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4 Nitro Phthalimide Synthesis Essay

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4 nitro phthalimide synthesis essay

Phthalimides

The most important synthesis of phthalimides is the dehydrative condensation of phthalic anhydride at high temperatures with primary amines, when the amine is available. When the amine is not readily accessible, the direct N -alkylation of phthalimides with alcohols under Mitsunobu conditions and of potassium phthalimide with alkyl halides (Gabriel Synthesis ) are popular alternative approaches to Phth-protected amines.

In peptide synthesis, the exhaustive substitution of primary amines is desirable to block both hydrogens and avoid racemization of the substrates. Phthalimides are suitable protective groups for this purpose, but beyond the most frequently used methods of hydrazinolysis and basic hydrolysis, there are only a few deprotection methods that are gentle and near-neutral, which is a drawback.

Protection of Amino Groups


An economical and practical method for the synthesis of a wide range of imide derivatives has been developed by using inexpensive and readily available reagents under mild conditions.
P. Y. Reddy, S. Kondo, T. Toru, Y. Ueno, J. Org. Chem.. 1997. 62. 2652-2654.


A Lewis acid catalyzed and solvent free procedure for the preparation of imides from the corresponding anhydrides uses TaCl5 -silica gel as Lewis acid under microwave irradiation.
S. Chandrasekhar, M. Takhi, G. Uma, Tetrahedron Lett.. 1997. 38. 8089-8092.


A highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III). The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. A plausible mechanism explains the crucial role of water.
L. Becerra-Figueroa. A. Ojeda-Porras, D. Gamba-S�nchez, J. Org. Chem.. 2014. 79. 4544-4552.

Other Syntheses of Phthalimide-protected Amino Groups


A convenient, efficient, and selective N-Alkylation of N-acidic heterocyclic compounds with alkyl halides is accomplished in ionic liquids in the presence of potassium hydroxide as a base. In this manner, phthalimide, indole, benzimidazole, and succinimide can be successfully alkylated.
Z.-G. Le, Z.-C. Chen, Y. Hu, Q.-G. Zheng, Synthesis. 2004. 208-212.


An efficient and simple method enables the N-alkylation of aromatic cyclic imides using cesium carbonate as the base in anhydrous N,N -dimethylformamide at low temperatures (20-70˚C). The employment of microwave irradiation presents noteworthy advantages over conventional heating. The method is compatible with base labile functional groups.
M. I. Escudero, L. D. Kremenchuzky, I. A. Perillo, H. Cerecetto, M. M. Blanco, Synthesis. 2011. 571-576.


Transition-metal-free multicomponent reactions involving arynes, isocyanides, and CO2 as the third component resulted in the formation of N -substituted phthalimides in good yields, whereas the use of water as the third component furnished benzamide derivatives in good yields. These reactions took place under mild conditions with broad scope.
T. Kaicharla, M. Thangaraj, A. T. Biju, Org. Lett.. 2014. 16. 1728-1731.


Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, enable a selective and practical deprotection sequence. Treatment of these intermediates with propylene glycol enables the rapid release of amine hydrochloride salts in good yields without epimerization of the amino center. The hydrochloride salts can be isolated or carried forward for subsequent chemistry.
S. G. Koenig, C. P. Vandenbossche, H. Zhao, P. Mousaw, S. P. Singh, R. P. Bakale, Org. Lett.. 2009. 11. 433-436.


The synthesis of isomerically pure allylic amines, including farnesyl amine, is achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis. 1995. 756-758.


A fully fluorous Mitsunobu reaction employing a fluorous phosphine and a fluorous azodicarboxylate is described. Pure products can be isolated by rapid solid phase extraction (spe) over fluorous silica in excellent yields. The fluorous fraction containing the flourous phosphine oxide and the flourous hydrazide can be separated and the starting reagents can be regenerated using appropriate redox reactions.
S. Dandapani, D. P. Curran, Tetrahedron. 2002 , 58. 3855-3864.


A highly chemoselective PPh3 -catalyzed three-component reaction of an imine, alkyl vinyl ketone, and phthalimide or succinimide gives various highly functional adducts with high diastereoselectivities via aza-Morita-Baylis-Hillman reactions of aryl-substituted imines and alkyl vinyl ketones followed by Michael additions of imides and then epimerization.
S.-e. Syu, Y.-T. Lee, Y.-J. Jang, W. Lin, J. Org. Chem.. 2011. 76. 2888-2891.


Suzuki-Miyaura cross-coupling enables a one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via coupling with sodium phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine.
N. Murai, M. Miyano, M. Yonaga, K. Tanaka, Org. Lett.. 2012. 14. 2818-2821.


Phthalimides are converted to primary amines in an efficient, two-stage, one-flask operation using NaBH4 /2-propanol, then acetic acid. Phthalimides of α-amino acids are smoothly deprotected with no measurable loss of optical activity.
J. O. Osby, M. G. Martin, B. Ganem, Tetrahedron Lett.. 1984. 25. 2093-2096.


The synthesis of isomerically pure allylic amines, including farnesyl amine, is achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis. 1995. 756-758.


The synthesis of isomerically pure allylic amines, including farnesyl amine, is achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis. 1995. 756-758.


Suzuki-Miyaura cross-coupling enables a one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via coupling with sodium phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine.
N. Murai, M. Miyano, M. Yonaga, K. Tanaka, Org. Lett.. 2012. 14. 2818-2821.

Phthalimides in Multi-step Syntheses


While 3,4;5,6-di-O -isopropylidene-N -phthaloyl-D-glucosamine propane-1,3-diyl dithioacetal underwent fast β-elimination, the corresponding N -acetyl derivative was easily deprotonated with butyllithium to form the dilithiated intermediate. Stoichiometry and temperature were crucial factors for selective C-C coupling with various electrophiles.
Y.-L. Chen, R. Leguijt, H. Redlich, R. Fr�hlich, Synthesis. 2006. 4212-4218.

