CN1124265C - 制备芳族二酰亚胺的方法 - Google Patents
制备芳族二酰亚胺的方法 Download PDFInfo
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- CN1124265C CN1124265C CN98804928A CN98804928A CN1124265C CN 1124265 C CN1124265 C CN 1124265C CN 98804928 A CN98804928 A CN 98804928A CN 98804928 A CN98804928 A CN 98804928A CN 1124265 C CN1124265 C CN 1124265C
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- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 125000003118 aryl group Chemical group 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000003949 imides Chemical class 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003512 tertiary amines Chemical class 0.000 abstract 1
- -1 Cyclic imide Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GRSMWKLPSNHDHA-UHFFFAOYSA-N Naphthalic anhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=CC3=C1 GRSMWKLPSNHDHA-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- KMOUUZVZFBCRAM-OLQVQODUSA-N (3as,7ar)-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione Chemical compound C1C=CC[C@@H]2C(=O)OC(=O)[C@@H]21 KMOUUZVZFBCRAM-OLQVQODUSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及制备式(I)所示的二酰亚胺的方法，其中R1、R2、R3和R4的定义同说明书所述。依据本发明的方法，式(II)R1-CO-O-R2和式(III)R3-CO-O-R4所示的二羧酸酐与式H2N-R-NH2所示的胺在叔胺存在下反应。
Description
本发明涉及制备芳族二酰亚胺的新方法。
环状酰亚胺通常是以环状羧酸酐和氨或伯胺为原料制备的(《化学评论》(Chem.Rev.)70(1970)439-469)。其它方法是用二羧酸与氨或伯胺在高温下(200℃)反应，或用二酯与氨或伯胺在乙醇钠存在下反应。此外，例如马来酰亚胺是在不同的溶剂，例如DMF、二氧六环或二甲基乙酰胺中，以及催化量的N-甲基吗啉存在下合成的(JP58096-066-A)。
为了制备芳族二酰亚胺例如双萘二甲酰亚胺，将萘二甲酸酐与多胺在溶剂例如DMSO、DMF、THF或乙醇中加热(WO 94/02466)。合成的双萘二甲酰亚胺是用色谱法纯化。J.H.Sun也用乙醇作为溶剂来制备双萘二甲酰亚胺(US 5488110)。然而，此合成方法不能以较大规模实施，因为用柱色谱法纯化产物太复杂。
现在已经发现了能以简单方式将萘二甲酸酐和邻苯二甲酸酐转化成其二酰亚胺的方法。
本发明涉及制备式I所示的二酰亚胺的方法，其中R是-Alk1-NH-Alk2-(NH-Alk3)a-，其中Alk1、Alk2和Alk3是C2-6-亚烷基，且a是0或1，R1+R2一起构成
或
R3+R4一起构成或
其中X1和X2可以是相同或不同的基团，它们是氢或卤原子，硝基，未取代或被1个或2个C1-4烷基取代的氨基，或羟基，巯基或C1-4烷基，X3和X4可以是相同或不同的基团，它们是氢或卤原子，未取代或被1个或2个C1-4烷基取代的氨基，或羟基，巯基或C1-4烷基，所述方法是用式II和III所示的二羧酸酐
R1-CO-O-CO-R2(II) R3-CO-O-CO-R4(III)其中R1、R2、R3和R4的定义同上与式H2N-R-NH2所示的胺反应，其中R的定义同上，其中反应是在叔胺类化合物存在下进行的。
合适的原料式II和III化合物尤其是未取代或取代的萘二甲酸酐。
X1和X2可以是相同或不同基团的，优选为氢，氟，氯或溴原子，未取代或被1个或2个甲基取代的氨基，或C1-4-烷基。尤其优选的是，X1是氢原子且X2是氢原子或氨基。
上述对X1和X2的优选定义也同样相应地适用于X3和X4。
X1-X4基团优选位于环的间位或对位。间位是特别优选的。
优选的是，X1和X3相同，且X2和X4相同。
特别合适的亚烷基Alk1、Alk2和Alk3是具有3个或4个碳原子的亚烷基。a优选为0。
适用于反应的叔胺类化合物是：三乙胺，二异丙基乙胺，二甲基环己基胺和C1-4-烷基-N-吗啉。其中，C1-4-烷基-N-吗啉，尤其是N-甲基吗啉是特别优选的。
叔胺类化合物通常也作为反应的溶剂。然而，也可以加入其它溶剂，例如具有高达6个、优选高达4个碳原子的仲醇和叔醇，二氧六环，四氢呋喃或甲苯。优选不使用其它溶剂。
