JP2005170848A - Method for producing 2,3-diaminopyridines - Google Patents
Method for producing 2,3-diaminopyridines Download PDFInfo
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- JP2005170848A JP2005170848A JP2003412887A JP2003412887A JP2005170848A JP 2005170848 A JP2005170848 A JP 2005170848A JP 2003412887 A JP2003412887 A JP 2003412887A JP 2003412887 A JP2003412887 A JP 2003412887A JP 2005170848 A JP2005170848 A JP 2005170848A
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- benzylamino
- diaminopyridines
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- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical class NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 29
- SLCKILPMRGVCQV-UHFFFAOYSA-N 2-n-benzylpyridine-2,3-diamine Chemical class NC1=CC=CN=C1NCC1=CC=CC=C1 SLCKILPMRGVCQV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000003939 benzylamines Chemical class 0.000 claims 1
- 238000000605 extraction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 16
- -1 methanesulfonic acid Chemical compound 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- 229940045803 cuprous chloride Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AGAHWZHAFZCJIB-UHFFFAOYSA-N 2-N-benzyl-4-methylpyridine-2,3-diamine Chemical compound CC1=CC=NC(NCC=2C=CC=CC=2)=C1N AGAHWZHAFZCJIB-UHFFFAOYSA-N 0.000 description 1
- HPXDGDPSTGMDLP-UHFFFAOYSA-N 2-N-benzyl-6-methylpyridine-2,3-diamine Chemical compound CC1=CC=C(N)C(NCC=2C=CC=CC=2)=N1 HPXDGDPSTGMDLP-UHFFFAOYSA-N 0.000 description 1
- JBLXDGXBSZYHKF-UHFFFAOYSA-N 2-n-benzyl-5-methylpyridine-2,3-diamine Chemical compound NC1=CC(C)=CN=C1NCC1=CC=CC=C1 JBLXDGXBSZYHKF-UHFFFAOYSA-N 0.000 description 1
- GKSMTEMNWWAJRD-UHFFFAOYSA-N 2h-pyrimidine-1,2-diamine Chemical class NC1N=CC=CN1N GKSMTEMNWWAJRD-UHFFFAOYSA-N 0.000 description 1
- UYMYMHQOWIHQKU-UHFFFAOYSA-N 4-methoxypyridine-2,3-diamine Chemical compound COC1=CC=NC(N)=C1N UYMYMHQOWIHQKU-UHFFFAOYSA-N 0.000 description 1
- RWGGFJXJRPCCGD-UHFFFAOYSA-N 4-methylpyridine-2,3-diamine Chemical compound CC1=CC=NC(N)=C1N RWGGFJXJRPCCGD-UHFFFAOYSA-N 0.000 description 1
- FVKXLPMRQXMHBX-UHFFFAOYSA-N 4-propan-2-ylpyridine-2,3-diamine Chemical compound CC(C)C1=CC=NC(N)=C1N FVKXLPMRQXMHBX-UHFFFAOYSA-N 0.000 description 1
- QLUQKHWXZSHTAD-UHFFFAOYSA-N 4-propylpyridine-2,3-diamine Chemical compound CCCC1=CC=NC(N)=C1N QLUQKHWXZSHTAD-UHFFFAOYSA-N 0.000 description 1
- QQEYMWZZKHKJGZ-UHFFFAOYSA-N 5-methoxypyridine-2,3-diamine Chemical compound COC1=CN=C(N)C(N)=C1 QQEYMWZZKHKJGZ-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
- ODALQHSKXQSKJQ-UHFFFAOYSA-N 5-propan-2-ylpyridine-2,3-diamine Chemical compound CC(C)C1=CN=C(N)C(N)=C1 ODALQHSKXQSKJQ-UHFFFAOYSA-N 0.000 description 1
- CEKDTXIEMMVPSX-UHFFFAOYSA-N 5-propylpyridine-2,3-diamine Chemical compound CCCC1=CN=C(N)C(N)=C1 CEKDTXIEMMVPSX-UHFFFAOYSA-N 0.000 description 1
- RRGXMFDOWYZQSZ-UHFFFAOYSA-N 6-ethylpyridine-2,3-diamine Chemical compound CCC1=CC=C(N)C(N)=N1 RRGXMFDOWYZQSZ-UHFFFAOYSA-N 0.000 description 1
