阅读说明：本技术 一种级联转化快速组装缩二脲-胍衍生物的制备方法 (Preparation method for rapidly assembling biuret-guanidine derivative through cascade conversion ) 是由 杨振 南敏伦 谷伟玲 刘建璇 赫玉芳 张红岩 王淑琴 王磊 于 2021-05-26 设计创作，主要内容包括：本发明涉及有机化合物合成技术,公开了一种缩二脲胍衍生物及其合成方法。所述缩二脲胍衍生物的结构如式(Ⅰ)所示,在式(Ⅰ)中X选自O,S；R选自C1-C7的直链、支链、环状烷基或烯基,取代或未取代的C6-C12芳基,或者取代或未取代的含有氮原子、氧原子和硫原子中的至少一种的杂环基团；该类化合物的合成方法是在没有催化剂的条件下,异氰酸酯及异硫氰酸酯类化合物与1,1,3,3-四甲基胍(TMG)快速反应。本发明方法的产率较高,反应体系简单,反应条件温和,用料来源广泛,成本低廉且环境友好。(The invention relates to the organic compound synthesis technology, and discloses a biuret guanidine derivative and a synthesis method thereof. The structure of the biuret guanidine derivative is shown as a formula (I), wherein X is selected from O and S; r is selected from C1-C7 straight chain, branched chain, cyclic alkyl or alkenyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted heterocyclic group containing at least one of nitrogen atom, oxygen atom and sulfur atom; the synthesis method of the compound is that under the condition of no catalyst, isocyanate and isothiocyanate compounds react with 1, 1, 3, 3-Tetramethylguanidine (TMG) rapidly. The method has the advantages of high yield, simple reaction system, mild reaction conditions, wide material sources, low cost and environmental friendliness.)

1. A biuret guanidine derivative is characterized by being shown as a formula I:

wherein: x is O, S; r is aryl or alkyl.

2. The biuret guanidine derivative according to claim 1, wherein R is selected from C1-C7 linear, branched, cyclic alkyl or alkenyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted heterocyclic group containing at least one of nitrogen atom, oxygen atom and sulfur atom.

3. The biuret guanidine derivative according to claim 1,2, characterized in that in the substituted C6-C12 aryl and substituted heterocyclic groups, the substituents are selected from halogen, methoxy, trifluoromethyl, trifluoromethoxy, nitro, phenyl and C1-C4 straight-chain, branched alkyl groups.

4. The biuret guanidine derivative according to claims 1 to 3, characterized in that the biuret guanidine derivative is selected from the group consisting of:

one of them.

5. A synthetic method of biuret guanidine derivatives shown in formula I is characterized in that:

putting a compound of formula II and a compound of formula III in a mixed solvent of toluene and 1, 2-dichloroethane for reaction, wherein the structures of the compound of formula II and the compound of formula III are shown in the specification

6. The synthesis method according to claim 5, wherein the ratio of the mixed solvent of toluene and 1, 2-dichloroethane is 3: 1 to 1: 3, or less.

7. The synthesis method according to claim 4, wherein the reaction conditions include a reaction temperature of 20-60 ℃ and a reaction time of 0.1-2.0 h.

Technical Field

The invention relates to an organic compound synthesis technology, in particular to a biuret guanidine derivative and a synthesis method thereof.

Background

Guanidine is a particularly important structural motif and is widely present in a variety of natural compounds and drugs that have biological activity. Due to the strong hydrogen bonding capability of the polar and basic moieties, guanidine derivatives have a variety of potent biological activities against diabetes, cancer, inflammation, hypertension and bacterial infections. It is present in a variety of natural products, including leonurine, saxitoxin and gentiline. In addition, the oral hypoglycemic agent metformin (metformin) is used to control blood glucose levels in type 2 diabetic adults. In addition, the combined application of metformin and hypoglycemia can damage the metabolic plasticity of tumors and inhibit the growth of tumor cells by adjusting the PP2A-GSK3 beta-MCL-1 axis route. In addition, biuret derivatives, oxidation or decomposition products of certain purines, have structural features similar to proteins. They typically exhibit a variety of superior biological activities, including anticonvulsant, antihypertensive, anti-inflammatory, antineoplastic, antioxidant and analgesic activities. Guanidine and biuret scaffolds are very important in pharmaceutical chemistry, and therefore we intend to combine guanidine and biuret drug carriers together to obtain new drugs with more potent biological activity.