Other articles

New N-aryloxy-phthalimide derivatives

First online: 18 July 2010

New N-aryloxy-phthalimide derivatives. Synthesis, physico-chemical properties, and QSPR studies
  • Madalina Tudose Affiliated with Institute of Physical Chemistry
  • . Florin D. Badea Affiliated with Organic Chemistry Department, University Politehnica Bucharest
  • . Miron T. Caproiu Affiliated with Center of Organic Chemistry
  • . Adrian Beteringhe Affiliated with Institute of Physical Chemistry
  • . Maria Maganu Affiliated with Center of Organic Chemistry
  • . Petre Ionita Affiliated with Institute of Physical Chemistry Organic Chemistry Department, University of Bucharest
  • . Titus Constantinescu Affiliated with Institute of Physical Chemistry
  • . Alexandru T. Balaban Affiliated with Texas A&M University at Galveston Email author

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Abstract

Starting from N-hydroxyphthalimide 1 and the reactive fluoro- or chloro-nitroaryl derivatives 2, 3 and 4a-e (2-chloro-3,5-dinitropyridine; 3. NBD-chloride; 4a. 1-fluoro-2,4-dinitrobenzene; 4b. picryl chloride; 4c. 4-chloro-3,5-dinitrobenzotrifluoride; 4d. 2-chloro-3,5- dinitrobenzotrifluoride; 4e. 4-chloro-3,5-dinitrobenzoic acid) the corresponding N-(2-nitroaryloxy)-phthalimide derivatives 5a-e. or 6 and 7 were obtained and characterized by IR, UV-Vis 1 H-NMR and 13 C-NMR spectroscopy. The TLC behavior and the hydrophobicity of these derivatives have been experimentally evaluated by RM0 parameters (using RP-TLC). The experimental RM0 parameters were compared with the calculated partition coefficient, log P. A QSPR study was also performed to establish possible correlations between the structure and physical properties (λmax and RM0 ) of compounds 5a-e, 6. and 7.

Keywords

N-aryloxy-phthalimide derivatives UV-Vis TLC RP-TLC QSPR

A comparison of poly(etherimide)s with 3-phthalimide and 4-phthalimide units: synthesis, characterization and physical properties

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A comparison of poly(etherimide)s with 3-phthalimide and 4-phthalimide units. synthesis, characterization and physical properties

Pethrick, R.A. and Eastmond, G.C. and Paprotny, J. and Santamaria-Mendia, F. (2006) A comparison of poly(etherimide)s with 3-phthalimide and 4-phthalimide units. synthesis, characterization and physical properties. Macromolecules, 39 (22). pp. 7534-7548. ISSN 0024-9297

Abstract

Bis(ether anhydride)s with 3- or 4-phthalimide moieties were prepared by reacting 3- or 4-nitrophthalodinitrile, respectively, with several diols and converting the resulting bis(ether dinitrile)s to bis(ether anhydride)s. Selected dianhydrides were converted into poly(ether imide)s in a two-stage solution polymerization and imidization process. It was found that, in most cases, the dianhydrides with 4-phthalic anhydride units gave high-molecular-weight polymers with any of several aromatic diamines. In contrast, dianhydrides with 3-phthalic anhydride units gave, primarily, low-molecular-weight products. Examination of several low-molecular-weight products by electrospray-ionization mass spectrometry demonstrated that the products consisted of small oligomers, cyclic or linear according to the structure of the diamine. A series of high-molecular-weight polymers were prepared from 4,4‘-bis(4‘ ‘-aminophenoxy)biphenyl (BAPB) and each of several bis(ether anhydride)s with 3- or 4-phthalic anhydride units; the anhydrides had isopropylidine or hexafluoroisopropylidine units or ortho-methyl or ortho-tert-butyl substituents in the diol residues. These polymers were characterized in terms of their molecular weights and glass-transition temperatures. The gas permeabilities, positron annihilation, and dielectric relaxation behaviors of the polymers were investigated and their properties related to their molecular structures. Dielectric relaxation spectroscopy measurements indicate that, in this group of polymers, the rates of the local chain mobility are comparable and are able to facilitate gas diffusion. An apparent linear correlation between the permeation coefficients and free volume as determined by positron annihilation lifetime spectroscopy was observed with certain gases. Comparison of polymers with similar molecular structures indicated that isomeric polymers with 3- and 4-linked phthalimide units have similar properties and that the introduction of branched chains or fluorinated groups leads to an increase in the free volume and consequently increased permeability.

Universal Aromatic - acetyl phthalimide Manufacturer & Exporters in Ankleshwar

Universal Aromatic

Manufacturer / Exporters / Wholesale Suppliers Of phthalimide derivative, Chemicals, Dyes Intermediates, Ethyl Bromo Acetate, Morpholine, phthalimide derivative, acetyl phthalimide, butyl phthalimide, ethyl phthalimide, hydroxyl phthalimide, isopropyl phthalimide, meta dinitro benzene, methyl phthalimide, Mono Bromo Acetic Acid, Triazole, 2 Chloro 4 Amino Phenol, Meta Uriedo Aniline HCL, 4 Chloro 2 Nitro Phenol, 2 Amino Phenol 4 Sulphonic Acid, Potassium 4 chloro 3 5 Dinitro Benzene Sulfonate, Ambazone, Sodium 1 2 4 Triazole, 4 Amino N Methyl Phthalimide, 4-Nitro N Methyl Phthalimide, Drug Intermediates, meta uriedo aniline, 4 Chloro 2 Amino Phenol, 5-Chloro 8-Hydroxy Quinoline, Pilot Plant

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Патент CN102199118A - Oxo-bi(N-Methylphthalimide) synthesis method - Google Патенты

Oxo-bi(N-Methylphthalimide) synthesis method
CN 102199118 A

An oxo-bi(N-Methylphthalimide) synthesis method, which solves problems existing in prior art, such as long reaction time, incomplete reaction and low yield. The method comprises the following steps: adding N-methyl-4-nitrophthalimide, sodium carbonate, potash, N- methyl pyrrolidone, toluene and alkyl guanidine haloid into a three-neck flask; then heating for refluxing; cooling to room temperatureand pouring into water; filtering solid; washing and drying to finish. The method of the invention has moderate reaction conditions without requiring a waterless condition or an inert gas protection,a short reaction time, a complete reaction, and a simple post treatment. The product, which is easy to separate, has a yield higher than 85%, a melting point of 269-271 DEG C, and a high purity. In addition, the method with a reduced production costs is environment-friendly and suitable for large scale production.

