KR830000676B1 - N ^ 2, N ^ 4, N ^ 6, -tris (substituted) -melamine production method - Google Patents
N ^ 2, N ^ 4, N ^ 6, -tris (substituted) -melamine production method Download PDFInfo
- Publication number
- KR830000676B1 KR830000676B1 KR1019790001126A KR790001126A KR830000676B1 KR 830000676 B1 KR830000676 B1 KR 830000676B1 KR 1019790001126 A KR1019790001126 A KR 1019790001126A KR 790001126 A KR790001126 A KR 790001126A KR 830000676 B1 KR830000676 B1 KR 830000676B1
- Authority
- KR
- South Korea
- Prior art keywords
- azabicyclo
- nonyl
- alkyl
- endo
- octyl
- Prior art date
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- -1 (substituted) -melamine Chemical class 0.000 title claims description 88
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000007983 Tris buffer Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical group C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000011968 lewis acid catalyst Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000000539 dimer Substances 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000013638 trimer Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 238000009966 trimming Methods 0.000 claims 1
- 210000003708 urethra Anatomy 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 40
- 238000002360 preparation method Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- 239000002904 solvent Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 8
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000011521 glass Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- RKMAYERHOYIOBY-UHFFFAOYSA-N 6-chloro-2-n,4-n-bis(2,3,3-trimethylbutan-2-yl)-1,3,5-triazine-2,4-diamine Chemical compound CC(C)(C)C(C)(C)NC1=NC(Cl)=NC(NC(C)(C)C(C)(C)C)=N1 RKMAYERHOYIOBY-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 206010003246 arthritis Diseases 0.000 description 6
- 239000002026 chloroform extract Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LICHZOBEUWVYSY-UHFFFAOYSA-N 3-azabicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CNC2 LICHZOBEUWVYSY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical group NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- PSQTVCAGKGYMJL-UHFFFAOYSA-N 4-(3-azabicyclo[3.2.2]nonan-3-yl)-6-chloro-n-(2,4,4-trimethylpentan-2-yl)-1,3,5-triazin-2-amine Chemical compound CC(C)(C)CC(C)(C)NC1=NC(Cl)=NC(N2CC3CCC(CC3)C2)=N1 PSQTVCAGKGYMJL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 229920000877 Melamine resin Polymers 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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- 238000005576 amination reaction Methods 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 150000001912 cyanamides Chemical class 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 238000010438 heat treatment Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
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- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 2
- QHZRZIWCGRXBRY-UHFFFAOYSA-N 2-methylhexan-2-amine Chemical compound CCCCC(C)(C)N QHZRZIWCGRXBRY-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- ZZNBOSYIBLHVCM-UHFFFAOYSA-N 3-[4-(3-azabicyclo[3.2.2]nonan-3-yl)-6-chloro-1,3,5-triazin-2-yl]-3-azabicyclo[3.2.2]nonane Chemical compound C1CC(C2)CCC1CN2C1=NC(N2CC3CCC(CC3)C2)=NC(Cl)=N1 ZZNBOSYIBLHVCM-UHFFFAOYSA-N 0.000 description 2
- CHRAJVQLWOMYQI-UHFFFAOYSA-N 5,8,8-trimethyl-3-azabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1(C)C2(C)C CHRAJVQLWOMYQI-UHFFFAOYSA-N 0.000 description 2
- IJMIBYDSWAUWFS-UHFFFAOYSA-N 6-(9-azabicyclo[3.3.1]nonan-5-yl)-2-n,4-n-bis(2,3,3-trimethylbutan-2-yl)-1,3,5-triazine-2,4-diamine Chemical compound CC(C)(C)C(C)(C)NC1=NC(NC(C)(C)C(C)(C)C)=NC(C23CCCC(CCC2)N3)=N1 IJMIBYDSWAUWFS-UHFFFAOYSA-N 0.000 description 2
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- WSTHFRSMWSASTE-UHFFFAOYSA-N 5-[4,6-bis(4-azabicyclo[3.2.2]nonan-5-yl)-1,3,5-triazin-2-yl]-4-azabicyclo[3.2.2]nonane Chemical compound C1CC(CCN2)CCC12C1=NC(C23CCC(CC2)CCN3)=NC(C23CCC(CC3)CCN2)=N1 WSTHFRSMWSASTE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 하기 구조식(I)로 표시되는 신규한 유기 화함물안 N2,N4,N6-트리스(치환)-멜라미류의 제조방법에 관한 것이다.The present invention relates to a method for producing N 2 , N 4 , N 6 -tris (substituted) -melamis in a novel organic compound represented by the following structural formula (I).
상기식에서 R1은 C4∼C8의 알킬아미노기로 예컨대 1-아다만틸 아미노, 2-아다만틸아미노, 엑소[2,2,1]-노르보닐아미노, 엔도[2,2,1] 노르보닐아미노, 3-아자비시클로 [3,2,1]-옥틸, 1,8,8-트리메틸-3-아자비시클로[3,2,1] 옥틸, 3-아자비시클로 [3,3,1] 노닐, 9-아자비시클로 [3,3,1] 노닐, 2-아자비시클로[3,2,2] 노년, 3-아자비시클로[3,2,2]노닐, 또는 엔도-3-히드록시-8-아자비시클로[3,2,1]옥트-8-일이 포함되며:Wherein R 1 is a C 4 to C 8 alkylamino group such as 1-adamantyl amino, 2-adamantylamino, exo [2,2,1] -norbornylamino, endo [2,2,1] Norbornylamino, 3-azabicyclo [3,2,1] -octyl, 1,8,8-trimethyl-3-azabicyclo [3,2,1] octyl, 3-azabicyclo [3,3,1] Nonyl, 9-azabicyclo [3,3,1] nonyl, 2-azabicyclo [3,2,2] old age, 3-azabicyclo [3,2,2] nonyl, or endo-3-hydroxy-8 Azabicyclo [3,2,1] oct-8-yl, including:
R2는 1-아다만틸아미노, 2-아다만틸아미노, 엑소[2,2,1]-노르보닐아미노, 엔도[2,2,1] 노르보닐아미노, 3-아자비시클로 [3,2,1]옥틸, 1,8,8-트리메틸-3-아자비시클로 [3,2,1]옥틸, 3-아자비시클로[3,3,1]노닐, 9-아자비시클로 [3,3,1]노닐, 3-아자비시클로[3,3,1]노닐, 9-아자비시클로[3,2,2]노닐 또는 엔도 -3-히드록시-8-아자비시클로[3,2,1]옥트-8-일이며 :R 2 is 1-adamantylamino, 2-adamantylamino, exo [2,2,1] -norbornylamino, endo [2,2,1] norbornylamino, 3-azabicyclo [3,2 , 1] octyl, 1,8,8-trimethyl-3-azabicyclo [3,2,1] octyl, 3-azabicyclo [3,3,1] nonyl, 9-azabicyclo [3,3,1] Nonyl, 3-azabicyclo [3,3,1] nonyl, 9-azabicyclo [3,2,2] nonyl or endo-3-hydroxy-8-azabicyclo [3,2,1] oct-8- Is and:
R3는 수소, C4까지의 알킬이며;R 3 is hydrogen, alkyl up to C 4 ;
R4는 2-(2-피리딜) 에틸 C4∼C8의 알킬로서 페닐, 모노할로 [F, Cl, Br] 페닐, 1-아다만틸, 2-아다만틸, 엑소[2,2,1] 노르보닐, 엔도[2,2,1]노르보닐 또는 구조식
(Q는-(CH2)2-, -(CH2)3-,
R6는 C4까지의 알킬이며, R5와 R6는 그들에 연결된 질소원자와 함께 피페리디노, 모르폴리노, 피롤리디노, 또는 티오모르폴리노를 형성한다) 단 R4가 알킬, 아다만틸 또는 노르보닐인 경우 R3는 수소여야하며 R3와 R4는 그들에 연결되어 있는 질소원자와 함께 3-아자비스클로[3,2,1]옥틸, 1,8,8-트리메틸-3-아자비시클로[3,2,1]옥틸, 3-아자비시클로[3,3,1]노닐, 9-아자비시클로[3,3,1]-노닐, 2-아자비시클로[3,2,2]노닐, 3-아자비시클로[3,2,2] 노닐, 엔도-3-히드록시-8-아자비시클로[3,2,1]옥트-8-일, 피롤리디노, 피페리디노, 헥틸렌이미노, 헵타메틸렌 이미노 또는 구조식,R 6 is alkyl up to C 4 , and R 5 and R 6 together with the nitrogen atom connected to them form piperidino, morpholino, pyrrolidino, or thiomorpholino) provided that R 4 is alkyl, In the case of adamantyl or norbornyl, R 3 must be hydrogen and R 3 and R 4 together with the nitrogen atom connected to them are 3-azabislo [3,2,1] octyl, 1,8,8-trimethyl 3-azabicyclo [3,2,1] octyl, 3-azabicyclo [3,3,1] nonyl, 9-azabicyclo [3,3,1] -nonyl, 2-azabicyclo [3,2, 2] nonyl, 3-azabicyclo [3,2,2] nonyl, endo-3-hydroxy-8-azabicyclo [3,2,1] oct-8-yl, pyrrolidino, piperidino, hex Thilenimino, heptamethylene imino or a structural formula,
(여기서 R은 수소, C4까지의 알킬, 페닐, P-메톡시페닐 또는 C4까지의 카트보알콕시기임)의 1가 성분을 형성한다.To form a monovalent component of hydrogen, alkyl up to C 4 , phenyl, P-methoxyphenyl or cartboalkoxy up to C 4 .
