CN103435618B - A kind of method of synthesizing fused heterocyclic compound - Google Patents

Abstract

The present invention relates to chemical field, be specifically related to a kind of novel method of synthesizing compound shown in general formula I.

Description

A kind of method of synthesizing condensed heterocyclic compound

technical field

The invention relates to the field of organic chemistry, in particular to a new method for synthesizing a condensed heterocycle composed of a benzimidazole in parallel with a lactam ring larger than five members.

Background technique

Benzimidazole is combined with caprolactam or enantholactam in the manner shown in general formula I to form 1H-1,3-diazepine[1,2-a]benzimidazol-4-one and 2-oxo Generation-1,2,3,4-tetrahydropyrimidine[1,2-a]benzimidazoles, their structures contain multiple groups or heteroatoms that can serve as hydrogen bond donors and acceptors, and have a certain plane Both exhibit specific biological activities, such as corticotropin receptor antagonists (US20090186879), topoisomerase I inhibitors (Synthesis, 2006, 2305-2312), immunomodulators (ArchivderPharmazie, 1998, 331 , 249-253) and so on. At present, 2-oxo-1,2,3,4-tetrahydropyrimidine[1,2-a]benzimidazole is mostly obtained by cyclization of benzimidazole and acrylate or other derivatives under high temperature conditions. Among them, acrylate is highly volatile and has certain toxicity. However, the synthesis method of 1H-1,3-diazepane[1,2-a]benzimidazol-4-one is rarely reported, and γ-halobutyrate is first condensed with benzimidazole to form amide Or replace halogen by benzimidazole, and then obtain it through intramolecular ring closure. In their synthesis, benzimidazole needs to be synthesized first, and then the product can be obtained through 1-2 steps of reaction, and the route is relatively long. When n>2 in the general formula I, there is no relevant synthetic method report for this structure.

Contents of the invention

The object of the present invention is to overcome above-mentioned deficiency, provide a kind of synthetic method of the structure shown in new synthetic general formula I.

The present invention realizes by following reaction formula:

Among them, n=1, 2, 3.

In the present invention, the target product can be obtained in one step by reacting II with BrCN as the starting material. Raw material II can be obtained from o-fluoronitrobenzene as a starting material by substitution with the corresponding amino acid methyl ester and hydrogenation reduction. These two steps can be easily and quickly completed by organic synthesis practitioners according to common sense and general operations. The resulting product can be directly used in the reaction without further purification.

Adding potassium carbonate, sodium carbonate, triethylamine and other bases during the reaction can accelerate the reaction.

The reaction temperature can be from room temperature to 200°C, preferably from 100 to 120°C.

The reaction solvent is water, an organic solvent, or a mixed solvent of water and an organic solvent, and the organic solvent is preferably one or more of ethanol, ethylene glycol, methanol, and acetonitrile.

During the reaction, the molar ratio of BrCN to raw material II is 1:1-2:1.

During the reaction, BrCN can be added all at once or in batches, preferably in batches.

detailed description

Example 1

2-Oxo-1,2,3,4-tetrahydropyrimidine[1,2-a]benzimidazole (I-1)

Add 0.3g (1.5mmol) of methyl 3-(o-aminoanilino)propionate, 0.18g (1.65mmol) of BrCN, 0.23g (1.65mmol) of potassium carbonate, and 20ml of water into a 50ml three-necked flask, and heat to 110°C , reacted for 10h, cooled, extracted with ethyl acetate (15ml×3), combined the organic phases and dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and the solid was recrystallized from ethanol to obtain 2-oxo-1,2,3, 4-tetrahydropyrimidine[1,2-a]benzimidazole (I-1) 0.24g, yield 86%.

¹ HNMR (300MHzDMSO-d6) δ: 11.42 (1H, s, -NH-), 7.37-7.42 (2H, m, ArH), 7.10-7.12 (2H, m, ArH), 4.22-4.27 (2H, t, -CH ₂ -), 2.86-2.91 (2H, t, -CH ₂ -). MS[M+H] ⁺ 188.6.

