have the purity greater than 99.5%
Wherein, R is hydrogen or C
1-C
3The straight or branched alkyl, and,
Wherein X is halogen, and it is selected from chlorine or bromine.
2. according to claim 1 method, wherein said catalyzer is copper catalyst, it is selected from cuprous sulfate, cuprous chloride, cupric chloride, cupric bromide.
3. according to claim 2 method, wherein said catalyzer is cuprous sulfate.
4. according to claim 1 method, wherein said ammonia pressure is 2-4kg/cm
2
5. according to claim 1 method, wherein said temperature range is 115-140 ℃.
6. according to claim 1 method, use therein organic solvent is selected from ethyl acetate, butylacetate, acetic acid diisopropyl ester and butanols.
7. according to claim 6 method, wherein said organic solvent is ethyl acetate.
8. according to claim 1 method, but wherein said ammonia is recirculation.
9. according to claim 1 method, but wherein said organic solvent is recirculation.
10. according to claim 1 method, wherein said method is applicable to make with less time large-scale industry the 2,3 diamino pyridine of pure formula (I).
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| 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 |
| CN102993090B (en) * | 2012-10-11 | 2014-09-03 | 南通市华峰化工有限责任公司 | Method for synthesizing 2,6-diamino pyridine |
| 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 |
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| 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 |
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| DE102009022830A1 (en) | 2010-04-29 |
| DE102009022830B4 (en) | 2013-07-04 |
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