- WEPOCTWSRWLQLL-UHFFFAOYSA-N 6-methoxypyridine-2,3-diamine Chemical compound COC1=CC=C(N)C(N)=N1 WEPOCTWSRWLQLL-UHFFFAOYSA-N 0.000 description 1
- XATOCNYGIWXIQM-UHFFFAOYSA-N 6-methylpyridine-2,3-diamine Chemical compound CC1=CC=C(N)C(N)=N1 XATOCNYGIWXIQM-UHFFFAOYSA-N 0.000 description 1
- WFHZWBPYSWPMAR-UHFFFAOYSA-N 6-propan-2-ylpyridine-2,3-diamine Chemical compound CC(C)C1=CC=C(N)C(N)=N1 WFHZWBPYSWPMAR-UHFFFAOYSA-N 0.000 description 1
- HUEGRMDMHNLENZ-UHFFFAOYSA-N 6-propylpyridine-2,3-diamine Chemical compound CCCC1=CC=C(N)C(N)=N1 HUEGRMDMHNLENZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
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- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、２，３−ジアミノピリジン類の製造方法に関する。 The present invention relates to a method for producing 2,3-diaminopyridines.
従来より、２，３−ジアミノピリジン類が、アンギオテンシンII拮抗剤、縮合イミダゾール系化合物等の医薬品の中間体として有用な化合物であることが知られている。２，３−ジアミノピリジン類の製造方法としては例えば、
（ｉ） ３−アミノピリジンとソーダアミドとを反応させることにより製造する方法。
（ｉｉ） ３−アミノ−２−クロロピリジンをアンモニア水の存在下で反応させることにより製造する方法。
が知られている（例えば、非特許文献１および非特許文献２参照。）。また、２，３−ジアミノピリジン類の酸付加塩の製造方法としては例えば、２−アミノ−３−ニトロ−５−ハロピリジン類をパラジウム触媒の存在下、水素ガス中で脱ハロゲン化及び還元を行った後、無機酸を加える方法が知られている（例えば、特許文献１参照。）
Conventionally, 2,3-diaminopyridines are known to be useful compounds as intermediates for pharmaceuticals such as angiotensin II antagonists and condensed imidazole compounds. As a production method of 2,3-diaminopyridines, for example,
(I) A method of producing by reacting 3-aminopyridine and sodaamide.
(Ii) A process for producing 3-amino-2-chloropyridine by reacting in the presence of aqueous ammonia.
Is known (see, for example, Non-Patent Document 1 and Non-Patent Document 2). As a method for producing an acid addition salt of 2,3-diaminopyridines, for example, 2-amino-3-nitro-5-halopyridines are dehalogenated and reduced in hydrogen gas in the presence of a palladium catalyst. After that, a method of adding an inorganic acid is known (see, for example, Patent Document 1).
しかしながら、２，３−ジアミノピリミジン類は水溶性を有するために、従来の製造方法においては副生する無機物質等の水溶性物質との分離のために、極めて大量の有機溶媒を用いての抽出操作が必要とされるなど、製造効率の点で重大な問題があった。
本発明は水溶性を有する２，３−ジアミノピリジン類の単離を簡便に行うために、抽出操作を必要としない新たな製造方法を提供することを課題とする。
However, since 2,3-diaminopyrimidines are water-soluble, extraction with a very large amount of organic solvent is required for separation from water-soluble substances such as inorganic substances by-produced in the conventional production method. There were serious problems in terms of production efficiency, such as the need for operation.
An object of the present invention is to provide a new production method that does not require an extraction operation in order to easily isolate 2,3-diaminopyridines having water solubility.
本発明者等は、これらの課題を解決するため鋭意検討した結果、２，３−ジアミノピリジン類の単離において、抽出操作を必要としない新たな製造方法を見出し、本発明の完成に至った。
即ち、本発明は式（１）
式（２）
で示される２，３−ジアミノピリジン類の製造方法（本発明製造方法（Ｉ）と記す。）、及び
式（３）
式（４）
That is, the present invention provides the formula (1)
And a method for producing 2,3-diaminopyridines represented by formula (3).