1. 一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法,其特征在于合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法按以下步骤实施:向带有搅拌器、冷凝器、温度计的三口瓶中加入80〜90gN-甲基-4-硝基邻苯二甲酰亚胺、20〜25g碳酸钠、8〜12g碳酸钾、 200〜500mlN-甲基吡咯烷酮、30〜IOOml甲苯和0. 1〜Ig烷基胍卤盐,然后在150〜 190°C下加热回流3〜7h,冷却至室温后倒入500〜2000ml的水中,过滤出棕褐色固体,经水洗和干燥后,即得氧代-双(N-甲基邻苯二甲酰亚胺);其中烷基胍卤盐为五烷基胍卤盐或六烷基胍卤盐。 A synthesis of oxo - Two (N- methyl phthalimide) method, wherein oxo synthesis - bis (N- methyl phthalimide) method as follows Step embodiment: the 80

90gN--methyl-4-nitro phthalimide, 20

12g potassium with a stirrer, a condenser, a thermometer, three-necked flask, 200

500mlN- methylpyrrolidone, 30

IOOml toluene and 0. 1

Ig alkyl halide guanidine salt, 150

190 ° C and then heated under reflux for 3

7h, cooled to room temperature, poured into water 500

2000ml filtration a tan solid which was washed with water and then dried to obtain the oxo - bis (N- methyl phthalimide); wherein the alkyl halide salt is guanidine pentaalkylguanidinium halide salt or brine hexaalkylguanidinium salt.

2.根据权利要求1所述的一种合成氧代_双(N-甲基邻苯二甲酰亚胺)的方法,其特征在于向带有搅拌器、冷凝器、温度计的三口瓶中加入82〜88gN-甲基-4-硝基邻苯二甲酰亚胺、21〜24g碳酸钠、9〜Ilg碳酸钾、300〜400mlN-甲基吡咯烷酮、40〜80ml甲苯和0. 3〜0. 8g烷基胍卤盐。 2. A synthetic oxo according to claim 1 _ bis (N- methyl-phthalimide) method, wherein the stirrer, a condenser, a thermometer with a three-necked flask was added 82

24g sodium carbonate, 9

Ilg potassium, 300

400mlN- methylpyrrolidone, 40

80ml toluene and 0.5 3

0. 8g alkylguanidinium halide salt.

3.根据权利要求1所述的一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法,其特征在于向带有搅拌器、冷凝器、温度计的三口瓶中加入85gN-甲基-4-硝基邻苯二甲酰亚胺、23g碳酸钠、IOg碳酸钾、350mlN-甲基吡咯烷酮、60ml甲苯和0. 5g烷基胍卤盐。 3. A synthetic oxo according to claim 1 - bis (N- methyl-phthalimide) method, wherein the three-necked flask equipped with a stirrer, a condenser, a thermometer was added 85gN- methyl-4-nitro-phthalimide, 23g sodium carbonate, IOg potassium, 350mlN- methylpyrrolidone, 60ml toluene, and 0. 5g alkylguanidinium halide salt.

4.根据权利要求1、2或3所述的一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法,其特征在于在160〜180°C下加热回流4〜6h,冷却至室温后倒入800〜1500ml的水中。 4. A synthetic-oxo-1, 2, or claim 3, wherein - bis (N- methyl-phthalimide) method, characterized in that at 160

180 ° C under heating at reflux for 4

6h, cooled to room temperature, poured into water 800

5.根据权利要求4所述的一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法,其特征在于在170°C下加热回流5h,冷却至室温后倒入IOOOml的水中。 A synthetic oxo according to claim 4, wherein - bis (N- methyl-phthalimide) method, characterized in that 170 ° C is heated under reflux for 5h, cooled to room temperature, poured into IOOOml water.

一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法 A synthetic oxo - bis (N- methyl phthalimide) method

技术领域 Technical Field

[0001] 本发明涉及一种氧代-双(N-甲基邻苯二甲酰亚胺)的合成方法。 [0001] The present invention relates to an oxo - bis (N- methyl phthalimide) synthesis method. 背景技术 Background

[0002] 氧代-双(N-甲基邻苯二甲酰亚胺)(OBI)是合成聚酰亚胺的重要单体3,3',4, 4' -二苯醚四甲酸二酐(ODPA)的中间体。 [0002] oxo - bis (N- methyl-phthalimide) (OBI) is an important monomer for the synthesis of the polyimide 3,3 ', 4, 4' - diphenyl ether tetracarboxylic dianhydride (ODPA) intermediates. 由ODPA合成的聚酰亚胺由于柔性醚键的引入, 除具有高耐热性,良好的机械性能和介电性能外,还具有可熔性。 Synthesized by the ODPA polyimide due to the introduction of flexible ether bond, in addition to a high heat resistance and good mechanical properties and dielectric properties, but also has a fusible. ODPA是目前用于聚酰亚胺合成的醚酐类单体中用量最大的一种。 ODPA is the amount of ether anhydride monomer used in the synthesis of polyimide biggest one.