본 발명의 신규화합물은 특정 융점각 흡수스펙트라를 가진 결정성물질로 얻어진다. 이들은 저급알카놀, 아세톤, 초산에틸과 같은 많은 유기용매에 잘 녹으나 물에는 일반적으로 불용이다. 이들 화합물은 치환기-NR3R4가 염기성질소원자를 함유하는 각종 유기 및 무기염 생성 시약과 산부가염 및 4급 암모늄염을 형성할 수 있다. 따라서 유기 유리염기를 적당한 중성용 매중에서 당량의 산각 혼합되어 생성되는 산부가염은 황산, 인산, 염산, 취화수소산, 구연산, 주석산, 초산 및 관련된 산과 함께 형성될 수 있다. 유사한 방법으로 4급 암모늄염은 유리염기를 황산할, 로겐화 수소산 및 방향족 설폰산의 각종 유기 에스테르당량과 함께 반응시켜 생성할 수 있다.The novel compounds of the present invention are obtained as crystalline materials with specific melting point absorption spectra. They are well soluble in many organic solvents such as lower alkanols, acetone and ethyl acetate, but are generally insoluble in water. These compounds can form acid addition salts and quaternary ammonium salts with various organic and inorganic salt generating reagents in which substituent-NR 3 R 4 contains basic nitrogen atoms. Thus, acid addition salts formed by mixing the equivalent free acid in an appropriate neutral solvent may be formed with sulfuric acid, phosphoric acid, hydrochloric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid and related acids. In a similar manner, quaternary ammonium salts can be produced by reacting the free base with various organic ester equivalents of hydrogenated hydrogen acids and aromatic sulfonic acids to sulfate.
4급 암모늄염 생성시 사용되는 유기시약으로는 지급 알킬할라이드가 바람직하다. 본 발명의 신규화합물의 산부가 염및 4급 암모늄염은 일반적으로 물, 에탄올, 메탄올에 비교적 잘 녹는 결정성 고체이나 디에틸에테르, 벤젠, 톨루엔 같은 비극성 용대에는 비교적 불용성이다. 본 발명의 목적을 위해 유기염기는 그들의 무독성산부가염과 4급 암모늄에 상당한다.As the organic reagent used in the production of the quaternary ammonium salts, a payment alkyl halide is preferable. Acid addition salts and quaternary ammonium salts of the novel compounds of the present invention are generally relatively insoluble in water, ethanol and methanol and are relatively insoluble in nonpolar solutions such as diethyl ether, benzene and toluene. For the purposes of the present invention, organic bases correspond to their non-toxic acid addition salts and quaternary ammonium.
본 발명의 신규화합물은 1일 체중 kg당 약 1∼250mg을 투여할 경우 포유동물에서 영증 및 관련된 관절변형을 개선하는데 특히 유용한 것으로 밝혀졌다.The novel compounds of the present invention have been found to be particularly useful for ameliorating zero and related joint deformities in mammals when administered from about 1 to 250 mg / kg body weight per day.
최적의 결과를 얻는데 바람직한 용량은 1일 체중 kg당 약 5mg∼100mg이며 따라서 체중 70kg인 사람은 1일 약 0.35∼7.0g을 사용한다. 이 용법은 최적 치료반응을 얻는데 적합하다.Preferred dosages for optimal results are from about 5 mg to 100 mg / kg body weight per day, so a person weighing 70 kg uses about 0.35 to 7.0 g per day. This regime is suitable for obtaining an optimal therapeutic response.
예컨대 1일 용량을 분복해서 투여하거나 치료상태에 따라 적당한 감량할 수 있다. 본 발명의 실질적인 이점은 활성성분을 경구 정맥내, 근육내, 국소적용 또는 피하투여 등 각종 편리한 방법으로 투여할 수 있다.For example, a daily dose may be administered in multiple doses or appropriately reduced depending on the condition of treatment. A substantial advantage of the present invention is that the active ingredient can be administered in a variety of convenient ways, including oral, intravenous, intramuscular, topical or subcutaneous administration.
비 경구용으로 바람직한 등명도, 안정성 및 적합성을 가진 본 발명이 따른 비경구용 조성물은 활성성분을 폴리히드릭 지방족 알콜 또는 그의 혼합물로 구성된 부형제에 0.10∼10.0% 중량 비율로 용해시켜 얻을 수 있다.Parenteral compositions according to the present invention having a preferred brightness, stability and suitability for oral use can be obtained by dissolving the active ingredient in an excipient composed of polyhydric aliphatic alcohols or mixtures thereof in a proportion of 0.10 to 10.0% by weight.
특히 바람직한 것으로는 글리세린, 프로필렌글리콜, 폴리메틸렌글리콜이다. 폴리메틸렌글리콜은 물과 유기액체에 모두 가용성인 비휘발성인 그리고 일반적으로 액체인 분자량 200∼1500의 폴리에틸렌 글리콜류의 혼합물로 구성된다.Particularly preferred are glycerin, propylene glycol and polymethylene glycol. Polymethylene glycol is composed of a mixture of polyethylene glycols having a molecular weight of 200 to 1500 which are soluble in both water and organic liquids and are generally liquid.
비록 상기 부형제에 용해된 활성 성분의 양은 0.10∼10.0 중량%로 다양하나 3.0∼9.0%를 적용하는 것이 바람직하다.Although the amount of the active ingredient dissolved in the excipient varies from 0.10 to 10.0% by weight, it is preferable to apply 3.0 to 9.0%.
비록 상기 언급한 바-휘발성 폴리에틸 렌글리콜류와 각종 혼합물을 사용할 수 있으나 평균 분자량 약200∼400의 혼합물을 사용하는 것이 바람직하다.Although various mixtures with the above-mentioned volatile polyethylene glycols can be used, it is preferable to use a mixture having an average molecular weight of about 200 to 400.
활성성분외에 비경구용 용액은 박테리아와 진균오염을 막기 위해 사용되는 각종 보존제를 함유할 수 있는 이런 목적으로 사용되는 보존제에는 예컨대 미리스틸-감마-피콜리늄 클로라이드, 페닐 머큐릭 나이트레이트, 벤질코니움 클로라이드, 펜에틸알콜, P-클로로-페닐-α-글리세를 에테르 메틸 및 에틸파라벤 및 티메로살이 있다. 실제로는 항산화제를 사용하는 것이 편리하다.In addition to the active ingredients, parenteral solutions may contain various preservatives used to prevent bacterial and fungal contamination. Examples of preservatives used for this purpose include, for example, myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, and benzylconium. Chloride, phenethyl alcohol, P-chloro-phenyl-α-glycerol, ether methyl and ethylparaben and thimerosal. In practice, it is convenient to use antioxidants.
적당한 항산화제에는 예컨대 준 아황산나트륨, 메타중 아황산나트륨 및 포름알데히드 설폭실산나트륨이 포함된다. 일반적으로 산화제는 약 0.05∼0.2%의 농도로 사용한다.Suitable antioxidants include, for example, quasi-sodium sulfite, sodium metasulfite, and formaldehyde sodium sulfoxylate. Generally, the oxidant is used at a concentration of about 0.05 to 0.2%.
근육주사용으로 바람직한 활성성분의 농도는 최종 생성물의 0.25∼0.50mg/㎖이다.Preferred active ingredient concentrations for intramuscular injection are 0.25-0.50 mg / ml of the final product.
이들 활성화합물은 물이나 또는 정맥내요법에서 사용되는 등장글루코스와 같은 희석제 적당량으로 회석하여 정맥내 투여할 수 있다. 정맥주사용으로 사용하기 위해 활성성분의 초기농도를 약 0.05∼0.25mg/㎖로 낮추는 것이 바람직하다.These active compounds can be administered intravenously by dilution with an appropriate amount of a diluent such as isotonic glucose used in water or intravenous therapy. It is desirable to lower the initial concentration of the active ingredient to about 0.05-0.25 mg / ml for intravenous use.
본 발명의 화성화합물은 예컨대 불활성 희석제나 또는 식용담체와 함께 경구 투여할 수 있으며 또는 경질 및 연질젤라틴 캅셀제로 하거나 또는 경제로 하거나 음식에 직접 혼입시킬 수 있다. 경구용을 위해 활성하합물을 부형제와 함께 혼합하며 정제, 트로기체, 캄셀제, 엘릭심제, 혈락제, 시험, 위퍼제 등으로 제제화시킬 수 있다. 이런 조성물 및 제제는 최저 0.1%이상의 활성화합물을 함유해야 한다.The chemical compounds of the present invention can be administered orally, e.g., with an inert diluent or with an edible carrier, or can be incorporated into the food, either economically or with hard and soft gelatin capsules. For oral use, the active compounds may be mixed with excipients and formulated into tablets, trogases, campels, eliximes, helacses, tests, whippers, and the like. Such compositions and preparations should contain at least 0.1% of active compound.
조성물 및 제제의 농도는 물론 다양하며 단위제형당 약 2∼60%범위내에서 사용될 수 있다. 이런 조성물중의 활성성분의 양은 적당량 용량이 얻어질 수 있는 그런 양으로 한다. 본 발명의 바람직한 조성물 및 또는 제제는 경구용 단위제형이 약 50∼250mg의 활성성분을 함유하도록 제제화 된다.The concentrations of the compositions and formulations may of course vary and can be used in the range of about 2 to 60% per unit dosage form. The amount of active ingredient in such a composition is such that an appropriate amount can be obtained. Preferred compositions and or formulations of the invention are formulated so that oral unit dosage forms contain about 50-250 mg of active ingredient.
정제, 트로키제, 환제, 캅셀제등은 하기와 같은 성분도 함유할 수 있다. 트라가칸트 고무, 아카시아, 옥수수전분, 젤라틴과 같은 결합제 : 인산칼슘 같은 부형제, 옥수수전분, 감자전분, 알긴산 같은 붕해제 : 스레아린산마그내슘과 같은 윤활제 : 서당, 유당, 사카린 같은 감피제, 동록유, 체리향, 박하향 같은 향료 단위제형이 캅셀인 경우 이것은 상기유형의 물질외에도 지방유와 같은 액체담체를 함유할 수 있다.Tablets, troches, pills, capsules and the like may also contain the following components. Binders such as tragacanth rubber, acacia, corn starch, gelatin: excipients such as calcium phosphate, corn starch, potato starch, disintegrants such as alginic acid: lubricants such as magnesium sureate: sucrose, lactose, saccharin-like skin repellent If the fragrance unit formulations such as oil, cherry flavors and peppermint flavors are capsules, it may contain liquid carriers such as fatty oils in addition to the substances of this type.