Formula (4)
本発明の製造方法により、水溶性を有する２，３−ジアミノピリジン類を効率的に製造及び単離することが可能である。 By the production method of the present invention, 2,3-diaminopyridines having water solubility can be efficiently produced and isolated.
本発明について以下に説明する。 The present invention will be described below.
本発明製造方法（Ｉ）
式（２）で示される２，３−ジアミノピリジン類は、式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類をパラジウム触媒の存在下で水素と反応させることにより製造することができる。
該反応は通常溶媒の存在下で行われる。
反応に用いられる溶媒としては、例えばトルエン、キシレン等の芳香族炭化水素類、酢酸エチル、酢酸ブチル等の脂肪族エステル類、メタノール、エタノール、イソプロパノール、ｎ−ブタノール等のアルコール類、水及びこれらの混合物があげられ、好ましくは水、イソプロパノール、水とトルエンとの混合物があげられる。
該反応に用いられる溶媒の量は、溶媒により異なるが、式（１）で示される化合物１重量部に対して、通常１〜１０重量部の範囲であり、好ましくは２〜５重量部の範囲である。
該反応に用いられるパラジウム触媒としては、金属パラジウム、水酸化パラジウム、酸化パラジウムなどが挙げられるが、好ましくは金属パラジウムが挙げられる。金属パラジウムはそのものを用いてもよいが、通常は活性炭、アルミナ及びシリカ等の担体に担持された金属パラジウムが用いられる。この場合、金属パラジウムと担体との割合はパラジウムが担体に対して、通常０．５〜２５重量％の範囲となる割合である。
該反応に用いられるパラジウム触媒の量は、式（１）で示される化合物１重量部に対して、担持されているパラジウム触媒の純分として通常０．０００１〜０．０１重量部の割合であり、好ましくは０．００１〜０．００５重量部の割合である。
該反応の反応温度は通常５０〜２００℃の範囲であり、好ましくは８０〜１３０℃の範囲である。反応温度が５０℃より低温である場合には反応の進行に長時間を要することになる。
該反応は常圧で行うことができるが、加圧下で行うこともできる。反応圧は通常常圧〜１０ＭＰａの範囲であり、好ましくは４〜６ＭＰａの範囲である。
反応終了後は、反応混合物を濾過して、その濾液を濃縮する等の後処理操作を行うことにより式（２）で示される化合物を単離することができる。単離された式（２）で示される化合物は、再結晶等によりさらに精製することもできる。
再結晶操作に用いられる溶媒としては、例えばトルエン、キシレン等の芳香族炭化水素類、酢酸エチル、酢酸ブチル等のエステル類、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール等のアルコール類、ペンタン、ヘキサン、ヘプタン、オクタン等の脂肪族炭化水素類、水及びこれらの混合物があげられるが、好ましくは芳香族炭化水素類とアルコール類との混合物、より好ましくはトルエンとブタノールとの混合物である。
Manufacturing method (I) of the present invention
2,3-diaminopyridines represented by the formula (2) are produced by reacting 3-amino-2- (benzylamino) pyridines represented by the formula (1) with hydrogen in the presence of a palladium catalyst. be able to.
The reaction is usually performed in the presence of a solvent.
Examples of the solvent used in the reaction include aromatic hydrocarbons such as toluene and xylene, aliphatic esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, isopropanol, and n-butanol, water, and these. Examples of the mixture include water, isopropanol, and a mixture of water and toluene.
The amount of the solvent used in the reaction varies depending on the solvent, but is usually in the range of 1 to 10 parts by weight, preferably in the range of 2 to 5 parts by weight with respect to 1 part by weight of the compound represented by the formula (1). It is.
Examples of the palladium catalyst used in the reaction include metal palladium, palladium hydroxide, palladium oxide, and the like, and preferably metal palladium. Although metallic palladium itself may be used, metallic palladium supported on a carrier such as activated carbon, alumina and silica is usually used. In this case, the ratio of metallic palladium to the carrier is such that palladium is usually in the range of 0.5 to 25% by weight with respect to the carrier.
