CN105833791B - A kind of surfactant containing o-nitrobenzyl ester photodegradation group and preparation method thereof - Google Patents

Abstract

The invention discloses a novel photodegradation surfactant and a preparation method thereof, belonging to the field of surfactants. The synthesis comprises three steps of reactions: acetic anhydride as a raw material of diethylenetriamine pentaacetic acid is taken as a dehydrating agent, and pyridine is catalyzed and dehydrated to generate diethylenetriamine pentaacetic anhydride; secondly, reacting the o-nitrobenzyl bromide derivative serving as a raw material with secondary amine after acyl chlorination to obtain intermediate para-double long-chain carbamide o-nitrobenzyl bromide. And the intermediate double long-chain benzyl bromide is subjected to nucleophilic substitution with the intermediate carboxyl of diethylene triamine pentaacetic acid dianhydride under the catalysis of a catalyst in a solvent to obtain the surface active molecule with the o-nitrobenzyl ester light-control group. The invention ingeniously utilizes diethylene triamine pentaacetic acid to dehydrate into anhydride, protects four carboxyl groups at the tail end, selectively utilizes intermediate carboxyl organic base DBU to catalyze into ester, and prepares the o-nitrobenzyl ester photodegradation surfactant. Compared with the traditional method, the method shortens the reaction flow and greatly improves the efficiency.

Description

A kind of surfactant containing o-nitrobenzyl ester photodegradation group and preparation method thereof

technical field

The invention relates to a novel light-controlling surface active molecule and a preparation method thereof, in particular to using o-nitrobenzyl ester as a photodegradation group, using secondary amine double long chains as a hydrophobic group, and diethylenetriaminepentaacetic acid as a hydrophilic A new surface-active molecule of a group and a new synthesis method thereof belong to the field of surfactants.

Background technique

Environment-responsive amphiphilic molecular assemblies have attracted much attention for their potential applications in the controlled release of drugs, while light-responsiveness is controllable in vitro and does not require specific chemical changes in vivo. The drug is wrapped in the carrier, injected intravenously into the blood circulation, and stimulated by ultraviolet or near-infrared light outside the body to realize the controlled release of the drug, thereby effectively reducing the loss of the drug and its toxic and side effects on the human body, and improving the bioavailability.

O-nitrobenzyl ester has a special structure with two-photon effect, and the ester bond can be broken under near-infrared light irradiation to achieve a controlled drug release effect. The near-infrared controllable release of o-nitrobenzyl ester has attracted the attention of researchers in recent years. Among them, Jiang Jinqiang et al. designed a block copolymer with o-nitrobenzyl alcohol as the hydrophobic end. The esterification reaction introduced ester groups to encapsulate the hydrophobic drug Nile Red, and the drug was completely released after 25 minutes of 365nm or 700nm light irradiation (Macromolecules 2006, 39, 4633-4640); Minhyuck Kang and Bongjin Moon et al used o-nitrobenzyl ester as a bridge to introduce into the middle of the designed molecule, acid chloride and benzyl alcohol reacted to introduce ester groups, and the o-nitrobenzyl ester system was basically broken by 350nm ultraviolet light irradiation for 2h (Macromolecules 2009,42,455-458); Dong Jianming and others introduced the o-nitrobenzyl ester group through benzyl bromide affinity substitution, and reduced the vesicle size by polycondensation, which improved the stability of the drug delivery carrier (Langmuir 2012,28,1733 -1737). However, the traditional method for introducing o-nitrobenzyl esters often uses o-nitrobenzyl alcohol as a substrate to introduce the desired photoresponsive ester group by reacting with acid anhydride, acid chloride, or active esterification. This method has certain structural limitations. The benzene ring is often only at the end of the structure. Once the benzene ring enters the middle of the structure, the activity of the carboxylic acid in the esterification reaction is highly demanding and limited.

