CN1471516A - 1,5-二取代-3-氨基-1,2,4-三唑的制备方法和作为中间体化合物的取代氨基胍 - Google Patents

1,5-二取代-3-氨基-1,2,4-三唑的制备方法和作为中间体化合物的取代氨基胍 Download PDF

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CN1471516A
CN1471516A CNA018181708A CN01818170A CN1471516A CN 1471516 A CN1471516 A CN 1471516A CN A018181708 A CNA018181708 A CN A018181708A CN 01818170 A CN01818170 A CN 01818170A CN 1471516 A CN1471516 A CN 1471516A
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S·伯克蒂
��ʲ
E·奇科什
C·根齐
F·豪伊社
I·海尔迈茨
G·海尧
B·珀丹伊
ж�
A·桑塔丘托尔
T·索莫尔
����ֲ
G·斯沃博达
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2603/58—Ring systems containing bridged rings containing three rings
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    • C07C2603/74—Adamantanes

Abstract

通式(I)的1，5－二取代－3－氨基－1，2，4－三唑的新制备方法，其中R的含义是C1－5烷基；C3－13环烷基－C0－4烷基，任选地被一个或多个C1－3烷基取代；苯基－C0－2烷基，(CH2)n－吗啉代，哌啶子基，吡咯烷代或哌嗪子基基团，任选地被一个或多个卤素原子，C1－3烷基，C1－3烷氧基取代，n是1－5，R1，R2，R3和R4独立地表示氢、卤素、C1－6烷基、C1－3烷氧基或三氟甲基，条件是取代基R1，R2，R3和R4至少一个表示氢。