式II和III所示的酸酐与胺以大约2∶1的摩尔比进行反应。
叔胺类化合物的用量可以在很宽的范围内变化。通常，叔胺类化合物的用量应足以使其中的反应物完全溶解。然而，少量的叔胺类化合物也能满足需要。
通常，在15-30℃开始反应，将反应温度缓慢地升至回流温度。根据反应温度增加的速度，大约2-4小时后反应完全。
通过将反应混合物部分浓缩以及随后在0-5℃进行沉淀，能以简单的方式将产物从反应混合物中分离出来。以这种方式获得的产物已经具有高的纯度。如果需要的话，可以通过重结晶将产物进一步纯化。
与已知的方法相比，本发明新方法的优点是，它可以很容易地实施，甚至以工业规模也是如此，能非常令人满意地获得化合物I。
化合物I适于，例如中止阴离子型荧光增白剂产生的荧光。萘二甲酰亚胺表现出制癌作用。
实施例1
在室温下，将1.89kg(11.75mol)双-1，3-(2’-氨基乙基)-丙基-1，3-二胺、4.80kg(23.5mol，纯度为97％)萘二甲酸酐和29升N-甲基吗啉置于50升的反应器中。用15分钟将反应温度升至38℃。将反应混合物在此温度下搅拌2小时，然后将反应温度缓慢地升至回流温度，在回流温度下维持1小时。蒸馏掉5.8升溶剂。在约90℃将反应混合物过滤，缓慢地冷却至0-5℃。过滤得到的沉淀，用冰冷的甲醇洗涤，减压干燥。得到了6.63kg N，N’-双[2-(1，8-萘二甲酰亚氨基)乙基]-1，3-二氨基丙烷，熔点为160℃。
实施例2
重复实施例1，但是将各反应物在29升N-甲基吗啉和5升乙醇的混合物中进行反应。得到了6.26kg产物。下述化合物可按照实施例1的方法制备到：
| 实施例 | A |
| 3 | 2-OH |
| 4 | 3-OH |
| 5 | 4-OH |
| 6 | 3-NO2 |
| 7 | 4-NO2 |
| 8 | 2-CH3 |
| 9 | 3-Br |
| 实施例 | F | G |
| 10 | H | H |
| 11 | H | 叔-C4H9 |
| 12 | F | F |
Claims (2)
1.制备式I所示的二酰亚胺的方法，
其中R是-Alk1-NH-Alk2-(NH-Alk3)a-，其中Alk1、Alk2和Alk3是C2-6-亚烷基，且a是0或1，R1+R2一起构成
或
R3+R4一起构成
或
其中X1和X2可以是相同或不同的基团，它们是氢或卤原子，硝基，未取代或被1个或2个C1-4烷基取代的氨基，羟基，巯基或C1-4烷基，X3和X4可以是相同或不同的基团，它们是氢或卤原子，未取代或被1个或2个C1-4烷基取代的氨基，羟基，巯基或C1-4烷基，所述方法是用式II和III所示的二羧酸酐
R1-CO-O-CO-R2(II) R3-CO-O-CO-R4(III)其中R1、R2、R3和R4的定义同上与式H2N-R-NH2所示的胺反应，其中R的定义同上，其中反应是在C1-4-烷基-N-吗啉中进行的。
2.根据权利要求1的方法，其中反应是在N-甲基吗啉中进行的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19720803.7 | 1997-05-16 | ||
| DE19720803A DE19720803A1 (de) | 1997-05-16 | 1997-05-16 | Verfahren zur Herstellung von aromatischen Bisimiden |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1255125A CN1255125A (zh) | 2000-05-31 |
| CN1124265C true CN1124265C (zh) | 2003-10-15 |
Family
ID=7829816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98804928A Expired - Fee Related CN1124265C (zh) | 1997-05-16 | 1998-05-04 | 制备芳族二酰亚胺的方法 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6177570B1 (zh) |
| EP (1) | EP0983247B1 (zh) |
| JP (1) | JP2001527564A (zh) |
| CN (1) | CN1124265C (zh) |
| DE (2) | DE19720803A1 (zh) |
| DK (1) | DK0983247T3 (zh) |
| ES (1) | ES2191314T3 (zh) |
| WO (1) | WO1998052924A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7947839B2 (en) * | 2004-12-01 | 2011-05-24 | Genentech, Inc. | Heterocyclic-substituted bis-1,8 naphthalimide compounds, antibody drug conjugates, and methods of use |