기타 각종물질들을 코팅제로서 또는 제형의 물리적 형태를 변경시키기 위해 첨가시킬 수 있다. 예컨대 정제, 환제 또는 캅셀제는, 쉘락 서당 또는 이들 둘다로 제피할 수 있다. 시럽이나 엘릭실제는 활성성분외에 감미제로서 서당, 방부제로서 메틸 및 프로필파라벤, 착색 및 향료로서 체리향 또는 오렌지 향을 함유할 수 있다. 물론 이들 제제를 제조하는 데 사용되는 물질은 제약상 순수해야 하며 실질적으로 사용량에서 무독성이어야 한다.Various other materials can be added as a coating or to alter the physical form of the formulation. For example, tablets, pills or capsules can be avoided with shellac sucrose or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propylparabens as preservatives, and cherry or orange flavors as coloring and flavoring. Of course, the materials used to prepare these formulations must be pharmaceutically pure and substantially non-toxic in use.
쥐의 특이전신병인 실험적 다발성관절염은 류마치스성 관절염과 유사하다. 이들 두 질환의 병리조직이 아주 유사한 것이 C.M. Pearson 등에 의해 보고 되었다.(Am. J.Pathol. 42, 73 (1963), E.M. Glenn, (Am. J. Vet. Res. 27 (116), 339(1966)온 아쥬반드 다발성 관절염을 쥐에서 특정 감수성 관절주위의 산재성 관련조직으로부터 생긴 불구성 또는 영구성 변형으로서 분류하였다. Zahiri등(Can. Med. Ass. J. 101, 269 (1969))은 말단관절의 방추 상땡윤이 부종, 울혈및 비화농성 임파 질염을 포함한 골막염과 관련이 있으며, 골및 연골의 궁극적 파손을 진행시킨다는 것을 밝혀 냈다. 또한 Zahiri등은 관절의 연골파손은 골막주위에 생기며, 관절표면으로 확장되어 관절을 침식하는 비화농성 임파절염에 의한 것이라고 지적했다. 인도메타신 같은 비스테르 이드성 항염제는 염증성 세포 침윤으로된 관절성 발팽윤을 억제할 때 그들은 또한 관절 및 골 변형도 억제하는 것으로 나타났다. (참조 : S. Wong 등 J. Pharm. &. Exptl. Ther. 185, 127(1973) 및 G. R. Bobalick 등, Agents & Actions 4,364(1974)) 관절염과 관절변형 사이의 관계는 Blackham등에 의해 야쥬반트 관절염의 X-레이분석에 의해 밝혀졌다.(Agents & Actions 7,145 (1977) 유사한방법으로 본 발명의 화합물로 처리된 쥐의 발에서의 관절염의 진행억제는 관련관절변형을 감소시키는 것으로 나타났다.Experimental polyarthritis, a mouse specific systemic disease, is similar to rheumatoid arthritis. The pathologies of these two diseases are very similar to those of C.M. Reported by Pearson et al. (Am. J. Pathol. 42, 73 (1963), EM Glenn, (Am. J. Vet. Res. 27 (116), 339 (1966)) on adjuvant polyarthritis in rats. Zahiri et al. (Can. Med. Ass. J. 101, 269 (1969)) reported that the lumbar spine of the distal joints was edema, congestive and non-purulent. It is associated with periostitis, including lymphadenitis, and has been shown to lead to the ultimate breakdown of bone and cartilage, and Zahiri et al. Bisterid anti-inflammatory agents such as indomethacin have also been shown to inhibit joint and bone deformity when inhibiting articular foot swelling due to inflammatory cell infiltration (S. Wong et al. J. et al. Pharm. &. Exptl.Th er.185, 127 (1973) and GR Bobalick et al., Agents & Actions 4,364 (1974). The relationship between arthritis and joint deformity has been revealed by Blackham et al. by X-ray analysis of Yajuvant's arthritis. (1977) Inhibiting the progression of arthritis in the paws of rats treated with the compounds of the present invention in a similar manner has been shown to reduce related joint deformities.
하기시험은 본 발명의 화합물이 관절파손을 수반한 야쥬반트-유발성 관절염에서 만성염증에 대해 활성을 가짐을 나타낸다. 체중 200±10g인 3개의 Royal-Hart, Wistar Strain 쥐군에게 오른쪽 뒷발에 Freunds야쥬반트(사람 T.B 균을 광물유 담체에 넣어 건조시킨 것)를 체중 kg당 2mg용량으로 피내주사했다.The following tests show that the compounds of the present invention have activity against chronic inflammation in Yajuvant-induced arthritis with joint damage. Three groups of Royal-Hart and Wistar Strain rats weighing 200 ± 10 g were injected intradermal with Freunds Yajuvant (dried with mineral oil carrier in human oil carrier) in the right hind paw at 2 mg / kg body weight.
시험 화합물을 다른 용량으로 하여 1.5%전담체에 담아 매일 1번씩 0∼13 포스트 공격으로 경구투여했다.Test compounds were taken at 1.5% vehicle in different doses and orally administered once daily with 0-13 post challenge.
대로쥐는 전분담체만을 유사한 방법으로 투여했다. 14일과 21일째 포스트 공격에서 주사된 발(1차 병도)의 직경을 마이크로 메터 카리퍼로 측정했다. 염증이 생긴 발의 용량을 측정하고 결과를 대로와 비교하여 팽윤억제%로 포시했다. 동시에 귀, 발, 꼬리(2차병도)와 같은 다른 염종부위를 관찰하고 각 쥐를 염증과 팽윤의 정도로 등급을 매긴다. 등급은 0∼24점으로 나누어 매겼으며 0은 관절결절에 이상이 전혀 없는 경우이며 24는 염증의 정도가 최대인 것을 나타낸다. 각 처리군의 평균점수를 계산하고 각 화합물의 효과를 대로 등급의 억제 %로 나타냈다.Boulevard rats were administered only starch in a similar manner. The diameters of the feet (primary pathology) injected in post-attack 14 and 21 days were measured with a micrometer caliper. The dose of inflamed feet was measured and the results were compared to the streets and indicated as% swelling inhibition. At the same time, observe other areas of edema, such as ears, feet, and tail (secondary disease), and grade each rat to the extent of inflammation and swelling. The grades were divided from 0 to 24 points, with 0 indicating no abnormality in the joint nodule and 24 indicating the maximum degree of inflammation. The average score of each treatment group was calculated and the effect of each compound was expressed as percent inhibition of grade.
하기표 1은 본 발명의 화합물과 기지의 항염제에 대해 수행된 시험결과를 나타낸 것이다.Table 1 below shows the test results performed on the compounds of the present invention and known anti-inflammatory agents.
본 발명의 화합물은 관전염 및 관련 관절변형의 진행을 억제하는 것으로 밝혀졌다.The compounds of the present invention have been found to inhibit the progression of endophthalmitis and related joint deformities.
[표 1]TABLE 1
쥐에서의 아쥬반트 관절염에 대한 항염제의 효과Effect of Anti-inflammatory Agents on Adjuvant Arthritis in Rats
본 발명의 신규한 N2,N4,N6-트리스(치환) 멜라민은The novel N 2 , N 4 , N 6 -tris (substituted) melamines of the present invention
(1) 일반식
(2) 일반식 R-X,
(3) 루이스산 촉매존재하 또는 부재하에 S-트리아진 생성물상의 치환분이 상이한 경우에는 단계적으로(3) stepwise when the substitution on the S-triazine product is different with or without Lewis acid catalyst
S-트리아진상의 치환분이 동일한 경우엔 단계적 및/또는 동시에 반응시키고,If the substitutions on the S-triazine are the same, reacted stepwise and / or simultaneously,
(4) X가
(5) 결과 생성된 화합물이 모노머형의 RNH-C≡N인 경우, 알칼리와 함께 열처리하여 트리스(치환-아미노)-S-트리아진으로 트리머화 시키고,(5) When the resulting compound is monomeric RNH-C≡N, it is heat treated with alkali to trimerize to tris (substituted-amino) -S-triazine,
(6) 결과 생성된 화합물이 이소멜라민 형태인 경우 염기로 처리하여 일반식(I)의 S-트리아진으로 이성화시킴으로써 쉽게 제조될 수 있다.(6) When the resultant compound is in isomeramine form, it can be easily prepared by isomerization with S-triazine of general formula (I) by treatment with base.
상기식들에서 n은 1, 2 또는 3이며,In which n is 1, 2 or 3,
Z은 동일 또는 상이한 것으로 Cl-, Br-, F-, I-, -0- 알킬, -0-페닐, -S-알킬, -N3, -CN, -N+(CH3)3, -NH2, 트리클로로메틸, 트리플루오르메틸, -R1, -R2또는 NR3R4이며(여기서 R1,P2,P3및 R4는 전술한 바와같음), A 및 B는 함께 단일 결합을 형성하는 화학적 원자가 이거나 또는 다른 원자에 결합되어 대칭, 비대칭 치환 다이머(dimer) 또는 트리머(trimer) 개쇄(Open chain)을 형성하거나 대칭 또는 비대칭 치환-S-트리아진환을 형성할 수 있으며; R은 C4∼C8의 알킬로서 1-아다만틸, 2-아다만틸엑소[2,2,1]-노트보닐 또는 엔도[2,2,1]노르보닐이며 ; X는 -NH2,
따라서 본 발명은 일반식
(여기서 Z은 상기한 바와 같음)을 일반식 R-X, H-NR3R4의 화합물들과 루이산 존재하 또는 부재화에 S-트리아진 생성물상의 최종 아미노치환분이 상이한 경우 상이한 아민을 사용하여 단계적으로, 이들 치환분이 동일한 경우 단계적으로 또는 동시에 반응시켜 일반식(I) 및 그의 제약상 허용되는 산부가염을 제조하는 방법을 제공한다.Wherein Z is as described above, stepwise using different amines when compounds of the general formula RX, H-NR 3 R 4 and the final aminosubstitution on the S-triazine product are different in the presence or absence of leunic acid As such, when these substitutions are the same, a method for preparing general formula (I) and pharmaceutically acceptable acid addition salts thereof by reacting stepwise or simultaneously is provided.