[0003] 传统合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法是在无机碱金属、碱土金属的亚硝酸盐、碳酸盐或氟化钾、氟化钠存在下,加上相转移催化剂如四乙基溴化铵、四丁基溴化铵、四苄基溴化铵、四苯基溴化磷等,在极性非质子性溶剂下进行自缩合反应。 [0003] The conventional synthetic oxo - bis (N- methyl-phthalimide) method is an inorganic alkali metal, alkaline earth metal nitrites, carbonates or potassium fluoride, in the presence of sodium fluoride. coupled with a phase transfer catalyst such as tetraethylammonium bromide, tetrabutylammonium bromide, benzyl bromide IV, tetraphenyl phosphonium bromide, etc. in a polar aprotic solvent from the condensation reaction. 该工艺路线虽较为成熟,但传统工艺中所用的催化剂如亚硝酸钠等在加热状态下在非质子性极性溶剂中的溶解度较小,导致反应时间延长并且反应不完全,产物收率较低,一般为65%〜 75%。 The process route, although more mature, but the traditional process used a catalyst such as sodium nitrite and so the solubility in a heated state in an aprotic polar solvent is small, resulting in reaction time and the reaction is incomplete, a lower product yield. typically 65% ​​to 75%.

[0004] 本发明目的是为了解决现有合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法存在反应时间长、反应不完全和产物收率低的问题,而提供一种合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法。 [0004] The object of the present invention is to solve the existing oxo synthesis - bis (N- methyl phthalimide) methods exist long reaction time, the reaction was incomplete and the problem of low product yield, while providing a synthetic oxo - bis (N- methyl-phthalimide) method.

[0005] 合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法按以下步骤实施:向带有搅拌器、 冷凝器、温度计的三口瓶中加入80〜90gN-甲基-4-硝基邻苯二甲酰亚胺、20〜25g碳酸钠、8〜12g碳酸钾、200〜500mlN-甲基吡咯烷酮、30〜IOOml甲苯和0. 1〜Ig烷基胍卤盐,然后在150〜190°C下加热回流3〜7h,冷却至室温后倒入500〜2000ml的水中,过滤出棕褐色固体,经水洗和干燥后,即得氧代-双(N-甲基邻苯二甲酰亚胺);其中烷基胍卤盐为五烷基胍商盐或六烷基胍卤盐。 [0005] Synthesis of oxo - bis (N- methyl phthalimide) method to implement the following steps: to with a stirrer, a condenser, a thermometer, a three-necked flask 80

90gN- methyl - 4-nitro-phthalimide, 20

12g potassium, 200

500mlN- methylpyrrolidone, 30

IOOml toluene and 0. 1

Ig alkylguanidinium halide salt, and then 150

190 ° C under heating reflux 3

7h, after cooling to room temperature, poured into water 500

2000ml, tan solid filtered off, washed with water and then dried to obtain the oxo - bis (N- methyl phthalamide A imide); wherein the alkyl halide salt is guanidine pentaalkylguanidinium List hexaalkylguanidinium halide salt or salts.

[0006] 本发明中的反应条件比较温和,不需要无水条件或惰性气体保护,同时反应时间短,反应完全,产品容易分离,产物收率高达85%以上,熔点为269〜271°C,反应后处理简单、产品纯度高,可以达到99%以上;本发明合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法,由于产品收率高,因此相对较少了三废的排放,不污染环境,同时也降低了生产成本,适用于大规模生产。 [0006] The present invention is relatively mild reaction conditions, no anhydrous conditions or inert gas, while short reaction time, the reaction was complete, the product is easy to separate, the yield up to 85%, melting point of 269

271 ° C, After the reaction is simple, high product purity, can reach more than 99%; the present invention oxo synthesis - bis (N- methyl phthalimide) method, because the product yield, relatively small and therefore the waste emissions, no pollution, but also reduce the production cost, suitable for mass production.

具体实施方式 DETAILED DESCRIPTION

[0007] 具体实施方式一:本实施方式合成氧代_双(N-甲基邻苯二甲酰亚胺)的方法按以下步骤实施:向带有搅拌器、冷凝器、温度计的三口瓶中加入80〜90gN_甲基-4-硝基邻苯二甲酰亚胺、20〜25g碳酸钠、8〜12g碳酸钾、200〜500mlN_甲基吡咯烷酮、30〜IOOml 甲苯和0. 1〜Ig烷基胍卤盐,然后在150〜190°C下加热回流3〜7h,冷却至室温后倒入500〜2000ml的水中,过滤出棕褐色固体,经水洗和干燥后,即得氧代-双(N-甲基邻苯二甲酰亚胺);其中烷基胍卤盐为五烷基胍卤盐或六烷基胍卤盐。 [0007] DETAILED DESCRIPTION OF A: Synthesis of the present embodiment oxo _ bis (N- methyl-phthalimide) embodiment of the method according to the following steps: To a stirrer, a condenser, a thermometer with a three-necked flask Join 80

90gN_ methyl-4-nitro-phthalimide, 20

25g sodium carbonate, 8

12g potassium, 200

500mlN_ methylpyrrolidone, 30

IOOml toluene and 0. 1

Ig alkylguanidinium halide salt, then heated to reflux under 150

7h, after cooling to room temperature, poured into water 500

2000ml, tan solid filtered off, washed with water and then dried to obtain the oxo - Double (N- methyl-phthalimide); wherein the alkyl halide salt is guanidine pentaalkylguanidinium hexaalkylguanidinium halide salt or halide salt.

[0008] 本实施方式中碳酸钠和碳酸钾属于碱金属碳酸盐,作为催化剂使用;烷基胍卤盐也作为催化剂使用;N-甲基吡咯烷酮属于极性非质子性溶剂。 [0008] In the present embodiment as sodium carbonate and potassium carbonate, alkali metal carbonate below, using as a catalyst; alkylguanidinium halide salts are also used as a catalyst; N- methylpyrrolidone belongs polar aprotic solvent.