The complexation of diethylenetriaminepentaacetic acid and gadolinium can be used as a nuclear magnetic contrast agent, and the introduction of surface active molecules into diethylenetriaminepentaacetic acid as a hydrophilic group in the present invention can be used as a functional nuclear magnetic contrast agent. Diethylenetriaminepentaacetic acid has five carboxyl groups, and the reaction often requires one carboxyl group, so the remaining four carboxyl groups need to be protected to obtain a more specific structure. The carboxyl group of traditional diethylenetriaminepentaacetic acid is generally protected by introducing tert-butyl alcohol into an ester during the synthesis process, but the synthesis process is cumbersome, the reaction time is long, the efficiency is not high, and the selective protection of carboxyl group is also a difficulty. Arano et al. used diethylenetriamine as a raw material to protect the carboxyl group through tert-butyl bromoacetate during the synthesis of diethylenetriaminepentaacetic acid, leaving a terminal carboxyl group (J.Med.Chem.1996,39,3451.). Giordano et al. also used diethylenetriamine as the initial raw material to protect the terminal amine, and finally synthesized diethylenetriamine derivatives with intermediate carboxyl groups (Synthesis 2004, 1835.). Davies et al. used 2,2'-dichlorodiethylamine hydrochloride as a raw material to protect the carboxyl groups at both ends and leave the middle carboxyl group in the process of synthesizing diethylenetriaminepentaacetic acid derivatives (J.Pept.Sci.2002,8,663 .).

Contents of the invention

The object of the present invention is to propose a kind of synthetic method that utilizes organic base DBU to synthesize the surfactant containing o-nitrobenzyl ester photosensitive group with benzyl bromide derivative and diethylenetriaminepentaacetic acid dianhydride as raw material. This method is considered in reverse, and the intermediate carboxyl group remaining in the carboxyl group is activated by cleverly using diethylene triamine pentaacetic anhydride to synthesize a degradable surfactant.

The present invention provides a surfactant containing a photosensitive group of o-nitrobenzyl ester, the general structural formula I is as follows:

Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. m and n may be the same or different; preferably m=n.

The present invention further provides a preparation method of a novel photodegradable surfactant ortho-nitrobenzyl ester light control surfactant molecule:

Put diethylenetriaminepentaacetic acid dianhydride in a single-necked flask, add anhydrous solvent and heat to 60-70°C to dissolve, cool to room temperature, dropwise add double long-chain brominated derivatives dissolved in anhydrous solvent; and dissolve in Catalyst DBU in anhydrous solvent, under the protection of nitrogen, react at 30-80°C for 1 hour, add an appropriate amount of water to the reaction solution to produce a milky white liquid, centrifuge to obtain a khaki solid in the lower layer, separate by column chromatography, and the eluent is dichloro A mixture of methane and methanol yields a bright yellow solid of o-nitrobenzyl ester light-controlling surface-active molecules;

The structure of the double long-chain brominated derivative is shown in the general formula II:

Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. m and n may be the same or different; preferably m=n.

Diethylenetriaminepentaacetic acid dianhydride: double long-chain brominated derivatives: catalyst DBU: water molar ratio is 1:0.8-1.2:0.8-1.2:40-60;

Diethylenetriaminepentaacetic acid dianhydride: solvent molar ratio: 1:250-350.

Further, in the above technical scheme, the molar ratio of the double-long-chain brominated derivatives to the dry solvent in the double-long-chain brominated derivatives dissolved in the anhydrous solvent is 1:50-60; The catalyst DBU in the anhydrous solvent The molar ratio of the catalyst DBU to the anhydrous solvent is 1:50-60.

Further, in the above technical scheme, the anhydrous solvent is selected from DMSO or DMF.

Further, in the above technical scheme, the preparation method of the double long-chain brominated derivative intermediate is:

Take o-nitrobenzyl bromide derivatives in a three-necked flask, add thionyl chloride dropwise, and remove excess thionyl chloride after reflux reaction for 2-5 hours. Add an appropriate amount of double long-chain secondary amine and an appropriate amount of potassium carbonate dropwise, react at 30-60°C for 12 hours, stop the reaction, add an appropriate amount of deionized water, separate the layers, and dry the organic layer with anhydrous sodium sulfate overnight. The eluent is dichloromethane and The mixture of methanol was separated by column chromatography to obtain light yellow oily liquid of benzyl bromide derivatives.

The structure of double long chain secondary amine is as general formula Ⅲ:

Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. m and n may be the same or different; preferably m=n.

The molar ratio of o-nitrobenzyl bromide derivatives: thionyl chloride: double long-chain secondary amines: potassium carbonate is: 1:60-80:0.8-1.2:0.8-1.2.

Further, in the above technical scheme, the o-nitrobenzyl bromide derivative is selected from 4-bromomethyl-3-nitrobenzoic acid or 4-bromomethyl-3-nitrobenzenesulfonic acid.

Further, in the above-mentioned technical scheme, the eluent used in the synthesis of the double long-chain brominated derivative intermediate is a mixed solution with a volume ratio of dichloromethane to methanol (20-40): 1;

The eluent used in the synthesis of o-nitrobenzyl ester light-controlling surface-active molecules is a mixture of dichloromethane and methanol with a volume ratio of (10-20):1.