| CN102702297B (zh) * | 2012-06-20 | 2014-07-02 | 河南省科学院化学研究所有限公司 | 胆酸-萘酰亚胺类化合物的制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993012092A1 (en) * | 1991-12-11 | 1993-06-24 | The Du Pont Merck Pharmaceutical Company | Highly water soluble bis-naphthalimides useful as anticancer agents |
| WO1994002466A1 (en) * | 1992-07-27 | 1994-02-03 | The Du Pont Merck Pharmaceutical Company | Unsymmetrical mono-3-nitro bis-naphthalimides as anticancer agents |
| WO1996025400A2 (en) * | 1995-02-16 | 1996-08-22 | The Du Pont Merck Pharmaceutical Company | 3-aromatic and 3-heteroaromatic substituted bisnaphthalimides |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4136489A1 (de) * | 1991-11-06 | 1993-05-13 | Bayer Ag | Neue diethylentriamin-derivate und deren verwendung zu diagnostischen und therapeutischen zwecken |
-
1997
- 1997-05-16 DE DE19720803A patent/DE19720803A1/de not_active Withdrawn
-
1998
- 1998-05-04 JP JP54987198A patent/JP2001527564A/ja active Pending
- 1998-05-04 WO PCT/EP1998/002621 patent/WO1998052924A1/de active IP Right Grant
- 1998-05-04 CN CN98804928A patent/CN1124265C/zh not_active Expired - Fee Related
- 1998-05-04 ES ES98930671T patent/ES2191314T3/es not_active Expired - Lifetime
- 1998-05-04 US US09/381,051 patent/US6177570B1/en not_active Expired - Lifetime
- 1998-05-04 EP EP98930671A patent/EP0983247B1/de not_active Expired - Lifetime
- 1998-05-04 DE DE59807019T patent/DE59807019D1/de not_active Expired - Lifetime
- 1998-05-04 DK DK98930671T patent/DK0983247T3/da active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993012092A1 (en) * | 1991-12-11 | 1993-06-24 | The Du Pont Merck Pharmaceutical Company | Highly water soluble bis-naphthalimides useful as anticancer agents |
| WO1994002466A1 (en) * | 1992-07-27 | 1994-02-03 | The Du Pont Merck Pharmaceutical Company | Unsymmetrical mono-3-nitro bis-naphthalimides as anticancer agents |
| WO1996025400A2 (en) * | 1995-02-16 | 1996-08-22 | The Du Pont Merck Pharmaceutical Company | 3-aromatic and 3-heteroaromatic substituted bisnaphthalimides |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001527564A (ja) | 2001-12-25 |
| US6177570B1 (en) | 2001-01-23 |
| ES2191314T3 (es) | 2003-09-01 |
| CN1255125A (zh) | 2000-05-31 |
| EP0983247B1 (de) | 2003-01-22 |
| DE19720803A1 (de) | 1998-11-19 |
| DK0983247T3 (da) | 2003-05-19 |
| EP0983247A1 (de) | 2000-03-08 |
| DE59807019D1 (de) | 2003-02-27 |
| WO1998052924A1 (de) | 1998-11-26 |
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