[0009] 本实施方式中进行的是自缩合反应。 [0009] In the present embodiment, since the condensation reaction is carried out.

[0010] 具体实施方式二:本实施方式与具体实施方式一的不同是向带有搅拌器、冷凝器、温度计的三口瓶中加入80gN-甲基-4-硝基邻苯二甲酰亚胺、20g碳酸钠、8g碳酸钾、 200mlN-甲基吡咯烷酮、30ml甲苯和0. Ig烷基胍卤盐。 [0010] DETAILED DESCRIPTION II: the present embodiment and the specific embodiment is different from the one with a stirrer, a condenser, a thermometer, three-necked flask 80gN- methyl-4-nitro-phthalimide. 20g sodium, 8g potassium, 200mlN- methylpyrrolidone, 30ml toluene and 0. Ig alkylguanidinium halide salt. 其它步骤及参数与具体实施方式一相同。 Other steps and parameters of one specific embodiment the same.

[0011] 具体实施方式三:本实施方式与具体实施方式一的不同是向带有搅拌器、冷凝器、 温度计的三口瓶中加入890gN-甲基-4-硝基邻苯二甲酰亚胺、25g碳酸钠、12g碳酸钾、 500mlN-甲基吡咯烷酮、IOOml甲苯和Ig烷基胍卤盐。 [0011] DETAILED DESCRIPTION III: the present embodiment, a specific embodiment is different from the 890gN- methyl-4-nitro-phthalimide with a stirrer, a condenser, a thermometer, three-necked flask. 25g sodium, 12g potassium carbonate, 500mlN- methylpyrrolidone, IOOml toluene and Ig alkylguanidinium halide salt. 其它步骤及参数与具体实施方式一相同。 Other steps and parameters of one specific embodiment the same.

[0012] 具体实施方式四:本实施方式与具体实施方式一的不同是向带有搅拌器、冷凝器、 温度计的三口瓶中加入82〜88gN-甲基-4-硝基邻苯二甲酰亚胺、21〜24g碳酸钠、9〜 Ilg碳酸钾、300〜400mlN-甲基吡咯烷酮、40〜80ml甲苯和0. 3〜0. 8g烷基胍卤盐。 [0012] BEST MODE FOR CARRYING IV: The present embodiment is different from the specific embodiment is a three-necked flask equipped with a stirrer, a condenser, a thermometer was added 82

88gN- methyl-4-nitro-phthalimide imide, 21

24g sodium carbonate, 9

Ilg potassium carbonate, 300

400mlN- methylpyrrolidone, 40

80ml toluene and 0. 3

0. 8g alkylguanidinium halide salt. 其它步骤及参数与具体实施方式一相同。 Other steps and parameters of one specific embodiment the same.

[0013] 具体实施方式五:本实施方式与具体实施方式一的不同是向带有搅拌器、冷凝器、温度计的三口瓶中加入85gN-甲基-4-硝基邻苯二甲酰亚胺、23g碳酸钠、IOg碳酸钾、 350mlN-甲基吡咯烷酮、60ml甲苯和0. 5g烷基胍卤盐。 [0013] DETAILED DESCRIPTION Five: specific embodiment of the present embodiment is different from the one 85gN- methyl-4-nitro-phthalimide with a stirrer, a condenser, a thermometer, three-necked flask. 23g of sodium carbonate, IOg potassium, 350mlN- methylpyrrolidone, 60ml toluene and 0. 5g alkylguanidinium halide salt. 其它步骤及参数与具体实施方式一相同。 Other steps and parameters of one specific embodiment the same.

[0014] 具体实施方式六:本实施方式与具体实施方式一至五之一的不同是在150°C下加热回流7h,冷却至室温后倒入500ml的水中。 [0014] Specific embodiments of six: one to five, one of the various embodiments of the present specific embodiment, at 150 ° C is heated to reflux for 7h, cooled, poured into 500ml water to room temperature. 其它步骤及参数与具体实施方式一至五之一相同。 One other one to five identical steps and parameters and specific embodiments.

[0015] 具体实施方式七:本实施方式与具体实施方式一至五之一的不同是在190°C下加热回流3h,冷却至室温后倒入2000ml的水中。 [0015] BEST MODE FOR CARRYING VII: with a specific embodiment of the present embodiment is different from one to five, one at 190 ° C under heating at reflux for 3h, cooled to room temperature, poured into 2000ml water. 其它步骤及参数与具体实施方式一至五之一相同。 One other one to five identical steps and parameters and specific embodiments.

[0016] 具体实施方式八:本实施方式与具体实施方式一至五之一的不同是在160〜 180°C下加热回流4〜6h,冷却至室温后倒入800〜1500ml的水中。 [0016] DETAILED DESCRIPTION VIII: The present embodiment is one to five, one specific embodiment of different 160

180 ° C is heated to reflux under 4

6h, cooled to room temperature, poured into water 800

1500ml. 其它步骤及参数与具体实施方式一至五之一相同。 One other one to five identical steps and parameters and specific embodiments.

[0017] 具体实施方式九:本实施方式与具体实施方式一至五之一的不同是在170°C下加热回流5h,冷却至室温后倒入IOOOml的水中。 [0017] DETAILED DESCRIPTION IX: with a specific embodiment of the present embodiment is different from one to five, one at 170 ° C under heating at reflux for 5h, cooled to room temperature, poured into water IOOOml. 其它步骤及参数与具体实施方式一至五之一相同。 One other one to five identical steps and parameters and specific embodiments.