Further, in above-mentioned technical scheme, the preparation method of described diethylenetriaminepentaacetic acid dianhydride (DTPAA) is:

Put diethylenetriaminepentaacetic acid in a single-necked flask, add acetic anhydride and pyridine in sequence, raise the temperature to 60-70°C under the protection of nitrogen, and react for 20-24 hours. Suction filtration after completion of the reaction to obtain white solid powder of diethylenetriaminepentaacetic acid dianhydride.

The chemical reaction synthetic formula of surface active molecule of the present invention is as follows:

Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. m and n may be the same or different; preferably m=n.

The ingenuity of this synthesis mechanism is that the carboxyl groups at both ends of diethylenetriaminepentaacetic acid are protected by dehydration into an anhydride to activate the carboxyl group, and the organic base DBU (1,8-diazabicycloundec-7-ene) Under the action of highly selective catalysis, the remaining carboxyl group in the middle reacts with benzyl halide. Later, the acid anhydrides at both ends can be used to carry out the next reaction, which not only increases the reaction selectivity but also improves the reactivity of the carboxyl groups at both ends, killing two birds with one stone.

Beneficial effect of the invention

The invention utilizes the characteristics of the organic base DBU to efficiently catalyze the affinity substitution reaction, and skillfully catalyzes the reaction of the relatively inactive carboxyl group in diethylenetriaminepentaacetic acid dianhydride with benzyl bromide derivatives to generate a degradable surfactant, which not only protects the terminal The carboxyl group improves the reaction selectivity again, killing two birds with one stone.

(1) The present invention skillfully utilizes diethylenetriaminepentaacetic acid to dehydrate itself into an anhydride, which not only plays the role of carboxyl protection but also selectively provides a carboxyl group required for the reaction.

(2) The present invention uses diethylenetriaminepentaacetic acid dianhydride as a raw material, which greatly shortens the complex reaction process of conventionally using n-butyl alcohol to protect carboxyl groups in the process of synthesizing diethylenetriaminepentaacetic acid, and improves efficiency.

(3) The present invention utilizes the high reaction catalytic activity of organic base DBU, and benzyl bromide reacts with carboxylic acid to form an ester, a single-phase reaction, and provides a new esterification reaction path.

Description of drawings

Fig. 1 is the mass spectrogram of the surface-active molecule (4-diethylenetriaminepentaacetate group)-3-nitro-N, N-dioctylbenzamide prepared in Example 1;

Fig. 2 is the ¹ H NMR chart of the surface active molecule (4-diethylenetriaminepentaacetate)-3-nitro-N,N-dioctylbenzamide prepared in Example 1.

detailed description

The method of the present invention will be further described below in conjunction with the examples, but the present invention is not limited.

Embodiment 1 The synthesis of photodegradable surfactant (4-diethylenetriaminepentaacetate)-3-nitro-N,N-dioctylbenzamide:

(1) Synthesis of diethylene triamine pentaacetic anhydride

Weigh 3.98g (0.01mol) of diethylenetriaminepentaacetic acid and a 100mL single-necked flask, add 4mL of acetic anhydride and 5mL of pyridine in sequence, raise the temperature to 65°C under nitrogen protection, and react for 24h. Suction filtration after the reaction was completed to obtain a white solid powder. Melting point: 178°C-184°C

(2) Synthesis of intermediates of N,N-dioctylbenzamide brominated derivatives

Take 1g (0.004mol) of 4-bromomethyl-3-nitrobenzoic acid in a 100mL three-necked flask, add 10mL of thionyl chloride dropwise under magnetic stirring, and reflux for 3 hours. sulfone. Add 0.96g (0.004mol) di-n-octylamine dropwise to the three-necked flask. After the dropwise addition, add 0.5g (0.004mol) potassium carbonate, react at 40°C for 12 hours, stop the reaction, add an appropriate amount of deionized water, separate the liquid, and the organic layer Dry it with anhydrous sodium sulfate, and use a 40:1 volume ratio mixture of dichloromethane and methanol as the eluent for column separation to obtain a pale yellow oily liquid. Yield 76.0%.