또한 본 발명은 n=1이고 A와 B가 함께 화학결합을 형성하는 일반식
로 트리머화하고, 이소멜라민 형태의 트리머가 있는 경우 이것을 알칼리와 합께 열처리하는 과정에서 멜라민 구조로 전위시킴으로써 일반식Trimmer, and isomerel form trimmer is converted into melamine structure during heat treatment with alkali.
의 화합물 및 그의 제약상 허용되는 산부가염을 제조하는 방법을 제공한다.Provided are methods for preparing compounds of and pharmaceutically acceptable acid addition salts thereof.
본 발명은 또한 일반식
(여기서 Z'는 Cl-, Br-, I-, F-, 트리할로메틸, 트리메틸암모니오, 또는-0-페닐이며 R1, R2는 상기한 바와 같음)의 화합물을 일반식
또한 본 발명은 일반식
여기서 Z은 Cl-, Br-, I-, F-, 트리할로메틸, 트리메틸암모니오, 또는-0-페닐임)의 화합물을 일반식
본 발명의 화합물의 제조공정을 도식화하면 다음과 같다.The production process of the compound of the present invention is as follows.
(상기식에서 N, R, Y 및 Z은 상기한 바와 같다.(Wherein N, R, Y and Z are as described above).
상기도식에서 보는 바와 같이 본 발명의 생성물은 치환분이 상이한 경우는 단계적으로 생성되며 치환분이 대칭인 경우에는 단계적 및/또는 동시에 생성된다.As shown in the above scheme, the products of the present invention are produced in stages when the substitutions are different and in stages and / or simultaneously when the substitutions are symmetric.
여기서 '단계적'이란 말은 중간체(모노-및 디-아민화 S-트리아진류)를 반응 혼합물로 부터 분리시킨후 다른 시약과 반응시켜 긍극적으로 본 발명의 생성물을 얻는 것을 의미하며 '동시에'란 말은 반응체들을 동일 반응용기내에서 함께 혼합하고 중간 생성물을 반응도 중 따로 분리시키지 않는 것을 의미한다.The term 'stepwise' herein means that the intermediates (mono- and di-amined S-triazines) are separated from the reaction mixture and then reacted with other reagents to ultimately obtain the product of the present invention. This means that the reactants are mixed together in the same reaction vessel and the intermediate product is not separated separately during the reaction.
출발물질 및/또는 중간체의 반응성은 비-아민화> 모노-아민화> 디-아민화의 순서로 감소되며 아미노기가 많이 존재하면 할수록 좀더 맹렬한 반응 조건이 필요함을 주목해야 한다. 상기 반응도식을 3개의 치-환성기를 함유하는 S-트리아진을 예로하여 좀더 상세히 나타내면 하기와 같다.It should be noted that the reactivity of the starting materials and / or intermediates is reduced in the order of non-amination> mono-amination> di-amination and the more amino groups present, the more intense reaction conditions are required. The reaction scheme is described in more detail by taking S-triazine containing three substituent groups as examples.
반응은 에컨대 H+, F3CCOOH, 2-피리돈, Sb(Hal)5와 같은 루이스 산촉매의 존재하에 수행될 수 있다.The reaction can be carried out in the presence of a Lewis acid catalyst such as H + , F 3 CCOOH, 2-pyridone, Sb (Hal) 5 .
치환 시안아미드의 트리머화에 의해 생긴 생성물은 일부가 하나 또는 그 이상의 환상 질소에 치환분을 함유하는 이소멜라민 형태일 수 있으며 이것은 예컨대 하기와 같이 이소멜라민을 열기로 처리함으로써 본발명의 화합물로 이성화 될 수 있다.The product resulting from the trimerization of substituted cyanamides may be in the form of isomeramine, some of which contain substitutions in one or more cyclic nitrogens, which may be isomerized to the compounds of the present invention, for example by treating isomeramine with hot air as follows. Can be.
본 발명의 2, 4, 6-트리스(알킬 아미노)-S-트리아진을 제조하는 바람직한 구체에는 하기도식과 같이 시안 우릭클로라이드와 적당한 아민과를 반응시키는 것이다.A preferred embodiment of the preparation of the 2, 4, 6-tris (alkyl amino) -S-triazines of the present invention is the reaction of cyan urichloride with a suitable amine as shown in the following scheme.
상기 각 경로는 본 발명의 비대칭 및 대칭-치환 S-트리아진류(즉 기 R1-, R2- 및 R3R4N-이상하거나 동일한 경우)를 제조하는 경우에는 단계적으로 이루어지며, 소망의 화합물이 대칭치환 S-트리아진 (즉 R1, - R2-, R3R4N-이 동일한 경우인)경우에는 동시에 이루어진다.Each of these pathways takes place step by step in the preparation of the asymmetric and symmetrically-substituted S-triazines of the invention (i.e. if the groups R 1- , R 2 -and R 3 R 4 N- is abnormal or identical), If the compound is symmetrically substituted S-triazines (ie where R 1 ,-R 2- , R 3 R 4 N- are the same), they are simultaneously.
또한 치환분중 둘이 동일하고 나머지 하나가 다른 경우 (예컨대 R3R4N-과 R2-는 동일하고 R1-이 다른 경우) 치환과정은 단계적인 것과 동시반응이 병용하여 일어나거나 단계적 방법으로 만일어난다.In addition, when two of the substitutions are the same and the other is different (for example, when R 3 R 4 N- and R 2 -are the same and R 1 -are different), the substitution process may occur in combination with a step and a simultaneous reaction or in a stepwise manner. If it comes out.
상기반응은 톨루엔, 크실렌과 같은 불활성 용매중에서 약 3∼24시간에 걸쳐 25∼200℃의 온도범위에서 일어날 수 있다. H+, CF3COOH, Sb (Hal)5, 2-피리돈과 같은 루이 스산이 상기반응중 촉매로서 또는 반응용대로서 사용될 수 있다.The reaction may occur in an inert solvent such as toluene, xylene over a temperature range of 25-200 ° C. over about 3 to 24 hours. Lewis acids such as H + , CF 3 COOH, Sb (Hal) 5 , 2-pyridone can be used as catalyst during the reaction or as a reaction zone.
반응시간과 온도는 아민 시약의 구조에 따라 달라지며 아민이 입체적으로 방해를 받은 경우 좀더 힘들게 반응 한다. 1∼2몰 당량의 아민이 사용되는 경우 중탄산나트륨 소다회 또는 디이소프로필에 틸아민과 같은 산스캐빈져가 반응중 생성된 열소를 제거하는데 사용될 수 있다. 과량의 아민이 사용되는 경우 산스캐빈적 및/또는 불활성 용매가 함께 쓰일 수 있다.The reaction time and temperature depend on the structure of the amine reagent and react more difficultly if the amine is steric hindrance. If 1-2 molar equivalents of amine are used, an acid scavenger such as sodium bicarbonate soda ash or diisopropyl ethylamine may be used to remove the heat produced during the reaction. If an excess of amine is used, acid-scavenging and / or inert solvents may be used together.
또 다른 제법으로는 멜라민 또는 N-치환 멜라민을 알칼리 존재하에 올레핀과 반응시켜 알킬아미노유도체를 얻고 아미노-치환 -S-트리아진을 알데히드, 케톤 또는 환상케톤과 반응시킨 다음 결과 생성된 생성물을 비등하는 포름산, 리틈알루미늄수소화물, 또는 에탄올 중 수소 같은 환원제로 백금, 팔라디움 또는 기타 귀금속 존재하에 환원시키고 적당히 치환된 시안아미드를 알칼리 존재하에 불활성 용매(메탄올, 에탄올 같은) 중에서 트리머화하거나 본 발명의 화합물의 N-아실 또는 N-하이드록시메틸유도체를 가수분해시키는 방법이 있다.Another process involves reacting melamine or N-substituted melamine with olefins in the presence of an alkali to obtain alkylamino derivatives, reacting amino-substituted -S-triazines with aldehydes, ketones or cyclic ketones and boiling the resulting product. Reducing agents in the presence of platinum, palladium or other precious metals with a reducing agent such as formic acid, rilimaluminum hydride, or hydrogen in ethanol and suitably substituted cyanamides are trimmered in an inert solvent (such as methanol, ethanol) in the presence of alkali or There is a method of hydrolyzing N-acyl or N-hydroxymethyl derivatives.
대칭 2,4,6-트리스(치환-아미노) -S-트리아진류의 제조는 시안우릭클로라이드를 2당량의 아민과 희수산화나트륨 또는 칼륨수용액 중에서 환류온도하에 3∼10시간동안 반응시킨후 생성된 2,4-비스-(치환-아미노)-6-클로로-S-트리아진을 용매 및 산-스캐빈져로 작용하는 각량의 아민과 함께 가열하거나 또는 디이소프로필에틸아민 같은 염기 및/또는 α-피리돈 또는 안티모니 펜타할라이트 같은 루이스산 촉매를 사용하여 불활성 용매중에서 몰 당량의 아민과 함께 반응시킴으를써 수행될 수 있다.Preparation of symmetrical 2,4,6-tris (substituted-amino) -S-triazines was carried out after reacting cyanuric chloride in an aqueous solution of 2 equivalents of amine and a dilute sodium or potassium solution at reflux for 3 to 10 hours. 2,4-bis- (substituted-amino) -6-chloro-S-triazine is heated with an amount of amine acting as solvent and acid-scavenger or a base such as diisopropylethylamine and / or α By reaction with a molar equivalent of amine in an inert solvent using a Lewis acid catalyst such as pyridone or antimony pentahalite.