[0018] 具体实施方式十:本实施方式合成氧代-双(N-甲基邻苯二甲酰亚胺)的方法按以下步骤实施:向带有搅拌器、冷凝器、温度计的三口瓶中加入82. 4gN-甲基-4-硝基邻苯二甲酰亚胺、21. 2g碳酸钠、IOg碳酸钾250mlN-甲基吡咯烷酮、50ml甲苯和0. 36g烷基胍卤盐,然后在160°C下加热回流5h,冷却至室温后倒入500ml的水中,过滤出棕褐色固体,经水洗和干燥后,即得氧代-双(N-甲基邻苯二甲酰亚胺);其中烷基胍卤盐为六烷基胍卤盐。 [0018] DETAILED DESCRIPTION ten: this embodiment oxo synthesis - bis (N- methyl phthalimide) method to implement the following steps: a three-necked flask with a stirrer, a condenser, a thermometer bottle 82. 4gN- added methyl-4-nitro-phthalimide, 21. 2g sodium, IOg potassium 250mlN- methylpyrrolidone, 50ml toluene, and 0. 36g alkylguanidinium halide salt, and then at 160 ° C and heated to reflux for 5h, cooled to room temperature and poured into 500ml water, filtered off a tan solid which was washed with water and then dried to obtain the oxo - bis (N- methyl phthalimide); wherein alkyl halide salt is guanidine hexaalkylguanidinium halide salt.

[0019] 本实施方式所得氧代-双(N-甲基邻苯二甲酰亚胺)为58. 3g,收率86. 76%,测其熔点为269. 4〜269. 9"C。 [0019] The present embodiment resulting oxo - bis (N- methyl-phthalimide) of 58. 3g, yield 86.76%, measured for a melting point of 269. 4

[0020] 具体实施方式十一:本实施方式合成氧代_双(N-甲基邻苯二甲酰亚胺)的方法按以下步骤实施:向带有搅拌器、冷凝器、温度计的三口瓶中加入84gN-甲基-4-硝基邻苯二甲酰亚胺、22g碳酸钠、12g碳酸钾、300mlN-甲基吡咯烷酮、60ml甲苯和0. 5g烷基胍卤盐,然后在180°C下加热回流4. 5h,冷却至室温后倒入600ml的水中,过滤出棕褐色固体, 经水洗和干燥后,即得氧代-双(N-甲基邻苯二甲酰亚胺);其中烷基胍卤盐为五烷基胍卤盐。 [0020] DETAILED DESCRIPTION XI: Synthesis of the present embodiment oxo _ bis (N- methyl-phthalimide) embodiment of the method according to the following steps: to with a stirrer, a condenser, a thermometer three bottles 84gN- was added methyl-4-nitro phthalimide, 22g of sodium carbonate, 12g of potassium carbonate, 300mlN- methylpyrrolidone, 60ml toluene and 0. 5g alkylguanidinium halide salt, and then 180 ° C heated under reflux for 4. 5h, cooled to room temperature, poured into 600ml of water and a tan solid filtered off, washed with water and then dried to obtain the oxo - bis (N- methyl phthalimide); wherein alkyl halide salt is guanidine pentaalkylguanidinium halide salt.

[0021] 本实施方式所得氧代-双(N-甲基邻苯二甲酰亚胺)为58. 6g,收率达85.5%,测其熔点为269. 8〜271 °C。 [0021] The resulting embodiment oxo - bis (N- methyl phthalimide) is 58. 6g, 85.5% yield, measured melting point of 269. 8

Synthesis and Evaluation of the Anxiolytic Activity of Some Phthalimide Derivatives in Mice Model of Anxiety

Synthesis and Evaluation of the Anxiolytic Activity of Some Phthalimide Derivatives in Mice Model of Anxiety

1 Department of Medicinal Chemistry, Isfahan University of Medical Sciences, Isfahan, Iran. Isfahan Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.

2 Department of Medicinal Chemistry, Isfahan University of Medical Sciences, Isfahan, Iran.


The aim of the present study was to synthesis a series of phthalimides based on our previous works and examine their anxiolytic properties. Using a three steps process, phthalimides were prepared from the corresponding di-methyl phthalate derivatives. Phthalic anhydride was nitrated to produce 3-nitrophthalic acid. Ring closer of either 3-nitrophthalic acid or di-methyl phthalate with urea were carried out in reflux condition. Final compounds were prepared by base catalyzed condensation of 4-methylbenzoyl chloride, benzoyl chloride and benzyl chloride with the resulting imides. From the tested compounds, only N-benzoyl 3-nitro-phthalimide was shown to produce anxiolytic activity by increasing the number of entries and time spent in open arms at 10 mg/kg.

Benzodiazepines are widely used as anxiolytic agents. A flat aromatic structure containing an electron withdrawing group at proper position (C7 on ring A) is necessary for benzodiazepine’s activities (1). Barbiturates which are used as sedative agents have flat structures containing imide functional groups (2). N-Benzoyl-phthalimide resembles both classic benzodiazepines and barbituric acids structures “two major families of sedatives and anxiolytics”. N-Benzoyl-phthalimide consists of a tricyclic hydrophobic structure comparable to that of benzodiazepines and possesses a conjugated ureid functional group as can be found in barbiturates (3). N-Benzoyl phethalimide was synthesized previously in our department and tested positive for anxiolytic activity at 0.5 mg/Kg dose in mice. In this study we aimed to synthesize and test some new derivatives of N-benzoyl phthalimide.

To examine the minor structural tuning on biological activity, introduction of an electron withdrawing moiety (NO2 ) on ring A, and or an electron donating group (CH3 ) on ring C and enhancing the flexibility of the structure by replacing the C=O bridge with methylen group are aimed.

All reagents and solvents used were of general purpose grade. Melting points were determined on an electrothermal 9200 apparatus and are uncorrected. Infra-red spectra were obtained as solid via a diffuse reflectance accessory using KBr matrix, using a Perkin Elmer 1420 series. 1 H-NMR spectra were recorded on a Bruker FT-80 spectrometer as dilute solutions in CDCl3 or DMSO-d6 with tetramethysilane as internal standard. Mass spectra were recorded on a fisons trio 1000 GC-Mass.