The amount of the palladium catalyst used in the reaction is usually 0.0001 to 0.01 part by weight as a pure part of the supported palladium catalyst with respect to 1 part by weight of the compound represented by the formula (1). The ratio is preferably 0.001 to 0.005 parts by weight.
The reaction temperature of the reaction is usually in the range of 50 to 200 ° C, preferably in the range of 80 to 130 ° C. When the reaction temperature is lower than 50 ° C., it takes a long time for the reaction to proceed.
The reaction can be performed at normal pressure, but can also be performed under pressure. The reaction pressure is usually in the range of normal pressure to 10 MPa, preferably in the range of 4 to 6 MPa.
After completion of the reaction, the compound represented by the formula (2) can be isolated by performing post-treatment operations such as filtering the reaction mixture and concentrating the filtrate. The isolated compound represented by the formula (2) can be further purified by recrystallization or the like.
Examples of the solvent used for the recrystallization operation include aromatic hydrocarbons such as toluene and xylene, esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, propanol, isopropanol, and butanol, pentane, hexane, Examples thereof include aliphatic hydrocarbons such as heptane and octane, water, and a mixture thereof, preferably a mixture of aromatic hydrocarbons and alcohols, more preferably a mixture of toluene and butanol.
本発明製造方法（ＩＩ）
式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類は、式（３）で示される化合物と式（４）で示されるベンジルアミン類とを反応させることにより製造することができる。
該反応は通常溶媒の存在下で行われる。
反応に用いられる溶媒としては、例えばメタノール、エタノール、イソプロパノール、ブタノール等のアルコール類、水及びこれらの混合物があげられる。
該反応は酸又は銅触媒の存在下で行うことにより、反応時間の短縮及び／又は反応収率の向上が可能となる。
反応に用いられる酸としては、例えば塩酸及び硫酸等の鉱酸類、メタンスルホン酸等のスルホン酸類、酢酸等のカルボン酸類があげられ、好ましくは鉱酸類があげられ、さらに好ましくは塩酸があげられる。
反応に用いられる酸の量は、式（３）で示される化合物１モルに対して、通常０．１〜２モルの範囲であり、好ましくは０．８〜１．２モルの範囲である。
反応に用いられる式（４）で示されるベンジルアミン類の量は、式（３）で示される化合物１モルに対して、通常１〜５モルの範囲であり、好ましくは１．５〜３モルの範囲である。式（４）で示されるベンジルアミン類の使用量が５モルより多いと、式（４）で示されるベンジルアミン類と式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類との分離回収操作が必要となり、工業的に不利である。
反応に用いられる銅触媒としては例えば塩化第一銅、臭化第一銅、沃化第一銅等のハロゲン化第一銅類、酸化第一銅、硫酸銅及び銅粉末が挙げられ、好ましくはハロゲン化第一銅が挙げられ、より好ましくは塩化第一銅が挙げられる。
該反応に銅触媒を用いる場合には、式（３）で示される化合物１モルに対して、銅触媒が通常０．０１〜０．５モルの範囲であり、好ましくは０．０５〜０．１モルの範囲である。
該反応の反応温度は、通常１５０〜２００℃の範囲であり、好ましくは１６０〜１９０℃の範囲である。反応温度が１５０℃より低温である場合には反応の進行に長時間を要することになり、また反応温度が２００℃より高温である場合には副生成物が増加し、収率は低下する。
Production method of the present invention (II)
3-Amino-2- (benzylamino) pyridines represented by the formula (1) can be produced by reacting a compound represented by the formula (3) with a benzylamine represented by the formula (4). it can.
The reaction is usually performed in the presence of a solvent.
Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, isopropanol and butanol, water, and mixtures thereof.
By performing the reaction in the presence of an acid or a copper catalyst, the reaction time can be shortened and / or the reaction yield can be improved.