이들 화합물의 제조는 시안아미드 특히 방해받은 t-알킬시안아미드 및 비치환-및 메틸치환-아다만탈시안아미드를 트리머화 시킴으로써 수행될 수 있다.The preparation of these compounds can be carried out by trimmering cyanamides, in particular hindered t-alkylcyanamides and unsubstituted- and methylsubstituted-adamantalcyanamides.
이들은 하기와 같이 트리머화 된다.These are trimmers as follows.
생성물은 반응 혼합물로 부터 분리시킨 후 본 분야에 숙련된 자에 잘 알려진 방법으로 정제할 수 있다.The product can be separated from the reaction mixture and then purified by methods well known to those skilled in the art.
R1-, R2- 및 R3NR4-가 모두 상이한 경우,When R 1- , R 2 -and R 3 NR 4 -are all different,
2-, 4- 6- 및 위치에서의 아미노기의 치환은 1단계에서 동몰량의 아민 및 시안우릭클로라이드를 사용하고 2단계에서는 또 다른 아민과 2, 4-디클로로-6-(치환아미노)-6-트리아진을 동몰량 사용하고, 최종단계에서는 과량의 아민과 2-클로로 -4,6-버스-(치환 아미노)-S-트리아진을 사용하여 상기 반응도식에서와 같이 단독적으로 수행된다.Substitution of the amino groups at the 2-, 4- 6- and positions is carried out using equimolar amounts of amines and cyanuric chlorides in step 1 and 2, 4-dichloro-6- (substituted amino) -6 with another amine in step 2. An equimolar amount of -triazine is used, and the final step is carried out alone as in the above scheme using excess amine and 2-chloro-4,6-bus- (substituted amino) -S-triazine.
치환은 순서에 관계 없이 수행될 수 있다.Substitutions may be performed in any order.
기중 2개가 동일한 경우 2몰량의 아민을 시안우릭클로라이드와 반응시키고 이어 중간체인 2-클로로-4,6-비스(치환-아미노)-S-트리아진을 과량의 다른 아민과 반응시킨다. 또한 기중 2개가 동일한 경우 1몰량의 아민을 시안우릭클로라이드와 반응시키고 중간체 2,4-디클로로 -6-(치환-아미노)-S-트리아진을 과량의 다른 아민과 반응시킨다.If the two groups are the same, 2 molar amounts of the amine are reacted with cyanurichloride and the intermediate 2-chloro-4,6-bis (substituted-amino) -S-triazine is reacted with excess of other amines. In addition, when two of the groups are the same, one molar amount of amine is reacted with cyanurichloride and the intermediate 2,4-dichloro-6- (substituted-amino) -S-triazine is reacted with an excess of other amines.
R1-, R2- 및 R3R4N-이 동일한 경우. 시안우릭클로라이드를 적당한 아민 과량으로 처리하여 상응하는 2,4,6-트리스(치환-아미노)-S-트리아진을 생성시킨다.When R 1- , R 2 -and R 3 R 4 N- are the same. Cyanuricchloride is treated with an appropriate amine excess to yield the corresponding 2,4,6-tris (substituted-amino) -S-triazine.
본 발명은 하기실시예에 의해 좀 더 상세히 설명된다.The invention is illustrated in more detail by the following examples.
[실시예 1]Example 1
2-클로로-4.6-비스(1,1,2,2-트리메틸프로필-아미노)-6-트리아진의 제조Preparation of 2-chloro-4.6-bis (1,1,2,2-trimethylpropyl-amino) -6-triazine
2,3,3-트리메틸-2-부틸아민 염산염 6.7g(0.044몰)과 NaOH 3.4g (0.84몰)의 물 20㎖ 중 용액을 사안우릭클로라이드 3.6g (0.02몰)을 물 150㎖에 넣어 슬러리화 하여 교반한 슬러리에 첨가한다.A solution of 6.7 g (0.044 mole) of 2,3,3-trimethyl-2-butylamine hydrochloride and 3.4 g (0.84 mole) of NaOH in 20 ml of water was added 3.6 g (0.02 mole) of saowoo chloride in 150 ml of water. It is added to the stirred slurry.
반응혼합물을 환류온도에서 2-1/2시간동안 가열하고 냉각한 후 여과하여 융점 129-131℃의 백색 고체상의 생성물 6.5g을 얻는다.The reaction mixture is heated at reflux for 2-1 / 2 hours, cooled and filtered to give 6.5 g of a white solid product having a melting point of 129-131 ° C.
[실시예 2]Example 2
2, 4-비스-(1,1,3,3-데트라메틸부틸아미노)-6-클로로-S-트리아진의 제조Preparation of 2, 4-bis- (1,1,3,3-detramethylbutylamino) -6-chloro-S-triazine
시안우릭클로라이드 18.4g (0.10몰)을 물 100㎖ 중에서 슬러리화한 후 현탁액을 빙옥중에서 냉각한다.18.4 g (0.10 mole) of cyanuric chloride is slurried in 100 ml of water and then the suspension is cooled in ice jade.
페놀프탈레인 용액 2적을 가하고 이어 2,4,4-트리메틸-2-펜틸아미노 32.3g (0.25몰)을 첨가하면 발열반응이 일어난다.Add 2 drops of phenolphthalein solution and then add 32.3 g (0.25 mole) of 2,4,4-trimethyl-2-pentylamino to generate an exothermic reaction.
현탁액을 환류하에 17시간 동안 교반하면서 가열한다. 처음 반시간중 수산화나트륨 8.0g (0.20몰)을 물40㎖에 녹인 용액을 반응 혼합물이 약 알칼리성이 되도록 서서히 첨가한다.The suspension is heated under reflux for 17 hours with stirring. A solution of 8.0 g (0.20 mol) of sodium hydroxide in 40 ml of water is added slowly over the first half hour to make the reaction mixture slightly alkaline.
반응혼합물을 냉각한 후 수용액을 왁스상 고체로 부터 경사제거 한다.After cooling the reaction mixture, the aqueous solution was decanted from the waxy solid.
아세톤을 고체에 가하고 혼합물을 여과하여 융점 164∼168℃의 생성물 33.3g을 얻는다. 뜨거운 에탄올로 부터 재결정하여 융점 165∼167℃의 액상물질 27.5g을 얻는다.Acetone is added to the solid and the mixture is filtered to give 33.3 g of product with a melting point of 164-168 ° C. Recrystallization from hot ethanol yields 27.5 g of a liquid substance with a melting point of 165 to 167 ° C.
[실시예 3]Example 3
3-{4,6-비스 [(1,1,2,2-테트라메틸프로필) 아미노] -S-트리아진-2-일}-3-아자비시클로3,2,2]노난의 제조Preparation of 3- {4,6-bis [(1,1,2,2-tetramethylpropyl) amino] -S-triazin-2-yl} -3-azabicyclo3,2,2] nonane
2-클로로-4,6-비스 [(1,1,2,2-테트라메틸프로필) 아미노]-S-트리아진 10. 25g과 3-아자비시클로-[3,2,2] 노난 7.65g을 디글라임(diglyme) 50㎖에 녹인 용액을 환류하에 3시간 가열하고 냉각하여 분홍색 고체를 얻는다. 이 고체를 모아 디글라임으로 세척하고 물 500㎖ 중에 현탁시킨 후 교반하고 여과하고 물로 세척하여 분홍색 고체를 얻는다. 이 고체를 에탄올로 부터 재결정하여(활성탄을 탈색제로 사용한다 )융점 282∼284℃의 소망의 화합물을 얻는다.10.25 g of 2-chloro-4,6-bis [(1,1,2,2-tetramethylpropyl) amino] -S-triazine and 7.65 g of 3-azabicyclo- [3,2,2] nonane The solution dissolved in 50 ml of diglyme is heated under reflux for 3 hours and cooled to give a pink solid. The solids are combined, washed with diglyme, suspended in 500 ml of water, stirred, filtered and washed with water to give a pink solid. This solid is recrystallized from ethanol (activated carbon is used as a bleaching agent) to obtain a desired compound having a melting point of 282 to 284 ° C.
[실시예 4]Example 4
3-[4, 6-비스(1,1,3,3-테트라메틸아미노-S-트리아진-2-일]-3-아자비시클로3,2,2] 노난의 제조Preparation of 3- [4, 6-bis (1,1,3,3-tetramethylamino-S-triazin-2-yl] -3-azabicyclo3,2,2] nonane
시안우릭클로라이드 552g, t-옥틸아민 969g 및 수산화나트륨 240g의 50% 수용액으로 구성된 반응혼합물을 시간환류 하고, 실온에서 하룻밤 교반하고 60℃에서 건조한다.The reaction mixture consisting of 50% aqueous solution of 552 g of cyanuric chloride, 969 g of t-octylamine and 240 g of sodium hydroxide was refluxed for time, stirred at room temperature overnight and dried at 60 ° C.
고체를 2B 알콜 19ℓ로부터 재결정하여 2-클로로-4,6-비스 [(1,1,3,3-데트라메틸부틸) 아미노]-S-트리아진 1,107g을 얻는다.The solid is recrystallized from 19 L of 2B alcohol to give 1,107 g of 2-chloro-4,6-bis [(1,1,3,3-detramethylbutyl) amino] -S-triazine.