Figure 2. Phthalimide

Dry urea (15 g, 0.25 mol) was added stepwise to a mixture of dimethyl phthalate (19.4 g, 0.1 mol) in 50 mL sodium methoxide solution and was stirred at reflux condition for 6 h. The resulting white suspension was concentrated under reduced pressure at 50°C. The residue was dispersed in 100 mL of ice water mixture and neutralized with diluted HCl and filtered. Precipitates were re-crystallized from ethanol to give the imide, as white crystals (9.19 g, 46.3 %), m.p. 228–230°C (Lit. [6]), 233-234°C) ; v max 3200 (N-H), 1720 (C=O), 1600 (C=C, Ar) cm -1 ; δ H (80 MHz ; CDCl3 ), 11.2-10.8 ( 1 H, br s, NH), 7.8 (4H, s, ph-H).

A mixture of phthalimide (2 g, 13.6 mmol) and 4-methylbenzoyl chloride (2.1 g, 13.6 mmol) was refluxed in dry acetone (50 mL) containing potassium carbonate (10 g, 0.1 mol) for 4 h to produce N-(4’-methylbenzoyl)-phthalimide as white crystals. Yield 40%, m.p. 204°C; [Found: M, 265. C16 H11 NO3 requires M, 265]; v max 1780 - 1680 (C=O ), 1590 (C=C,Ar); δH (80 MHz, CDCl3 ), 8.1–7.7 (6H, m, COC=CH-CH=CH-CH=CCO, CH-CC=O-CH ), 7.4–7.2 (2H, d, J=8 Hz, CH-CCH3 -CH), 2.5 (S, 3H, CH3 ).

Figure 3.N -(4'-Methylbenzoyl) -phthalimide.

3-Nitro Phthalic acid

To a preheated (to 80°C) mixture of phthalic anhydride (100 g, 0.675 mol) and concentrated sulfuric acid (100 mL), a mixture of fuming nitric acid (42 mL) and concentrated sulfuric acid (30 mL) was added drop-wise. The mixture was added to sufficient amount of crashed ice to obtain the 3-nitro compound as a yellow solid. The yield was 30%, m.p. 212°C (Lit. [4,5]), 208-210°C); vmax 3500-2500 (OH), 1720 - 1680 (C=O ), 1600 (C=C,Ar), 1550, 1350 (NO2 ); δH (80 MHz, DMSO-d6), 8.4 – 8.3 (1H, d, J = 8 Hz CNO2 -CH), 8.2 – 8.1 (1H, d, J = 8 Hz, CO-C-CH-CH), 7.9–7.7 (1H, t, J = 8 Hz, CO-C-CH-CH).

A mixture of 3-nitro phthalic acid (21.1 g, 0.1 mol) and urea (6 g, 0.1 mol) was refluxed in ethylene glycol mono methyl ether (40 mL) for 12 h. The resulting mixture was transferred to a beaker containing crashed ice to deposit the 3-nitro derivative as a yellow powder which was recrystalized in ethyl acetate. Yield 67%. m.p. 223°C; vmax 3150 (NH), 1780 - 1680 (C=O ), 1600 (C=C,Ar), 1550–1350 (NO2 ); δH (80 MHz, DMSO-d6 ), 11.8–11.6 (1H, br, NH), 8.2–7.9 (3H, m, Ph-H).

A mixture of -3-nitro-phthalimide (1.92 g, 0.01 mol) and benzoyl chloride (1.40 g, 0.01 mol) was refluxed in dry acetone (50 mL) containing potassium carbonate (5 g) for 6 h to produce N-benzoyl 3- nitro- phthalimide as yellow crystal. Yield 50%. m.p. 199°C; [Found: M, 296. C15 H10 N2 O4 requires M, 296]; vmax 3060 (CH), 1800 -1670 (C=O ), 1600 (C=C, Ar), 1530–1350 (NO2 ); δH (80 MHz, CDCl3 ), 8.5–8 (5H, m, CNO2 =CH-CH=CH, CH-CCO=CH), 7.8–7.5 (3H, m, CH-CCO=CH-CH=CH-CH).

A mixture of 3-nitro-phthalimide (1.92 g, 0.01 mol) and 4-methylbenzoyl chloride (1.54 g, 0.01 mol) was refluxed in dry acetone (50 mL) containing potassium carbonate (10 g, 0.1 mol) for 4 h to produce N-(4-methylbenzoyl)-3-nitro-phthalimide as white crystals. Yield 48%. m.p. 150°C; [Found: M, 310. C15 H11 BrNO2 requires M, 310]; vmax 3020 (CH), 1770-1690 (C=O), 1600 (C=C,Ar), 1530–1370 (NO2 ); δH (80 MHz, DMSO-d6 ), 8.1–7.6 (5H, m, CNO2 =CH-CH=CH, CH-CCO=CH), 7.6 – 7.3 (2H, d, J=8Hz, CH-CCH3 =CH), 2.4 (3H, s, CH3 ).

A mixture of 3-nitro-phthalimide (0.75 g, 0.003 mol) and benzyl chloride (0.4 g, 0.003 mol) was refluxed in dry acetone (50 mL) containing potassium carbonate (5 g, 0.05 mol) for 3 h to produce N-benzyl 3-nitro-phthalimide as yellow crystals. Yield 13.3%. m.p. 100°C; [Found: M, 282. C15 H10 N2 O4 requires M, 282]; vmax 3040 (C-H, Ar), 2925 (C-H), 1780 - 1700 (C=O), 1600 (C=C, Ar), 1530 – 1370 (NO2 ); δH (80 MHz, CDCl3 ), 8.2 – 7.6 (3H, m, PhNO2 -H), 7.5–7.1 (5H, m, ph-H), 4.9 (2H, s, CH2 ).