Examples of the acid used in the reaction include mineral acids such as hydrochloric acid and sulfuric acid, sulfonic acids such as methanesulfonic acid, and carboxylic acids such as acetic acid, preferably mineral acids, and more preferably hydrochloric acid.
The amount of the acid used in the reaction is usually in the range of 0.1 to 2 mol, preferably in the range of 0.8 to 1.2 mol, with respect to 1 mol of the compound represented by the formula (3).
The amount of the benzylamine represented by the formula (4) used in the reaction is usually in the range of 1 to 5 mol, preferably 1.5 to 3 mol, relative to 1 mol of the compound represented by the formula (3). Range. When the amount of the benzylamine represented by the formula (4) is more than 5 mol, the benzylamine represented by the formula (4) and the 3-amino-2- (benzylamino) pyridine represented by the formula (1) This is industrially disadvantageous.
Examples of the copper catalyst used in the reaction include cuprous halides such as cuprous chloride, cuprous bromide and cuprous iodide, cuprous oxide, copper sulfate and copper powder, preferably A cuprous halide is mentioned, More preferably, a cuprous chloride is mentioned.
When a copper catalyst is used for the reaction, the copper catalyst is usually in the range of 0.01 to 0.5 mol, preferably 0.05 to 0.00 mol, per 1 mol of the compound represented by the formula (3). The range is 1 mol.
The reaction temperature of the reaction is usually in the range of 150 to 200 ° C, preferably in the range of 160 to 190 ° C. When the reaction temperature is lower than 150 ° C., it takes a long time for the reaction to proceed, and when the reaction temperature is higher than 200 ° C., by-products increase and the yield decreases.
反応終了後は、反応混合物に有機溶媒を加えて抽出するが、必要により抽出において水を加えてもよい。また、反応に酸を用いた場合には水酸化ナトリウム、水酸化カリウム等の塩基性水溶液を加えて水層を中和した後、抽出する。得られた有機層を必要に応じて濃縮してから冷却し、生成する結晶を濾過する等の後処理操作を行うことにより式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類を単離することができる。 After completion of the reaction, the reaction mixture is extracted by adding an organic solvent, but if necessary, water may be added in the extraction. When an acid is used in the reaction, the aqueous layer is neutralized by adding a basic aqueous solution such as sodium hydroxide or potassium hydroxide, and then extracted. The resulting organic layer is concentrated as necessary, cooled, and subjected to post-treatment operations such as filtration of the resulting crystals, thereby producing 3-amino-2- (benzylamino) pyridine represented by the formula (1) Can be isolated.
式（２）で示される化合物は、例えば３−アミノ−２−クロロ−４−アルキルピリジンは特許第３１３３３３２号公報に記載された公知化合物であり、該文献に記載の方法に準じて製造することができる。 The compound represented by the formula (2) is, for example, 3-amino-2-chloro-4-alkylpyridine, which is a known compound described in Japanese Patent No. 3133332, and is prepared according to the method described in the document. Can do.
該反応により製造される式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類を用いて本発明製造方法（Ｉ）で反応させることにより、式（２）で示される２，３−ジアミノピリジン類は、式（３）で示される化合物及び式（４）で示されるベンジルアミン類から製造することができる。 By reacting 3-amino-2- (benzylamino) pyridine represented by the formula (1) produced by the reaction in the production method (I) of the present invention, 2, 3-Diaminopyridines can be produced from a compound represented by the formula (3) and a benzylamine represented by the formula (4).
本発明において、Ｒ１及びＲ２で表される
Ｃ１−Ｃ４アルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基及びｓｅｃ−ブチル基があげられ、
Ｃ１−Ｃ４アルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基及びイソブトキシ基があげられ、
Ｘで表されるハロゲン原子としては、例えば塩素原子、臭素原子及びヨウ素原子があげられる。
In the present invention, examples of the C1-C4 alkyl group represented by R 1 and R 2 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec-butyl group.
Examples of the C1-C4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and an isobutoxy group.
Examples of the halogen atom represented by X include a chlorine atom, a bromine atom and an iodine atom.