상기와 같이 제조된 생성물 11.1g과 3-아자비시클로 [3,2,2]노난 11.25g의 디글라임 100㎖ 중 혼합물을 3시간 환류하고 냉각한 후 물에 붓는다. 침전된 물질을 여과하여 소망의 생성물을 얻는다. 생성물을 80% 에탄올로부터 재결정한다. 융점 126∼127℃The mixture in 100 ml of diglyme of 11.1 g of the above-prepared product and 11.25 g of 3-azabicyclo [3,2,2] nonane was refluxed for 3 hours, cooled and poured into water. The precipitated material is filtered to give the desired product. The product is recrystallized from 80% ethanol. Melting point 126 ~ 127 ℃
[실시예 5]Example 5
50mg경제의 조제Preparation of 50mg economy
2-(1-아다만틸 아미노)-4,6-비스(1,1,2,2-테트라메틸 부딜아미노-S-트리아진, 유당, 옥수수전분(혼합용)을 함께 혼합한다. 옥수수 전분(페이스트 용)을 물 600㎖ 중에 현탁하고 교반하면서 가열하여 페이스트를 형성한다. 이 페이스트는 혼합 분말을 과립화하는데 사용한다. 필요하면 물을 더 사용한다.2- (1-adamantyl amino) -4,6-bis (1,1,2,2-tetramethyl butylamino-S-triazine, lactose and corn starch (mixed together) are mixed together. (For paste) is suspended in 600 ml of water and heated with stirring to form a paste, which is used to granulate the mixed powder, further water is used if necessary.
습윤과립을 No.8 핸드 스크린을 통과시킨후 120℉에서 건조한다. 건조과립을 No.16 스크린을 통과시킨다. 혼합물을 1% 스테아린산 마그네슘으로 윤활하게 한후 적당한 타정기내에서 정제로 압축시킨다.The wet granules are passed through No. 8 hand screen and dried at 120 ° F. Dry granules are passed through No. 16 screen. The mixture is lubricated with 1% magnesium stearate and then compressed into tablets in a suitable tablet press.
[실시예 6]Example 6
소르비톨액을 증류수 40㎖에 가한후 여기에 2-(2-아다틸 아미노)-4,6-비스(1,1,3-트리메틸부틸아미노)-S-트리아진을 현락시킨다.The sorbitol solution was added to 40 ml of distilled water, followed by suspending 2- (2-adatyl amino) -4,6-bis (1,1,3-trimethylbutylamino) -S-triazine.
사카린, 안식향산 나트륨, 향료, 염료를 가해 용해시킨다. 증류수를 가해 100㎖로 한다.Saccharin, sodium benzoate, flavors and dyes are added to dissolve. Distilled water is added to make 100 ml.
시럽은 ㎖ 당 2-(2-아다만틸-아미노)-4,6-비스(1,1,3-트리메틸부틸아미노) S-트리아진 5mg을 함유한다.The syrup contains 5 mg 2- (2-adamantyl-amino) -4,6-bis (1,1,3-trimethylbutylamino) S-triazine per ml.
[실시예 7]Example 7
비 경구용 용액 조제Preparation of non-oral solution
프로필렌글리콜 700㎖와 주사용 증류수 200㎖에 N2-(액소[2,2,1] 노르보닐) -N4, N6-비스(1,1,4-트리메틸펜릴) 멜라민 20.0g을 교반하면서 현탁시킨다. 현탁액을 만든 후 pH를 염산을 사용하여 5.5로 맞추고 주사용 증류수를 사용하여 총 용량을 1,000㎖로 한다.Of propylene glycol and distilled water 700㎖ 200㎖ N 2 - (aekso [2,2,1] NORD-carbonyl) -N 4, N 6 - stirring the bis (1,1,4- trimethyl penril) melamine 20.0g Suspend. After the suspension is made, the pH is adjusted to 5.5 using hydrochloric acid and the total volume is 1,000 ml using distilled water for injection.
멸균 후 5㎖ 앰플에 2.0㎖ (활성성분 40mg 함유)씩 채운 후 질소하에 밀봉한다.After sterilization, 5 ml ampoules are filled with 2.0 ml (containing 40 mg of active ingredient) and sealed under nitrogen.
[실시예 8]Example 8
국소용 크림의 조제Preparation of topical creams
에록시화스테아릴알콜과 이소프로필팔미테이트를 가열하여 액화온도로 한다. 물 총량의 약 95%를 다른 용기에 넣은 후 글리세린 및 소르비를 용액을 넣는다.Steoxyl oxy alcohol and isopropyl palmitate are heated to the liquefaction temperature. Add about 95% of the total amount of water to another container, and then add the solution of glycerin and sorbide.
이 수성혼합물을 끓인 후 60∼75℃로 냉각시킨다.The aqueous mixture is boiled and then cooled to 60 to 75 ° C.
2-(엔도[2,2,1] 노르보닐아미노-4,6-비스(1,1,2,2-레트라메틸부틸아미노)-S-트리아진을 젖산으로 pH4.0∼5.0으로 맞춘다. 뱃치를 크림이 최종 형태로 될때까지 최소한 진탕하면서 냉각한다.Adjust 2- (endo [2,2,1] norbornylamino-4,6-bis (1,1,2,2-retramethylbutylamino) -S-triazine to pH 4.0-5.0 with lactic acid Cool the batch with at least shaking until the cream is in its final form.
[실시예 9]Example 9
관절 내 생성물의 조제Preparation of intra-articular products
[실시예 10]Example 10
주사용 뎁포 현탁액에 조제Prepared in injectable depot suspension
[실시예 11]Example 11
3,3'-(6-클로로-S-트리아진-2,4-디일) 비스-3-아자비시클로[3,2,2] 노난의 제조Preparation of 3,3 '-(6-chloro-S-triazine-2,4-diyl) bis-3-azabicyclo [3,2,2] nonane
시안우릭클로라이드 80g (0.43몰)을 아세톤 800㎖에 녹인 후 10℃ 이하로 냉각한 다음 물 1ℓ를 가하고 3-아자비시클로 [3,2,2] 노난 120g (0.96 몰)을 가한다. 2시간 후 반응물을 실온으로 되게가온하고 2시간더 있다가 NaOH 35g (0.87 몰)의 물 200㎖ 중 용액을 2시간에 걸쳐 가한다.80 g (0.43 mole) of cyanuric chloride is dissolved in 800 ml of acetone, cooled to 10 ° C. or lower, then 1 L of water and 120 g (0.96 mole) of 3-azabicyclo [3,2,2] nonane are added. After 2 hours, the reaction was allowed to warm to room temperature, followed by another 2 hours, followed by the addition of a solution in 200 ml of 35 g (0.87 mol) of NaOH over 2 hours.
반응물을 1시간 교반한 후 1시간 동안 더 가열환류한다.The reaction is stirred for 1 hour and then heated to reflux for 1 hour.
물 2ℓ로 희석하여 흰색 침전을 얻고 이것을 여별한 후 물로 세척한다. 침전을 클로로포름 1ℓ에 녹인후 수용액을 분리시킨다. 수용액을 클로로포름으로 추출하고 클로로포름 추출물을 합해 물로 세척한 후 항상 마그네슘 상에서 건조하고 마그네솔
[실시예 12]Example 12
3, 3'-(6-부틸아미노-5-트리아진-2,4-디일) 비스-3-아자비시클로[3,2,2] 노난의 제조Preparation of 3, 3 '-(6-butylamino-5-triazine-2,4-diyl) bis-3-azabicyclo [3,2,2] nonane
3,3'-(6-클로로-S-트리아진-2,4-디일)비스-3-아자비시클로[3,2,2]노난 9g (0.025 몰)과 n-부틸아민 9.7g (0.13몰)을 봄브(bomb) 중의 글라스라이너(glass liner)에 넣은 후 160∼180℃로 유지시킨 오일욕중에서 16시간 동안 가열한다.9 g (0.025 mol) of 3,3 '-(6-chloro-S-triazine-2,4-diyl) bis-3-azabicyclo [3,2,2] nonane and 9.7 g (0.13 mol) of n-butylamine ) Is placed in a glass liner in a bomb and heated for 16 hours in an oil bath maintained at 160-180 ° C.
냉각후 봄브의 내용물을 클로로 름세정하고 물을 플라스크에 넣은 후 10N NaOH 50㎖를 가한다.After cooling, the contents of the bomb are chlorowashed, water is added to the flask, and 50 ml of 10N NaOH is added.
용액을 진공증발 시키고 남은 수용액을 클로로포름으로 추출한다. 추출물을 합해물로세 척하고 황산마그네슘상에서 건조시킨 후 마그네솔
[실시예 13]Example 13
3-(4,6-디클로로-S-트리아진-일)-3-아자비시클로-[3,3,2] 노난 의 제조Preparation of 3- (4,6-dichloro-S-triazin-yl) -3-azabicyclo- [3,3,2] nonane
시안우릭클로라이드 280g (1.5몰)을 아세톤 1.4ℓ이 녹이고, 물 1.8ℓ를 가한후 혼합물을 드라이아이스/아세톤 욕에서 -10℃로 냉각한다.280 g (1.5 moles) of cyanuric chloride are dissolved in 1.4 L of acetone, 1.8 L of water is added and the mixture is cooled to -10 ° C in a dry ice / acetone bath.
3-아자비시클로[3,2,2] 노난 130g (1.0 몰)을 아세톤 200㎖에 넣어 슬러리화하고 이것을 한꺼번에 가한 후 반응물을 -10℃에서 15분간 고반한다. 10N NaOH 100㎖를 한꺼번에 모두 가하면 발열반응이 일어난다. 드라이아이스/아세톤 욕을 사용하여 -10℃로 냉각한 후, 반응 혼합물을 더 냉각하지 않고 3.8시간 교반하여 온도를 약 20℃로 올린다. 물 2ℓ를 첨가한 후 침전을 여별하고 물로 세척한다. 침전을 클로로포름에 녹인후 과량의 물을 분리하고 클로로름 용액을 황산마그네슘 상에서 건조한후 마그네술
마그네솔 R을 클로로포름으로 세척한 후 용매를 진공건조하고 디클로로 매탄-헥산으로 재결정하여 융점 153°∼154°의 침상 결정 170g을 얻는다.After washing the magnesol R with chloroform, the solvent was dried in vacuo and recrystallized with dichloro methane-hexane to give 170 g of needle crystals with melting points of 153 ° to 154 °.