To date, some methods for synthesizing biurets have been reported (as shown in formula 1). The addition reaction of urea and isocyanate remains the most common method currently used to build biurets. In addition, the reaction of urea and phosgene preferentially produces chlorocarbonyl groups, which are then treated with various amines to form a one-pot assembly of various biurets. In addition, thiourea reacts with bis (trichloromethyl) carbonate to generate quaternary 4-imino-1, 3-thiazolidine-2-ketone ring, and then reacts with hydroxylamine for ring opening to synthesize biuret. However, these methods have some disadvantages such as low yield, high toxicity, unstable substrate, etc., severe reaction conditions or limited substrate range. Here, we disclose a novel preparation method, which rapidly synthesizes various (thio) biuret guanidine derivatives from various isocyanates and isothiocyanates and 1, 1, 3, 3-Tetramethylguanidine (TMG).

Synthesis method of biuret guanidine derivative currently reported in structural formula 1

Before the present invention was completed, there was no literature reporting the preparation method of biuret guanidine derivative disclosed in the present invention.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the biuret guanidine derivative and the synthesis method thereof, and the method has the characteristics of wide substrate range, mild reaction conditions and high efficiency (38 compounds, yield 46-93%).

In order to achieve the above object, the present invention provides a biuret guanidine derivative represented by formula (i):

wherein: x is O, S; r is aryl, alkyl

Wherein R is selected from a linear, branched, cyclic alkyl or alkenyl group of C1-C7, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted heterocyclic group containing at least one of a nitrogen atom, an oxygen atom and a sulfur atom.

Wherein in the substituted C6-C12 aryl and substituted heterocyclic groups, the substituents are selected from the group consisting of halogen, methoxy, trifluoromethyl, trifluoromethoxy, nitro, phenyl, and C1-C4 straight-chain, branched alkyl groups.

Preferably, the biuret guanidine derivative is selected from:

the second aspect of the invention provides a method for synthesizing the biuret guanidine derivative shown in the formula (I), which comprises the following steps:

and (3) placing the compound of the formula II and the compound of the formula III in a mixed solvent of toluene and 1, 2-dichloroethane for reaction.

Wherein: x is O, S; r is aryl, alkyl

Wherein R is selected from a linear, branched, cyclic alkyl or alkenyl group of C1-C7, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted heterocyclic group containing at least one of a nitrogen atom, an oxygen atom and a sulfur atom.

Wherein in the substituted C6-C12 aryl and substituted heterocyclic groups, the substituents are selected from the group consisting of halogen, methoxy, trifluoromethyl, trifluoromethoxy, nitro, phenyl, and C1-C4 straight-chain, branched alkyl groups.

Preferably, the compound of formula II and the compound of formula III are placed in a mixed solvent of toluene and 1, 2-dichloroethane (1:1) and reacted at room temperature for 1 hour.

In a third aspect, the present invention provides a biuret guanidine derivative obtained by the above-mentioned synthesis method. Through the technical scheme, the invention has the beneficial effects that:

1. the invention adopts the technical scheme of converting isocyanate, isothiocyanate compounds and 1, 1, 3, 3-tetramethylguanidine into biuret guanidine derivatives without a catalyst for the first time, the sources of reaction raw materials are wide, the raw materials do not need pretreatment, and the reaction economy is high;

2. the synthesis reaction does not need a catalyst, so that the environmental pollution is reduced, and the cost of raw materials is saved;

3. the synthesis method adopts one-step reaction to directly and selectively synthesize the target compound, has high yield, overcomes the difficulties of manpower, material resources and financial resources waste caused by the existing multi-step synthesis method, and saves a large amount of development time and production period;

4. the synthetic method overcomes the defect of higher cost of the existing multi-step synthetic method, and creates basic conditions for further performing functional modification on the derivatives;

5. the synthetic method has scientific and reasonable process, easy operation and few reaction steps, and adopts conventional reaction equipment;

6. the synthetic method has the advantages of good adaptability to functional groups, wide adaptability to substrates, low investment, high yield and easy mass production and popularization.

The present invention is illustrated in detail by the following examples, which are not intended to limit the invention thereto, and the following specific embodiments are provided:

EXAMPLE 1N- [ bis (dimethylamino) methylene]-N, N → -bis (4- (trifluoromethyl) phenyl-2-imidan-yldimethyl Process for preparing a diamide

Putting 0.4mmol of p-trifluoromethylphenyl isothiocyanate and 1.2mmol of 1, 1, 3, 3-tetramethylguanidine into a round-bottom flask, adding 1.0ml of a mixed (1:1) solvent of toluene and 1, 2-dichloroethane, stirring at room temperature for reaction for 1 hour till the end point, evaporating the solvent under reduced pressure after the reaction is finished, and separating by using a silica gel column to obtain the compound preparation, wherein the yield is 71.5%.