Example 2

2-Oxo-1,2,3,4-tetrahydropyrimidine[1,2-a]benzimidazole (I-1)

Add 0.3g (1.5mmol) of methyl 3-(o-aminoanilino)propionate, 0.23g (1.65mmol) of potassium carbonate, and 20ml of acetonitrile into a 50ml three-necked flask, heat to 100°C, and add BrCN0. 24g (2.25mmol), reacted for 8h, cooled, concentrated, added 30ml of ice water, extracted with ethyl acetate (15ml×3), combined the organic phases and dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solid was recrystallized from ethanol, 0.25 g of 2-oxo-1,2,3,4-tetrahydropyrimidine[1,2-a]benzimidazole (I-1) was obtained with a yield of 89%.

Example 3

1H-1,3-diazepane[1,2-a]benzimidazol-4-one (I-2)

Add 0.5 g (2.4 mmol) of methyl 4-(o-aminoanilino) butyrate, 0.51 g (4.8 mmol) of BrCN, 0.66 g (4.8 mmol) of potassium carbonate, 23 ml of water, and 2 ml of acetonitrile into a 50 ml three-necked flask, and heat To 100°C, react for 10h, cool, extract with ethyl acetate (15ml×3), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and recrystallize the solid with ethanol to obtain 1H-1,3-diazo Heptane[1,2-a]benzimidazol-4-one (I-2) 0.4g, yield 82.8%.

¹ HNMR (300MHzCDCl ₃ -d6) δ: 7.45 (1H, s, -CONH-), 7.07-7.20 (4H, m, ArH), 4.03-4.11 (2H, t, -CH ₂ -), 2.40-2.47 ( 2H, t, _-CH2- ), 2.07-2.20 (2H, m, _-CH2- ). MS[M+Na] ⁺ 234.0, MS[MH] ^- 200.1.

Example 4

1H-1,3-diazaoctane[1,2-a]benzimidazol-4-one (I-3)

Add 0.5g (2.2mmol) of methyl 4-(o-aminoanilino)valerate, 0.47g (4.4mmol) of sodium carbonate, 20ml of water, and 5ml of methanol into a 50ml three-necked flask, heat to 120°C, and divide into three parts within 6h. BrCN0.47g (4.4mmol) was added in batches, reacted for 12h, cooled, extracted with ethyl acetate (20ml×3), the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the solid was recrystallized from ethanol to obtain 1H- 0.38 g of 1,3-diazaoctane[1,2-a]benzimidazol-4-one (I-3), yield 80%.

¹ HNMR (300MHzCDCl ₃ -d6) δ: 7.44 (1H, s, -CONH-), 7.08-7.20 (4H, m, ArH), 4.04-4.13 (2H, t, -CH ₂ -), 2.39-2.45 ( 2H, t, -CH ₂ -), 2.06-2.20 (2H, m, -CH ₂ -), 1.62-1.80 (2H, m, -CH ₂ -). MS [M+H] ⁺ 216.1.

Claims (6)

1. synthesize a method for compound of Formula I, it is characterized in that raw material II and BrCN react, a step obtains the target product I after cyclization, and its reaction formula is as follows:

Wherein, n=1,2,3;

Concrete operation step is:

Raw material II, BrCN are dissolved in solvent, add mineral alkali and serve as acid binding agent, and reacting by heating is complete, and with extraction into ethyl acetate after cooling, anhydrous magnesium sulfate drying organic phase, namely obtains corresponding target product I with ethyl alcohol recrystallization after concentrated.

2. the method for claim 1, is characterized in that alkali is salt of wormwood, sodium carbonate or cesium carbonate.

3. the method for claim 1, is characterized in that the mol ratio of BrCN and raw material II is 1: 1 ~ 2: 1.

4. the method for claim 1, solvent is water, organic solvent, or the mixed solvent of water and organic solvent, and organic solvent is selected from ethanol, ethylene glycol, methyl alcohol or acetonitrile.

5. the method for claim 1, the scope of temperature of reaction is room temperature to 200 DEG C.

6. the method for claim 1, it is characterized in that BrCN is disposable and add, or BrCN adds in batches.