[실시예 14]Example 14
3-[4,6-비스(t-부틸아미노)-S-트리아진-2-일]-3-아자비시클로[3,2,2] 노난의 제조Preparation of 3- [4,6-bis (t-butylamino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] nonane
3-(4,6-디클로로-S-드리아진-2-일)-3-아자비시클로[3,2,2]-노난(8.2g, 0.03몰)과 t-부틸아민 25㎖ (0.24 몰)을 봄브중의 글라스라이너에 넣고 160∼180℃로 유지시킨 오일욕중에서 16시간 동안 가열한다. 냉각후 봄브 내용물을 클로로 포름으로 세척하고 플라스크에 물을 넣은후 10N-NaOH 50㎖를 가한다. 용액을 진공증발시키고 남은 수용액을 클로로포름으로 추출한다. 클로로포름 추출물을 합해 물로 세척한 후 황산마그네슘 상에서 건조하고 마그네솔
용매를 진공제거하고 실리카겔상에서 컬럼크로마토그라피한 후 좀더 극성 성분을 함유하는 순수 분획물을 헵탄으로 재결정하여 융점 217~222℃의 무색미세 결정 4.8g을 얻는다.The solvent was removed in vacuo, column chromatography on silica gel, and the pure fractions containing more polar components were recrystallized from heptane to obtain 4.8 g of colorless fine crystals having a melting point of 217-222 ° C.
[실시예 15]Example 15
3-[4-클로로-6-(1,1,3'3-테트라메틸부틸 아미노)-S-트리아진-2-일]-3-아자비시클로[3,2,2]노난의 제조Preparation of 3- [4-chloro-6- (1,1,3'3-tetramethylbutyl amino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] nonane
3-(4,6-디클로로-S-드리아진-2-일)-3-아자비 시클로-[3,2,2] 노난 30g (0.11 몰)을 아세톤 300㎖에 녹인 후 물 370㎖를 가하고 이어 t-옥틸아민(0.15 몰) 20g을 가한다. 10분간 교반한 후 NaOH 4.4g (0.11 몰)을 물 30㎖에 녹인 용액을 20분에 걸쳐 가한다. 반응물을 19시간 동안 환류하에 가열한다. 실온으로 냉각한 후 물 1ℓ를 가하고 1시간 교반한 후 백색침전을 여별한다.30 g (0.11 mol) of 3- (4,6-dichloro-S-driazin-2-yl) -3-azabicyclo- [3,2,2] nonane was dissolved in 300 ml of acetone, and then 370 ml of water was added. 20 g of t-octylamine (0.15 mol) is added. After stirring for 10 minutes, a solution of 4.4 g (0.11 mol) of NaOH in 30 ml of water is added over 20 minutes. The reaction is heated at reflux for 19 h. After cooling to room temperature, 1 L of water is added and stirred for 1 hour, followed by filtration of white precipitate.
침전을 물로 세척하고 하룻밤 건조한 후 디클로로메탄에 녹이고 마그네솔
[실시예 16]Example 16
3-[4-P-플루오로아닐리노-6-(1,1,3,3-테트라메틸-부틸아미노)-S-트리 아진-2-일]-3-아자비시클로[3,2,2] 노난의 제조3- [4-P-fluoroanilino-6- (1,1,3,3-tetramethyl-butylamino) -S-triazin-2-yl] -3-azabicyclo [3,2,2 Nonnan Manufacturing
3-[4-클로로-6-(1,1,3,3-테트라메틸부틸아미노)-S-트리아진-2-일]-3-아자비시클로[3,2,2]-노난 8g(0.022 몰)과 P-플루오로아닐린 21㎖ (0.22 몰)을 봄브중 유리라이너에 넣고 온도를 190∼205℃로 유지시킨 오일욕중에서 약 40시간 가열한다. 냉각 후 봄브중 인디고 성분을 클로로포름 및 물로 세척하여 플라스크에 넣은 후 10N NaOH 50㎖를 가한다.8 g (0.022) of 3- [4-chloro-6- (1,1,3,3-tetramethylbutylamino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] -nonane Mole) and 21 mL (0.22 mole) of P-fluoroaniline are placed in a glass liner in a bomb and heated for about 40 hours in an oil bath maintained at 190-205 ° C. After cooling, the indigo component in the bomb was washed with chloroform and water, placed in a flask, and 50 ml of 10N NaOH was added thereto.
용액을 진공 증발한 후 남은 수용액을 클로로포름으로 추출한다. 추출물을 합해 물로 세척하고 화산마그네슘상세서 건조시킨 후 마그네솔
아세톤으로 부터 재결정하여 융점 173.5℃∼174.5℃의 무색결정 7.1g을 얻는다.Recrystallization from acetone gives 7.1 g of colorless crystals having a melting point of 173.5 ° C to 174.5 ° C.
[실시예 17]Example 17
3-[4-tert-부틸-6-(1,1,3,3-테트라메틸부틸-아미노)-S-트리아진-2-일]-3-아지비시클로[3,2,2] 노난의 제조3- [4-tert-butyl-6- (1,1,3,3-tetramethylbutyl-amino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] nonane Manufacture
3-[4-클로로-6-(1,1,3,3-테트라메틸부틸아미노)-S-트리아진-2-일]-3-아지비시클로[3,2,2]-노난 8g (0.022 몰)과 t-부틸아민 23㎖ (0.22 몰)을 봄브중 글라스라이너에 넣고 185°∼200℃로 유지시킨 오일욕중에서 약 40시간 가열한다.8 g of 3- [4-chloro-6- (1,1,3,3-tetramethylbutylamino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] -nonane ( 0.022 mol) and 23 ml (0.22 mol) of t-butylamine are placed in a glass liner in a bomb and heated for about 40 hours in an oil bath maintained at 185 ° to 200 ° C.
냉각 후 봄브내용을 클로로포름과 물로 씻어 플라스크에 넣고 10N NaOH 50㎖를 가한다. 용액을 진공증발하고 남은 수용액을 클로로포름으로 추출한다.After cooling, the contents of the bomb were washed with chloroform and water and placed in a flask, and 50 ml of 10N NaOH was added. The solution is evaporated in vacuo and the remaining aqueous solution is extracted with chloroform.
클로로포름 추출물을 합해 물로 세척하고 황산마그네슘상에서 건조한 후 마그네솔
[실시예 18]Example 18
3-[4-(1,1,3,3-테트라메틸부틸아미노)-6-[(1,1,2,2-테트라메틸프로필)아미노]-S-트리아진-2-일]-3-아자비시클로[3,2,2]-노난의 제조3- [4- (1,1,3,3-tetramethylbutylamino) -6-[(1,1,2,2-tetramethylpropyl) amino] -S-triazin-2-yl] -3 Preparation of Azabicyclo [3,2,2] -Nonane
3-[4-클로로-6-(1,1,3,3-테트라메틸부틸 아미노)-S-트리아진-2-일]-3-아자비시클로[3,2,2]-노난 8g (0.022 몰)과 t-헵틸아민 20g (0.17 몰)을 봄브중 글라스 라이너에 넣고 220℃로 유지시킨 오일욕중에서 88시간 동안 가열했다.3- [4-Chloro-6- (1,1,3,3-tetramethylbutyl amino) -S-triazin-2-yl] -3-azabicyclo [3,2,2] -nonane 8 g (0.022 Mole) and 20 g (0.17 mole) of t-heptylamine were placed in a glass liner in a bomb and heated for 88 hours in an oil bath maintained at 220 ° C.
냉각후 봄브 내용물을 클로로포름과 물로 세척하여 플라스크에 넣고 10N NaOH 50㎖를 가했다.After cooling, the contents of the bomb were washed with chloroform and water, and the flask was added to 50 mL of 10N NaOH.
용액을 진공증발시키고 남은 수용액을 클로로포름으로 추출했다. 클로로포름 추출물을 함해 물로 세척하고 황산마그네슘상에서 건조한 후 마그네솔
[실시예 19]Example 19
2-클로로-4,6-비스 [(1,1,2,2-테트라메틸프로필)-아미노]-S-트리아진의 제조Preparation of 2-chloro-4,6-bis [(1,1,2,2-tetramethylpropyl) -amino] -S-triazine
NaOH 20g (0.5 몰)을 물 220㎖에 녹인 용액을 시안우릭 클로라이드 44g (0.24 몰)과 t-헵틸아민 60g(0.46 몰)을 물 1ℓ에 넣어 교반한 현탁액에 한번에 가한다. 반응물을 환류 가열하고 3시간 후 실온으로 냉각되게 방치한다.A solution of 20 g (0.5 mol) of NaOH in 220 ml of water was added to a stirred suspension of 44 g (0.24 mol) of cyanuric chloride and 60 g (0.46 mol) of t-heptylamine in 1 liter of water. The reaction is heated to reflux and left to cool to room temperature after 3 hours.
침전을 여별하고 깔대기증에서 하룻밤 공기건조한 후 융점 131∼133.5℃의 흰색분말 76g을 얻는다.The precipitates were filtered off and air dried overnight in a funnel to obtain 76 g of white powder with a melting point of 131-133.5 ° C.