¹H NMR(400MHz,DMSO-d6)：δ＝12.89(s，1H)，8.32(s，1H)， 7.74(d，J＝8.3Hz，2H))，7.71–7.65(m，3H)，7.49(d，J＝8.1Hz， 2H)，2.84(s，12H)。¹³C NMR(101MHz，DMSO-d6)：δ＝165.91， 164.70，158.72，153.52，131.01，126.71，126.67，126.63，126.23， 126.10，126.05，125.86，125.82，123.92，119.38，117.55，113.41， 40.15。HRMS(ESI):calcd for C₂₁H₂₂F₆N₅O₂[M+H]⁺ 490.1654，found 490.1662。

EXAMPLE 2N- [ bis (dimethylamino) methylene]-N, N → -bis (4- (trifluoromethoxy) phenyl) -2-iminodiacetic acid Process for preparing methyldiamide

Putting 0.4mmol of p-trifluoromethoxyphenyl isothiocyanate and 1.2mmol of 1, 1, 3, 3-tetramethylguanidine into a round-bottom flask, adding 1.0ml of a mixed (1:1) solvent of toluene and 1, 2-dichloroethane, stirring at room temperature for reaction for 1 hour till the end, after the reaction is finished, evaporating the solvent under reduced pressure, and separating by using a silica gel column to obtain the compound preparation, wherein the yield is 68.2%.

¹H NMR(400MHz，DMSO-d6)：δ＝12.71(s，1H)，7.61–7.59 (m，2H)，7.35–7.29(m，6H)，2.84(s，12H)。¹³C NMR(101MHz， DMSO-d6)：δ＝165.89，159.08，153.67，147.16，143.67，140.34， 138.48，131.89，122.42，122.25，121.84，121.75，121.29，120.74， 119.34，119.27，118.90，114.53，55.37，40.15。HRMS(ESI)：calcd for C₂₁H₂₂F₆N₅O₄[M+H]⁺522.1528，found 522.1537。

Example 3N- [ bis (dimethylamino) methylene]-N, N → -bis (3,4 difluorophenyl) -2-imidodimethyldiacyl Process for the preparation of amines

Putting 0.4mmol of 3, 4-difluorophenyl isocyanate and 1.2mmol of 1, 1, 3, 3-tetramethylguanidine into a round-bottom flask, adding 1.0ml of a mixed (1:1) solvent of toluene and 1, 2-dichloroethane, stirring at room temperature for reaction for 1 hour till the end, evaporating the solvent under reduced pressure after the reaction is finished, and separating by using a silica gel column to obtain the product with the yield of 65.8%.

¹H NMR(600MHz,CDCl₃)：δ＝12.42(s，1H)，7.54–7.50(m， 1H)，7.38–7.32(m，1H)，7.23–7.17(m，2H)，7.05–6.96(m，3H)，6.74–6.69(m，1H)，2.89(s，12H)。¹³C NMR(151MHz，DMSO-d6)： δ＝161.73，159.09，154.65，154.54，152.32，152.22，151.39，151.27， 149.01，148.89，133.43，133.40，133.30，133.28，116.68，116.62， 116.59，116.53，111.33，111.30，111.12，111.09，103.99，103.76， 103.73，103.50，39.68。HRMS(ESI)：calcd for C₁₉H₂₀F₄N₅O₂[M+H]⁺ 426.1596，found 426.1608。

Example 4N- [ bis (dimethylamino) methylene]-N, N → -bis (2,4 difluorophenyl) -2-imidodimethyldiacyl Process for the preparation of amines

Putting 0.4mmol of 2, 4-difluorophenyl isocyanate and 1.2mmol of 1, 1, 3, 3-tetramethylguanidine into a round-bottom flask, adding 1.0ml of a mixed (1:1) solvent of toluene and 1, 2-dichloroethane, stirring at room temperature for reaction for 1 hour till the end, evaporating the solvent under reduced pressure after the reaction is finished, and separating by using a silica gel column to obtain the product with the yield of 78.9%.

¹H NMR(400MHz，CDCl₃)：δ＝12.66(s，1H)，8.27–8.21(m,1H)， 7.28–7.22(m，1H)，6.92–6.78(m，4H)，2.91(s，12H)。¹³C NMR (101MHz，CDCl₃)：δ＝166.83，163.60，163.49，161.14，161.02， 160.42，160.30，159.38，159.27，157.93，157.81，156.96，156.84， 154.29，154.18，153.60，151.84，151.73，132.24，132.22，132.14， 132.12，124.29，124.25，124.19，124.15，122.32，122.29，122.23，122.20，111.64，111.61，111.42，111.38，111.35，111.17，111.14， 104.97，104.72，104.71，104.46，103.91，103.67，103.64，103.41， 40.53。HRMS(ESI)：calcd for C₁₉H₂₀F₄N₅O₂[M+H]⁺ 426.1588，found 426.1595。