Description

1，5-二取代-3-氨基-1，2，4-三唑的制备方法和 作为中间体化合物的取代氨基胍
本发明涉及通式(I)的1，5-二取代-3-氨基-1，2，4-三唑的制备方法，
其中R的含义是
C1-5烷基；C3-13环烷基-C0-4烷基，任选地被一个或多个C1-3烷基取代；苯基-C0-2烷基，(CH2)n-吗啉代，哌啶子基，吡咯烷代(pyrrolidino)或哌嗪子基(piperazino)基团，任选地被一个或多个卤素原子，C1-3烷基，C1-3烷氧基取代，
n是1-5，
R1，R2，R3和R4独立地表示氢、卤素、C1-6烷基、C1-3烷氧基或三氟甲基，条件是取代基R1，R2，R3和R4中至少一个表示氢。
通式(I)的1，5-二取代-3-氨基-1，2，4-三唑是在专利申请WO98/51686中描述的通式(VI)治疗有用化合物的中间体，
对于3-氨基-1，2，4-三唑的合成，从氨基胍开始的途径是长期以来已知的(K.T.Potts.Chem.Rev.61，(1961))：在高温下采用合适的酸处理氨基胍盐，或将分离的酰基氨基胍采用碱处理和/或进行热环合。除了在乙酸中进行环合，收率是低到中等。
当由Schotten-Baumann酰化制备氨基胍时情况相似，其中水解发生为竞争性反应。然后在180℃下在DMSO中或采用NaOEt热环化分离的酰基氨基胍(J.Med.Chem.41.2985-93(1998))。
导致生成3-氨基-1，2，4-三唑的氨基胍与酯的反应也是已知的(J.Med.41，2985(1998)；和Chem.Rev.61，87(1961))。
由于在位置1和2中的氮对亲电试剂的反应性几乎相同，1-取代-3-氨基-三唑的合成不能经济地由氨基三唑的制备和随后取代反应解决，因此大约以相同的比例，同等地形成在位置1和位置2取代的衍生物。具有非常相似物理化学性能的异构体的分离是不容易的并且通常仅可由色谱解决，而色谱在工业规模上是昂贵和复杂的。
在文献中仅找到一个例子，其中将取代氨基胍环化成1，2，4-三唑。从酰肼和氨腈开始逐步合成取代的氨基胍，由热解在吡啶盐酸盐中进行环合。然而，合成没有采用一些在氨基胍结构中给出的合理可能性[Ger.Offen.1,808,677(C.A.72，90561m 1970)]。
令我们惊奇的是，我们已经发现通式(I)的1，5-二取代-3-氨基-1，2，4-三唑，
Figure A0181817000051
可以在醇钠或醇钾存在下，由通式(IV)的氨基胍衍生物
Figure A0181817000061
与通式(V)的酸衍生物
以良好的收率通过区域选择合成来制备。
这意味着在氨基胍的四个氮原子中，酰化专有地发生在一个所需要的位置上。甚至通过处理母液也不获得副产物。进一步的惊奇是对碱敏感的氨基胍(Houben-Weil VIII，193.)以良好的收率得到产物，这意味着避免了氨基胍的分解。
与以上内容一致，本发明的目的是提供通式(I)的1，5-二取代-3-氨基-1，2，4-三唑的制备方法，
其中R的含义是
C1-5烷基；C3-13环烷基-C0-4烷基，任选地被一个或多个C1-3烷基取代；苯基-C0-2烷基，(CH2)n-吗啉代，哌啶子基，吡咯烷代或哌嗪子基基团，任选地由一个或多个卤素原子，C1-3烷基，C1-3烷氧基取代，
n是1-5，
R1，R2，R3和R4独立地表示氢、卤素、C1-6烷基、C1-3烷氧基或三氟甲基，条件是取代基R1，R2，R3和R4中至少一个表示氢，
该方法包括
使通式(II)的醛
RCHO         (II)
其中R的含义如上所定义，与通式(III)的氨基胍或它的盐进行反应，并在碱金属醇盐存在下，采用通式(V)的酸衍生物
Figure A0181817000072
其中R1，R2，R3和R4的含义如上所定义并且R5表示氢原子或C1-5烷基，处理生成的通式(IV)的氨基胍衍生物
Figure A0181817000073
其中R的含义如上所定义。
通式II的醛可购得或它们可以由文献已知的方法合成。
在根据本发明的方法中，对于碱金属醇盐，优选使用醇钠或醇钾。
对于通式(II)的化合物，优选1-环己基乙醛，并且对于通式(V)的酸衍生物，优选应用2，5-二甲氧基-4-甲基苯甲酸甲酯。
我们的方法由如下实施例说明：
实施例1
将51.74g环己基乙基氨基胍HCl盐和49.4g的2，5-二甲氧基-4-甲基苯甲酸乙酯溶于150ml甲醇，加入到28g甲醇钠在甲醇的溶液中并将反应混合物回流5小时。在加入稀碱之后，将混合物另外回流1小时并冷却。将获得的晶体滤出，洗涤和干燥，获得55.1g(67％)1-(2-环己基乙基)-5-(2，5-二甲氧基-4-甲基苯基)-3-氨基-1，2，4-三唑。
Mp：136-137℃。由HPLC测得的纯度为99.5％。
起始环己基乙基氨基胍HCl的制备：
将11.05g(0.1mol)氨基胍盐酸盐溶于150ml的96％乙醇中并加入12.62g(0.1mol)1-环己基乙醛。在大气压并在室温下，使用pd/c催化剂氢化获得的席夫碱(Schiff-base)。最后将催化剂滤出，蒸发滤液，将残余物从水结晶，获得17.2g(78％)产物。
Mp：132-134℃。
实施例2-43
应用实施例1描述的程序和使用适当的起始原料，可以制备如下产物(R4＝H)，见表1。表1
Figure A0181817000091
Figure A0181817000101
Figure A0181817000111

Claims (5)