本発明製造方法（Ｉ）及び本発明製造方法（ＩＩ）に用いられる式（１）で示される３−アミノ−２−（ベンジルアミノ）ピリジン類としては、具体的には下記の化合物があげられる。
３−アミノ−２−（ベンジルアミノ）ピリジン、３−アミノ−２−ベンジルアミノ−４−メチルピリジン、３−アミノ−２−ベンジルアミノ−５−メチルピリジン、３−アミノ−２−ベンジルアミノ−６−メチルピリジン、３−アミノ−２−ベンジルアミノ−４−エチルピリジン、３−アミノ−２−ベンジルアミノ−５−エチルピリジン、３−アミノ−２−ベンジルアミノ−６−エチルピリジン、３−アミノ−２−ベンジルアミノ−４−プロピルピリジン、３−アミノ−２−ベンジルアミノ−５−プロピルピリジン、３−アミノ−２−ベンジルアミノ−６−プロピルピリジン、３−アミノ−２−ベンジルアミノ−４−イソプロピルピリジン、３−アミノ−２−ベンジルアミノ−５−イソプロピルピリジン、３−アミノ−２−ベンジルアミノ−６−イソプロピルピリジン、３−アミノ−２−ベンジルアミノ−４−メトキシピリジン、３−アミノ−２−ベンジルアミノ−５−メトキシピリジン、３−アミノ−２−ベンジルアミノ−６−メトキシピリジン。
Specific examples of the 3-amino-2- (benzylamino) pyridine represented by the formula (1) used in the production method (I) and the production method (II) of the present invention include the following compounds. .
3-amino-2- (benzylamino) pyridine, 3-amino-2-benzylamino-4-methylpyridine, 3-amino-2-benzylamino-5-methylpyridine, 3-amino-2-benzylamino-6 -Methylpyridine, 3-amino-2-benzylamino-4-ethylpyridine, 3-amino-2-benzylamino-5-ethylpyridine, 3-amino-2-benzylamino-6-ethylpyridine, 3-amino- 2-benzylamino-4-propylpyridine, 3-amino-2-benzylamino-5-propylpyridine, 3-amino-2-benzylamino-6-propylpyridine, 3-amino-2-benzylamino-4-isopropyl Pyridine, 3-amino-2-benzylamino-5-isopropylpyridine, 3-amino-2-benzylamino- - isopropyl pyridine, 3-amino-2-benzylamino-4-methoxypyridine, 3-amino-2-benzylamino-5-methoxypyridine, 3-amino-2-benzylamino-6-methoxypyridine.
本発明製造方法（Ｉ）及び本発明製造方法（ＩＩ）に製造される式（２）で示される２，３−ジアミノピリジン類としては、具体的には下記の化合物があげられる。
２，３−ジアミノピリジン、２，３−ジアミノ−４−メチルピリジン、２，３−ジアミノ−５−メチルピリジン、２，３−ジアミノ−６−メチルピリジン、２，３−ジアミノ−４−エチルピリジン、２，３−ジアミノ−５−エチルピリジン、２，３−ジアミノ−６−エチルピリジン、２，３−ジアミノ−４−プロピルピリジン、２，３−ジアミノ−５−プロピルピリジン、２，３−ジアミノ−６−プロピルピリジン、２，３−ジアミノ−４−イソプロピルピリジン、２，３−ジアミノ−５−イソプロピルピリジン、２，３−ジアミノ−６−イソプロピルピリジン、２，３−ジアミノ−４−メトキシピリジン、２，３−ジアミノ−５−メトキシピリジン、２，３−ジアミノ−６−メトキシピリジン。
Specific examples of the 2,3-diaminopyridines represented by the formula (2) produced by the production method (I) and the production method (II) of the present invention include the following compounds.
2,3-diaminopyridine, 2,3-diamino-4-methylpyridine, 2,3-diamino-5-methylpyridine, 2,3-diamino-6-methylpyridine, 2,3-diamino-4-ethylpyridine 2,3-diamino-5-ethylpyridine, 2,3-diamino-6-ethylpyridine, 2,3-diamino-4-propylpyridine, 2,3-diamino-5-propylpyridine, 2,3-diamino -6-propylpyridine, 2,3-diamino-4-isopropylpyridine, 2,3-diamino-5-isopropylpyridine, 2,3-diamino-6-isopropylpyridine, 2,3-diamino-4-methoxypyridine, 2,3-diamino-5-methoxypyridine, 2,3-diamino-6-methoxypyridine.