Figure 5. 3-Nitro-Phthalimide

Figure 6.N -Benzoyl 3-Nitro-Phthalimide

Male NMRI mice (Pasture, Tehran) weighing 25-30 g were housed in a cage with controlled room temperature at 22-25°C. Food and water were available ad libitum. Tests were performed only after the mice had been acclimatized to the above environment for at least 7 days. All experiments were carried out between 09:00 and 13:00 h. Each mouse received a single intraperitoneal (IP) injection of drug or vehicle and was tested once in the EPM.

The EPM test is described in details elsewhere (6-9). Briefly, the apparatus comprised of two open arms (35 ´ 5 cm) and two closed arms (30 ´ 5 ´ 15 cm) that extended from a common central platform (5 ´ 5 cm). The floor and the walls of each arm were wooden and painted black. The entire maze was elevated to a height of 50 cm above floor level as validated and described by Lister (Lister, 1987). Testing was conducted in a quiet room that was illuminated only by a dim light. Mice were given a single ip dose of various test compounds or diazepam (Sobhan Pharmaceutical Co. Iran) 30 min before their placement on the EPM. To begin a test session, mice were placed on the open arm facing the center of the maze. An entry into an arm was defined as the animal placing all four paws over the line marking that area. The number of entries and the time spent in the open and closed arms were recorded during a 5 min test period. The percentage of open arm entries (100 ´ open/total entries) was calculated for each animal. Between each trial, the maze was wiped clean with a damp sponge and dried with paper towels.

Statistical analysis was performed using one-way analysis of variance (ANOVA) with post hoc Tukey test. P < 0.05 was considered significant. All data are expressed as mean ± standard error of mean (SEM).

Figure 7.N -(4'-Methylbenzoyl)-3-Nitro-phthalimide

Figure 8.N -Benzyl 3-Nitro-Phthalimide.

Elevated plus-maze results

Diazepam at the dose of 1.5 mg/kg significantly increased both the time and the number of entry in to the open arms (Figures 9 and10). Various doses (5, 10 and 50 mg/kg) of phthalimide derivatives namely, N -benzoyl 3-nitro-phthalimide, N -benzyl 3-nitro-phthalimide and N -(4›-methylbenzoyl)-3-nitro-phthalimide were tested for anxiolytic properties using EPM model. The only compound that significantly increased the time and entries into the open arm was N -benzoyl 3-nitro-phthalimide at 10 mg/kg (Figures 9 and 10 p < 0.01). The anxiolytic properties of the N -benzyl 3-nitro-phthalimide, studied in a separate set of experiments showed to be ineffective in changing the EPM parameters (data not presented).

The aim of the present study was evaluation of the anxiolytic actions of some phthalimide derivatives in comparison to that of diazepam. As expected, diazepam produced significant increases in open arm time and in number of entries into the open arms. These data are consistent with the results of numerous previous studies, which have shown that diazepam and other benzodiazepines produce robust anxiolytic effects in a variety of anxiolytic screening procedures. Among the derivatives of phtalimide that were tested in this study only N -benzoyl 3-nitro-phthalimide produced anxiolytic action, the effect that was seen with an increase in time spent on the open arm and the number of entries. This effect of the phtalimide derivative was produced at a dose of 10 mg/Kg which is higher than that of diazepam (2.5 mg/Kg).

N -Benzoyl-3-nitro-phthalimide showed a lower activity compare to that of diazepam and N -benzoyl phthalimide that was tested in our previous study and showed to be effective at 0.5 mg/Kg (3). An electron withdrawing group (Cl, NO2 ) on C7 of benzodiazepines is essential for sedative and anxiolytic activities of classic benzodiazepine agonists. Substitution of Cl or NO2 on other positions of the aromatic ring (6, 8, 9) of benzodiazepines dramatically reduce activity (1). Alpidem (an imidazopyridazine partial agonist) which is a selective anxiolytic (one-eighths as potent as diazepam), without sedative and muscle relaxant effects of benzodiazepines has a flat structure with an electron withdrawing group (Cl) at meta position of ring A (10). Reduction in activity of N -benzoyl, 3-nitro-phthalimide might be due to the improper accommodation of electron withdrawing group (NO2 ) in the benzodiazepine active site. Substitution of an electron donating group (CH3 ) on the C ring of the parent compound in N -(4’-methylbenzoyl)-3-nitro-phthalimide and N -(4’-methylbenzoyl)-phthalimide was also in favor for anxiolytic activity, this also has been seen in benzodiazepine series. Substitution at the 4’-(para)-position of the phenyl ring of benzodiazepines is unfavorable for agonist activity; however, 2’-(ortho)-substituents are not detrimental to agonist activity.

Figure 9. Effects of diazepam and the test compounds "N -benzoyl 3-nitro-phthalimide (A), N -(4'-methylbenzoyl)-3-nitro-phthalimide (B) and N -(4'-methylbenzoyl) -phthalimide (C), on the open arm entries of the EPM during a 5 min test in mice. Data are presented as mean values (± SEM) from group of 6 mice p

Figure 10. Effects of diazepam and the test compounds: "N -benzoyl 3-nitro-phthalimide (A), N -(4'-methylbenzoyl)-3-nitro-phthalimide (B) and N -(4'-methylbenzoyl)-phthalimide (C), on the time spent in the open arms, of the EPM during a 5 min test in mice. Data are presented as mean values (± SEM) from group of 6 mice. *p < 0.05 compared with vehicle-treated control.

N -Benzyl 3-nitro-phthalimide distorted from planarity due to the change of C=O group of N -benzoyl phthalimide to CH2 group. This distortion probably prevents the accommodation of the compound with its receptor and makes the compound ineffective as an anxiolytic agent. In benzodiazepines, the phenyl ring is attached directly to the ring B and its relationship to the ring A planarity may be important for agonist activity. All GABAA partial agonists including imidazopyridines (alpidem and zolpidem) also have flat structures.

Figure 11. Alpidem and n - Benzoyl phathalimide.

This work was supported by the research council of Isfahan University of Medical Sciences.