1.通式(I)的1，5-二取代-3-氨基-1，2，4-三唑的制备方法，
Figure A0181817000021
其中R的含义是
C1-5烷基；C3-13环烷基-C0-4烷基，任选地被一个或多个C1-3烷基取代；苯基-C0-2烷基，(CH2)n-吗啉代，哌啶子基，吡咯烷代或哌嗪子基基团，任选地被一个或多个卤素原子，C1-3烷基，C1-3烷氧基取代，
n是1-5，
R1，R2，R3和R4独立地表示氢、卤素、C1-6烷基、C1-3烷氧基或三氟甲基，条件是取代基R1，R2，R3和R4中至少一个表示氢，
该方法包括
使通式(II)的醛
RCHO         (II)
其中R的含义如上所定义，与通式(III)的氨基胍，
Figure A0181817000022
或它的盐进行反应，并在碱金属醇盐存在下，采用通式(V)的酸衍生物
Figure A0181817000023
其中R1，R2，R3和R4的含义如上所定义并且R5表示氢原子或C1-5烷基，处理生成的通式(IV)的氨基胍衍生物，
其中R的含义如上所定义。
2.权利要求1的方法，该方法包括使用醇钠或醇钾作为碱金属醇盐。
3.权利要求1的方法，该方法包括使用1-环己基乙醛作为通式(II)化合物。
4.权利要求1的方法，该方法包括使用2，5-二甲氧基-4-甲基苯甲酸甲酯作为通式(V)化合物。
5.通式(IV)的化合物，
Figure A0181817000032
其中R的含义是
C1-5烷基；C3-13环烷基-C0-4烷基，任选地被一个或多个C1-3烷基取代；苯基-C0-2烷基，(CH2)n-吗啉代，哌啶子基，吡咯烷代或哌嗪子基基团，任选地被一个或多个卤素原子，C1-3烷基，C1-3烷氧基取代。
CNA018181708A 2000-10-26 2001-10-25 1,5-二取代-3-氨基-1,2,4-三唑的制备方法和作为中间体化合物的取代氨基胍 Pending CN1471516A (zh)

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CH530965A (de) * 1964-05-05 1972-11-30 Wander Ag Dr A Verfahren zur Herstellung von 2,6-Dihalogen-phenylalkylaminoguanidinen
CH530964A (de) * 1964-05-05 1972-11-30 Wander Ag Dr A Verfahren zur Herstellung von Phenylalkylaminoguanidinen
CH533603A (de) * 1966-06-02 1973-02-15 Wander Ag Dr A Verfahren zur Herstellung von Phenylalkylaminoguanidinen
FR1537892A (fr) * 1966-07-21 1968-08-30 British Petroleum Co Composition de lubrifiant synthétique
US3515723A (en) * 1967-11-14 1970-06-02 Merck & Co Inc 2 - (5 - amino - 1h - 1,2,4 - triazol - 3 - yl)- 3-aminopyrazines and processes for their preparation
US3541218A (en) * 1969-06-18 1970-11-17 Lilly Co Eli Omicron-fluorobenzylaminoguanidine for diabetes
US3541217A (en) * 1969-06-30 1970-11-17 Lilly Co Eli Omicron-chlorobenzylaminoguanidine for treating bovine ketosis
US3714363A (en) * 1970-08-11 1973-01-30 Sandoz Ag Substituted amino guanidine as anti-diabetic agents
DE4321109C2 (de) * 1993-06-25 1998-01-29 Sanol Arznei Schwarz Gmbh Pharmakologisch aktive Verbindungen mit Nitrosohydrazinpartialstruktur
US5994577A (en) * 1994-11-23 1999-11-30 Larsen; Scott D. Aminoguanidine carboxylates for the treatment of non-insulin-dependent diabetes mellitus
CA2329709A1 (en) * 1998-04-24 1999-11-04 Mitokor Compounds and methods for treating mitochondria-associated diseases

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JP2004512329A (ja) 2004-04-22
PL360786A1 (en) 2004-09-20
MXPA03003506A (es) 2004-05-04
WO2002034729A1 (en) 2002-05-02
CZ20031437A3 (cs) 2004-10-13
CA2427045A1 (en) 2002-05-02
HUP0004154A3 (en) 2003-11-28
BR0114828A (pt) 2003-10-28
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