(3) Synthesis of (4-diethylenetriaminepentaacetate)-3-nitro-N,N-dioctylbenzamide

Take 0.22g (0.0006mol) of diethylenetriaminepentaacetic acid dianhydride in a 100mL single-necked flask, add 10mL of anhydrous DMF and heat to 60°C to dissolve, cool to room temperature, first drop the brominated product dissolved in DMF, and then drop Add 0.1 g of DBU dissolved in DMF, react at 50°C for 1 h under the protection of nitrogen, add an appropriate amount of water to the reaction solution to produce a milky white liquid, centrifuge to obtain a khaki solid in the lower layer, and separate it by column chromatography. The eluent is dichloro A mixture of methane and methanol at a volume ratio of 10:1 gave bright yellow solid (4-diethylenetriaminepentaacetate)-3-nitro-N,N-dioctylbenzamide. Yield 18.2%.

Fig. 1 is the mass spectrogram of the surface-active molecule (4-diethylenetriaminepentaacetate group)-3-nitro-N, N-dioctylbenzamide prepared in Example 1;

MS: m/z[MH] ^- 794.50, [M/2-H] ^- 396.88, [M+H] ⁺ 796.45, [M+Na] ⁺ 818.45

Fig. 2 is the ¹ H NMR chart of the surface active molecule (4-diethylenetriaminepentaacetate)-3-nitro-N,N-dioctylbenzamide prepared in Example 1.

¹ H NMR (400MHz, CD ₂ Cl ₂ , CD ₃ OD): δin ppm 0.90-0.84(m, 6H, 2×CH ₃ -CH ₂ -); 1.37-1.13(m, 24H, 2×-(CH ₂ ) ₆ -CH ₃ ); 2.21-1.53(m,8H,2×-N-CH ₂ -CH ₂ -N-); 3.33(s,14H,5×-N-CH ₂ -COO-,2×- CO-N-CH ₂ -CH ₂ -); 5.50-5.54(s,2H,-O-CH ₂ -C ₆ H ₆ -); 7.68(d,1H,-C ₆ H ₆ -); 7.95(d ,1H,-C ₆ H ₆ -); 8.09(s,1H,-C ₆ H ₆ -)

Example 2 Synthesis of photodegradable surfactant (4-diethylenetriaminepentaacetate)-3-nitro-N,N-didecylbenzamide:

(1) Synthesis of diethylene triamine pentaacetic anhydride

Same as Example 1

(2) Synthesis of N,N-Didecylbenzamide Brominated Derivative Intermediates

Take 1g (0.004mol) of 4-bromomethyl-3-nitrobenzoic acid and a 100mL three-necked flask, add 10mL of thionyl chloride dropwise under magnetic stirring, and reflux for 4 hours. sulfone. Add 1.19g (0.004mol) di-n-decylamine dropwise to the three-necked flask. After the dropwise addition, add 0.5g (0.004mol) potassium carbonate, react at 50°C for 15h, stop the reaction, add an appropriate amount of deionized water, separate the liquid, and the organic layer Dry it with anhydrous sodium sulfate, and use a 40:1 volume ratio mixture of dichloromethane and methanol as the eluent for column separation to obtain a pale yellow oily liquid. Yield 62.1%.

(3) Synthesis of (4-diethylenetriaminepentaacetate)-3-nitro-N,N-didecylbenzamide

Take 0.22g (0.0006mol) of diethylenetriaminepentaacetic acid dianhydride in a 100mL single-necked flask, add 10mL of anhydrous DMF and heat to 70°C to dissolve, cool to room temperature, first drop the brominated derivative dissolved in DMF, and then Add 0.1 g of DBU dissolved in DMF dropwise, react at 60°C for 3 hours under nitrogen protection, add an appropriate amount of water to the reaction solution to produce a milky white liquid, and centrifuge to obtain a khaki solid in the lower layer. The chromatographic column separation eluent is dichloro A mixture of methane and methanol with a volume ratio of 10:1 was separated by a column to obtain a bright yellow solid (4-diethylenetriaminepentaacetate)-3-nitro-N,N-didecylbenzyl amides. Yield 18.6%.

Example 3 Synthesis of photodegradable surface active molecule (4-diethylenetriaminepentaacetate)-3-nitro-N,N-behenylbenzamide:

(1) Synthesis of diethylene triamine pentaacetic anhydride

Same as Example 1

(2) Synthesis of intermediates of brominated derivatives

Take 1g (0.004mol) of 4-bromomethyl-3-nitrobenzoic acid and a 100mL three-necked flask, add 10mL of thionyl chloride dropwise under magnetic stirring, and reflux for 3 hours. sulfone. Add 1.47g (0.004mol) didodecylamine dropwise to the three-necked flask. After the dropwise addition, add 0.5g (0.004mol) potassium carbonate, react at 40°C for 12 hours, stop the reaction, add an appropriate amount of deionized water, separate the liquid, and the organic layer Dry it with anhydrous sodium sulfate, and use a 40:1 volume ratio mixture of dichloromethane and methanol as the eluent for column separation to obtain a pale yellow oily liquid. Yield 46.5%.