次に、本発明について製造例等の実施例によりさらに詳しく説明するが、本発明はこれらに限定されるものではない。
なお、実施例に記載のＬＣ純度とは、高速液体クロマトグラフィーにおける面積百分率法により求められた数値を表す。
Next, the present invention will be described in more detail with reference to examples such as production examples, but the present invention is not limited thereto.
In addition, LC purity as described in an Example represents the numerical value calculated | required by the area percentage method in a high performance liquid chromatography.
製造例１
１Ｌガラス耐圧反応器に、３−アミノ−２−クロロピリジン１８０．０ｇ（１．４００モル）、ベンジルアミン３００．０ｇ（２．８００モル）及び３５％塩酸１４５．６ｇ（１．４００モル）を加えて密閉し、１７０℃で２０時間保温した。その後、８０℃で反応混合物に水２８３．８ｇを加えた。高速液体クロマトグラフィーにて分析した結果、３−アミノ−２−（ベンジルアミノ）ピリジンが収率９１．２％で生成した。
該混合液にトルエン４５０．０ｇを加えた後、４８％水酸化ナトリウム水溶液１１６．７ｇ（１．４００モル）を加えｐＨ８とした。その後昇温して７０℃で分液して、得られた有機層を２３３．３ｇの水で７０℃にて洗浄した後、有機層を１０℃に冷却して生成した結晶を濾別した。得られた結晶をトルエンで洗浄後、減圧乾燥して３−アミノ−２−（ベンジルアミノ）ピリジンを２００．９ｇ（ＬＣ純度９８．６％）を得た。収率７１．０％。
Production Example 1
In a 1 L glass pressure-resistant reactor, 180.0 g (1.400 mol) of 3-amino-2-chloropyridine, 300.0 g (2.800 mol) of benzylamine and 145.6 g (1.400 mol) of 35% hydrochloric acid were added. In addition, it was sealed and kept at 170 ° C. for 20 hours. Thereafter, 283.8 g of water was added to the reaction mixture at 80 ° C. As a result of analysis by high performance liquid chromatography, 3-amino-2- (benzylamino) pyridine was produced in a yield of 91.2%.
After adding 450.0 g of toluene to the mixed solution, 116.7 g (1.400 mol) of 48% aqueous sodium hydroxide solution was added to adjust the pH to 8. Thereafter, the temperature was raised and liquid separation was carried out at 70 ° C., and the obtained organic layer was washed with 233.3 g of water at 70 ° C., and then the organic layer was cooled to 10 ° C. and the produced crystals were separated by filtration. The obtained crystals were washed with toluene and dried under reduced pressure to obtain 200.9 g (LC purity 98.6%) of 3-amino-2- (benzylamino) pyridine. Yield 71.0%.
比較製造例１
３５％塩酸１４５．６ｇの代わりに水９４．６ｇを用いた以外は製造例１と同様の操作で反応を行った。高速液体クロマトグラフィーにて分析した結果、３−アミノ−２−（ベンジルアミノ）ピリジンの収率は３９．５％であった。
Comparative production example 1
The reaction was performed in the same manner as in Production Example 1, except that 94.6 g of water was used instead of 145.6 g of 35% hydrochloric acid. As a result of analysis by high performance liquid chromatography, the yield of 3-amino-2- (benzylamino) pyridine was 39.5%.