[실시예 20]Example 20
2-(1,8,8-트리메틸-3-아자비시클로[3,2,1] 옥틴]-4,6-비스(1,1,2,2-테트라메틸프로필아미노)-S-트리아진의 제조Of 2- (1,8,8-trimethyl-3-azabicyclo [3,2,1] octin] -4,6-bis (1,1,2,2-tetramethylpropylamino) -S-triazine Produce
2-클로로-4.6-비스 [(1,1,2,2-테트라메틸프로필) 아미노]-S-트리아진 7g (0.02 몰)과 1,8,8-트리메틸-3-아자비시클로 [3,2,1] 옥틴 31g과 N, N-디이소프로필에틸아민 7.1㎖ (0.04 몰)과 크실렌을 아르곤 분위기하에서 22시간동안 환류한다. 냉각후 반응물을 초산에틸과 물로 회석한다. 혼합물로 물로 희석하고 유기상을 황산마그네슘상에서 건조하고 규조로로 여과한후 진공증발 시킨다. 톨루엔을 가하고 진공에서 수회 재증발시켜 고체를 얻는다. 고체를 디클로로 메탄중에 녹이고 마그네솔
[실시예 21]Example 21
N2-1-1아다만틸-N4,N6-비스 (1,1,2,2-테트라메틸-프로필) 멜라민의 제조Preparation of N 2 -1-1 Adamantyl-N 4 , N 6 -bis (1,1,2,2-tetramethyl-propyl) melamine
2-클로로-4,6-비스 [(1,1,2,2-테트라메틸프로필) 아미노]-S-트리아진 7g (0.02 몰)을 몰타르에 분쇄하고 1-아다만틸아민 24g (0.16 몰)을 잘 혼합한 후 봄브증 글라스라이너중에 넣고 210℃∼220℃로 유지시킨 오일욕중에서 20시간 동안 가열한다. 냉각 후 봄브 내용물을 클로로포름과 물로 세척하며 플라스크에 넣고 10N NaOH 50㎖를 가한다. 용액을 진공증발시키고 남은 수용액을 클로로포름으로 추출한다.7 g (0.02 mol) of 2-chloro-4,6-bis [(1,1,2,2-tetramethylpropyl) amino] -S-triazine was triturated in mortar and 24 g (0.16 mol) of 1-adamantylamine ), Mix well and place in Bomber glass liner and heat for 20 hours in oil bath maintained at 210 ℃ -220 ℃. After cooling, the contents of the bomb are washed with chloroform and water and placed in a flask, and 50 ml of 10N NaOH is added. The solution is evaporated in vacuo and the remaining aqueous solution is extracted with chloroform.
클로로포름 추출물을 합해 물로 세척한 후 황산마그네슘상에서 건조하고 마그네솔
이 고체를 실리카겔 상에서 컬럼크로마로그라피하고 가장 극성이 적은 성분을 함유하는 순수분획물을 아세톤으로 재결정하여 융점 215.5°∼218℃의 무색결정 7.9g을 얻는다.This solid was chromatographed on silica gel and the pure fraction containing the least polar component was recrystallized with acetone to obtain 7.9 g of colorless crystals having a melting point of 215.5 ° to 218 ° C.
[실시예 22]Example 22
N2-2-아다만틸-N4,N6-비스(1,1,2,2-페트라메틸-프로필 멜라민의 제조N 2 -2- adamantyl -N 4, N 6 - bis (1,1,2,2 Petra methyl-producing the profile of melamine
2-클로로-4,6-비스 [(1,1,2,2-테트라메틸프로필) 아미노]-S-트리아진 7g (0.02 몰)과 2-아다만틸 아민 염산염 7.7g (0.041 몰)과 크실렌과 N,N-디이소프로필에틸아민 11㎖ (0.061 몰)을 아르곤 분위기가에서 20시간 동안 환류한다.7 g (0.02 mol) of 2-chloro-4,6-bis [(1,1,2,2-tetramethylpropyl) amino] -S-triazine and 7.7 g (0.041 mol) of 2-adamantyl amine hydrochloride Xylene and 11 ml (0.061 mol) of N, N-diisopropylethylamine are refluxed for 20 hours in an argon atmosphere.
냉각 후 반응물을 초산에틸과 물로 희석한다.After cooling, the reaction is diluted with ethyl acetate and water.
혼합물로 세척하고 유기상을 황산마그네슘상에서 건조한 후 규조토를 통해 여과하고 진공증발시켜 미황색고체 11g을 얻는다. 고체를 디클로로에탄에 녹인 후 마그네솔
[실시예 23]Example 23
엑소-N2-2-노르보닐-N4,N6-비스-[(1,1,2,2-테트라메틸프로필) 아미노]-멸라민의 제조Exo -N 2 -2- Nord carbonyl -N 4, N 6 - bis [(1,1,2,2-tetramethyl-propyl) amino] - Preparation of destroy lamin
2-클로로-4,6-비스 [(1,1,2,2-테트라메틸 프로필) 아미노]-S-트리아진 7g (0.02 몰)과 엑소-2-노르보닐아민 24㎖ (0.2 몰)을 봄브중 글라스라이너에 넣고 185∼195℃로 유지시킨 오일욕 중에서 19∼20시간 동안 가열한다. 냉각후 봄브 내용물을 클로로포름과 물로 세척하여 플라스크에 넣고 10N-NaOH 50m를 가한다. 용액을 진공중에서 증발시킨 후 남은 수용액을 클로로포름으로 추출한다. 클로로포름 추출물을 합해 물로 세척하고 황산마그네슘상에서 건조한 후 마그네솔
[실시예 24]Example 24
2-(3-아자비시클로 [3,3,1] 노닐)-4,6-비스 (1,1,2,2-테트라메틸프로필 아미로)-S-트리아진의 제조Preparation of 2- (3-azabicyclo [3,3,1] nonyl) -4,6-bis (1,1,2,2-tetramethylpropyl amiro) -S-triazine
실시예 20에서의 1,8,8-트리메틸-3-아자비시클로[3,2,1]-옥탄을 동몰량의 3-아자비시클로[3,3,1]노난으로 대치하여 상응하는 2-(3-아자비시클로 [3,3,1] 노닐)-4,6-비스 (1,1,2,2-테트라메틸프로필아미노)-S-트리아진을 우수한 수율로 얻는다.Replace 1,8,8-trimethyl-3-azabicyclo [3,2,1] -octane in Example 20 with an equimolar amount of 3-azabicyclo [3,3,1] nonane to yield the corresponding 2- ( 3-azabicyclo [3,3,1] nonyl) -4,6-bis (1,1,2,2-tetramethylpropylamino) -S-triazine is obtained in good yield.
[실시예 25]Example 25
2-(9-아자비시클로 [3,3,1] 노닐)-4,6-비스 (1,1,2,2-테트라메틸프로필아미노)-S-트리아진의 제조Preparation of 2- (9-azabicyclo [3,3,1] nonyl) -4,6-bis (1,1,2,2-tetramethylpropylamino) -S-triazine
실시예 20에서의 1,8,8-트리메틸-3-아자비시클로 [3,2,1] 옥탄 대신 동몰량의 9-아자비시클로[3,3,1]-노난을 대치하여 2-(9-아자비시클로 [3,3,1]노닐)-4,6-비스 (1,1,2,2-테트라메틸프로필 아미노)-S-트리아진을 무색 결정으로 얻는다.Equivalent molar amount of 9-azabicyclo [3,3,1] -nonane is substituted for 1,8,8-trimethyl-3-azabicyclo [3,2,1] octane in Example 20, replacing 2- (9- Azabicyclo [3,3,1] nonyl) -4,6-bis (1,1,2,2-tetramethylpropyl amino) -S-triazine is obtained as colorless crystals.
[실시예 26]Example 26
2-(3-아자비시클로 [3,2,1]-옥틸)-4-(3-아자비시클로-[3,2,2] 노닐)-6-(1,1,3,3-테트라메틸부틸 아미노)-S-트리아진의 제조2- (3-azabicyclo [3,2,1] -octyl) -4- (3-azabicyclo- [3,2,2] nonyl) -6- (1,1,3,3-tetramethylbutyl Preparation of Amino) -S-triazine
실시예 16과 유사한 방법으로 3-[4-클로로-6-(1,1,3,3-테트라메틸부틸아미노)-S-트리아진-2-일]-3-아자비시클로 [3,2,2] 노난을 3-아자비시클로 [3,2,1] 옥탄과 반응시킨 후 컬럼 크로마토그라피로 정제하여 표제화합물을 얻는다.In a manner similar to Example 16, 3- [4-chloro-6- (1,1,3,3-tetramethylbutylamino) -S-triazin-2-yl] -3-azabicyclo [3,2, 2] The nonane is reacted with 3-azabicyclo [3,2,1] octane and purified by column chromatography to obtain the title compound.
[실시예 27]Example 27
2, 4, 6-트리스 (2-아자비시클로 [3,2,2] 노닐)-S-트리아진의 제조Preparation of 2, 4, 6-tris (2-azabicyclo [3,2,2] nonyl) -S-triazine
시안우릭클로라이드를 3배 과몰량의 2-아자비시클로 [3,2,2] 노난으로 디그라임 용매중 환류온도하에서 3시간 처리하여 표제화합물을 무색 결정으로 얻는다.Cyanuric chloride is treated with 3-fold excess molar amount of 2-azabicyclo [3,2,2] nonane for 3 hours at reflux in a dilimine solvent to give the title compound as colorless crystals.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790001126A KR830000676B1 (en) | 1979-04-10 | 1979-04-10 | N ^ 2, N ^ 4, N ^ 6, -tris (substituted) -melamine production method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790001126A KR830000676B1 (en) | 1979-04-10 | 1979-04-10 | N ^ 2, N ^ 4, N ^ 6, -tris (substituted) -melamine production method |
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| Publication Number | Publication Date |
|---|---|
| KR830000676B1 true KR830000676B1 (en) | 1983-03-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019790001126A KR830000676B1 (en) | 1979-04-10 | 1979-04-10 | N ^ 2, N ^ 4, N ^ 6, -tris (substituted) -melamine production method |
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| KR (1) | KR830000676B1 (en) |
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1979
- 1979-04-10 KR KR1019790001126A patent/KR830000676B1/en active
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