(3) Synthesis of (4-diethylenetriaminepentaacetate)-3-nitro-N,N-didodecylaminobenzamide

Take 0.22g (0.0006mol) of diethylenetriaminepentaacetic acid dianhydride in a 100mL single-necked flask, add 10mL of anhydrous DMF and heat to 70°C to dissolve, cool to room temperature, and add dropwise the brominated product dissolved in DMF. After the dropwise addition, add 0.1g of DBU dissolved in DMF dropwise, and react at 50°C for 1.5h under the protection of nitrogen, add an appropriate amount of water to the reaction solution to produce a milky white liquid, centrifuge to obtain a khaki solid in the lower layer, and separate it by chromatography The eluent is a mixture of dichloromethane and methanol with a volume ratio of 10:1, and the column is separated to obtain a bright yellow solid (4-diethylenetriaminepentaacetate)-3-nitro-N,N -Didodecanylbenzamide. Yield 18.4%.

Claims (10)

1. A surfactant containing o-nitrobenzyl ester photodegradable groups, with a structure such as general formula I, Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. 2. A preparation method of a surfactant containing o-nitrobenzyl ester photodegradation group, characterized in that: Add the anhydrous solvent to diethylenetriaminepentaacetic acid dianhydride, heat to 60-70°C to dissolve, cool to room temperature, add the double long-chain brominated derivative dissolved in the anhydrous solvent dropwise; Catalyst DBU in the solvent, under the protection of nitrogen, react at 30-80°C for 1-2h, add water to the reaction solution to produce a milky white liquid, centrifuge to obtain a khaki solid in the lower layer, separate by column chromatography, and the eluent is dichloromethane Mixed solution with methanol to obtain bright yellow solid of o-nitrobenzyl ester light control surface active molecule; The structure of the double long-chain brominated derivative is shown in the general formula II: Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. 3. The preparation method according to claim 2, characterized in that: diethylenetriaminepentaacetic acid dianhydride: double long-chain brominated derivatives: catalyst DBU: water molar ratio is 1:0.8-1.2:0.8-1.2: 40-60. 4. The preparation method according to claim 2, characterized in that: the molar ratio of diethylenetriaminepentaacetic acid dianhydride: anhydrous solvent is 1:250-350. 5. The preparation method according to claim 2, characterized in that: the anhydrous solvent is selected from DMSO or DMF. 6. The preparation method according to claim 2, characterized in that the preparation method of the two long-chain brominated derivative intermediates is: Add thionyl chloride dropwise to the derivative of o-nitrobenzyl bromide, and remove excess thionyl chloride after reflux reaction for 2-5 hours; add double long-chain secondary amine and potassium carbonate dropwise, react at 30-60°C for 10-14 hours to stop the reaction , adding deionized water, separating the layers, drying the organic layer with anhydrous sodium sulfate overnight, using a mixed solution of dichloromethane and methanol as the eluent, and separating by column chromatography to obtain a light yellow oily liquid of benzyl bromide derivatives; The structure of double long chain secondary amine is as general formula Ⅲ: Wherein, m and n are independently selected from 6, 8, 10, 12 or 14, respectively. 7. According to the preparation method described in claim 6, it is characterized in that: o-nitrobenzyl bromide derivative: thionyl chloride: double long chain secondary amine: potassium carbonate molar ratio is 1:60-80:0.8-1.2: 0.8-1.2. 8. The preparation method according to claim 6, characterized in that: the o-nitrobenzyl bromide derivative is selected from 4-bromomethyl-3-nitrobenzoic acid or 4-bromomethyl-3-nitro Benzenesulfonic acid. 9. The preparation method according to claim 6, characterized in that: The eluent used in the synthesis of double long-chain bromo-derivative intermediates is a mixture of dichloromethane and methanol at a volume ratio (20-40):1. 10. The preparation method according to claim 2, characterized in that: the eluent used in the synthesis of o-nitrobenzyl ester light-controlling surface active molecules is a mixture of dichloromethane and methanol with a volume ratio of (10-20): 1 liquid.