製造例２
５００ｍｌのオートクレーブに製造例１により得られた３−アミノ−２−（ベンジルアミノ）ピリジン８０．０ｇ（０．３９６モル）、含水率が５０重量％のパラジウム炭素（パラジウム担持量；５重量％）８．０ｇ及び水２４０．０ｇを加えて水素圧４ＭＰａ、１１０℃で６時間保温した。その後、反応混合物を濾過して、濾液を減圧濃縮した。得られた残渣をトルエン／ｎ−ブタノール混合溶媒（トルエン／ｎ−ブタノール＝５重量比）で再結晶操作を行い、析出した結晶を１℃にて濾過した。濾別した結晶を洗浄後、減圧乾燥し、２，３−ジアミノピリジン３１．７ｇ（ＬＣ純度９９．９９％）を得た。収率７３．４％、融点１１６℃。
Production Example 2
80.0 g (0.396 mol) of 3-amino-2- (benzylamino) pyridine obtained in Production Example 1 in a 500 ml autoclave, palladium carbon having a water content of 50% by weight (palladium supported amount: 5% by weight) 8.0 g and 240.0 g of water were added, and the mixture was kept at 6 ° C. and 110 ° C. for 6 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized with a toluene / n-butanol mixed solvent (toluene / n-butanol = 5 weight ratio), and the precipitated crystals were filtered at 1 ° C. The crystals separated by filtration were washed and dried under reduced pressure to obtain 31.7 g (LC purity 99.99%) of 2,3-diaminopyridine. Yield 73.4%, melting point 116 ° C.
製造例３
１Ｌガラス耐圧反応器に、３−アミノ−２−クロロピリジン９６．５ｇ、ベンジルアミン４０１．９ｇ、水９６．５ｇ及び塩化第一銅３．７ｇを加えて密閉し、１７５℃で５時間保温した。その後、反応混合物を冷却した。高速液体クロマトグラフィーにて分析した結果、３−アミノ−２−（ベンジルアミノ）ピリジンが収率３４．３％で生成した。
Production Example 3
To a 1 L glass pressure-resistant reactor, 96.5 g of 3-amino-2-chloropyridine, 401.9 g of benzylamine, 96.5 g of water and 3.7 g of cuprous chloride were added and sealed, and kept at 175 ° C. for 5 hours. . The reaction mixture was then cooled. As a result of analysis by high performance liquid chromatography, 3-amino-2- (benzylamino) pyridine was produced in a yield of 34.3%.
比較製造例２
塩化第一銅を用いなかったこと以外は、製造例３と同様の操作を行った。高速液体クロマトグラフィーにて分析した結果、３−アミノ−２−（ベンジルアミノ）ピリジンが収率７．２％で生成した。
Comparative production example 2
The same operation as in Production Example 3 was performed except that cuprous chloride was not used. As a result of analysis by high performance liquid chromatography, 3-amino-2- (benzylamino) pyridine was produced in a yield of 7.2%.
Claims (4)
式（２）
で示される２，３−ジアミノピリジン類の製造方法。 Formula (1)
The manufacturing method of 2, 3- diamino pyridines shown by these.
式（３）
式（４）
Formula (3)
Formula (4)
The method for producing 2,3-diaminopyridines according to claim 3, wherein the mineral acid is hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003412887A JP2005170848A (en) | 2003-12-11 | 2003-12-11 | Method for producing 2,3-diaminopyridines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003412887A JP2005170848A (en) | 2003-12-11 | 2003-12-11 | Method for producing 2,3-diaminopyridines |
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| Publication Number | Publication Date |
|---|---|
| JP2005170848A true JP2005170848A (en) | 2005-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003412887A Pending JP2005170848A (en) | 2003-12-11 | 2003-12-11 | Method for producing 2,3-diaminopyridines |
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| JP (1) | JP2005170848A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009022830A1 (en) | 2008-10-24 | 2010-04-29 | Jubilant Organosys Ltd. | Preparing 2,3-diaminopyridine compounds, useful e.g. as intermediates to produce pharmaceutical compounds, comprises aminating 3-amino-2-halopyridine compounds with aqueous ammonia in the presence of catalyst, heating and extracting |
| 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 |
-
2003
- 2003-12-11 JP JP2003412887A patent/JP2005170848A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009022830A1 (en) | 2008-10-24 | 2010-04-29 | Jubilant Organosys Ltd. | Preparing 2,3-diaminopyridine compounds, useful e.g. as intermediates to produce pharmaceutical compounds, comprises aminating 3-amino-2-halopyridine compounds with aqueous ammonia in the presence of catalyst, heating and extracting |
| 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 |
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