Triphosgene_Industrial Additive

Triphosgene [Background and Overview]

The important chemicals phosgene and diphosgene are widely used in the synthesis of medicines, pesticides, organic intermediates and polymer materials. However, their use is greatly limited due to their own properties. Phosgene is a gas and diphosgene is a liquid. Both have low boiling points, are highly volatile, and are highly toxic. They are very dangerous chemicals, and their use has been banned or restricted in many countries. The two, especially phosgene, are difficult to transport and store, and can only be used and made in the factory. Therefore, due to the needs of the organic chemical industry, there is an urgent need to study its substitutes, and triphosgene is its ideal substitute.

Triphosgene is the popular name for the chemical name bis(trichloromethyl)carbonate, abbreviated as BTC. Its English name is Bis(Trichloromethyl)Carbonate, and its molecular formula is CO(OCCl₃)₂. The CA registration number is 32315-10-9. Triphosgene is a white crystal with a high melting and boiling point, low volatility, and low toxicity. Even at the boiling point, it only decomposes in a small amount. It is only treated as a general toxic substance in industry; the conditions required for its synthesis and participation in chemical reactions are all It is very mild, has strong selectivity, high yield, safe and convenient use, and is easy to transport and store. In medicine, pesticides, organic chemicals and polymer materials, it can completely replace phosgene or diphosgene in the synthesis of related chemicals, which is being widely used. Triphosgene was first discovered and produced in 1880. As early as 1900, there were reports of its reaction with amines, alcohols, and phenols, but no attention was paid to it. It was not until the publication of a paper using BTC as a substitute for phosgene in 1987 that it attracted attention. In the past ten years, a large number of literatures have reported on the methods of preparing BTC in laboratories and industries and its wide application in the synthesis of important types of organic compounds.

Triphosgene [Physical and Chemical Properties]

1. Physical properties

BTC is white crystal; molecular weight is 296.75; melting point is 79~83 ℃; boiling point: 203 ℃/0.1 MPa, 124 ℃/6.6kPa; solid density is 1.78 g/cm³; Melt density 1.629 g/cm³, soluble in carbon tetrachloride, ethane, benzene, chloroform, ether and tetrahydrofuran, etc., stored at room temperature. BTC is very stable and only decomposes to a small amount at the boiling point to produce trichloromethyl chloroformate and phosgene.

2. Chemical activity

BTC Under the action of auxiliary nucleophile Nu (such as pyridine, triethylamine, etc.) (reaction with amine does not require auxiliary nucleophile), one molecule of BTC can generate three molecules of active intermediate (ClCONu⁺ Cl^–), can react with various nucleophiles under mild conditions. The reaction process is shown in the figure below:

Triphosgene [reaction mechanism] [2]

Under the action of nucleophiles (Nu) such as triethylamine, pyridine, diisopropylethylamine and dimethylformamide, triphosgene reacts with the substrate as follows:

Based on this mechanism, triphosgene can react with alcohols, aldehydes, amines, amides, carboxylic acids, phenols, hydroxylamine and other compounds. Its reaction types that replace phosgene and diphosgene include chloromethylation , urealysis, carbonation, isocyanation, chlorination, isonitrilation, cyclization reaction, alcohol oxidation, etc., and are widely used in the synthesis and production of medicines, pesticides, dyes, pigments and various polymer materials.

Triphosgene [Synthesis][3]

1. Solvent method

Because carbon tetrachloride has a strong ability to dissolve chlorine and can absorb photoelectron free radicals to initiate chlorination. More importantly, its relative volatility is higher than that of dimethyl carbonate. It can quickly remove the heat of reaction during the evaporation process, thus ensuring Safe Production. The solvent method was reported in 1987. Dissolve 05 mol (45.09) DMC in 250 mL. Add chlorine gas to the external bath at 10 to 20°C with stirring and light. The reaction will be completed in about 28 hours. After the reaction is completed, the solvent will be evaporated under reduced pressure. , a crystalline solid product was obtained. After vacuum drying, product 14 309 (melting point 79°C) was obtained, with a yield of 97%. In 1993, someone improved the previous method by changing the external bath to an internal cooling device. The reaction temperature was controlled at 5-10°C, the reaction time was shortened to 18 h, the yield was 9%, and the reaction time was shortened to 75 h.

2.Ontology method

The chlorination reaction is completed under the conditions of disaster light and ultraviolet light as well as medium and low temperature mixed initiators. The entire reaction process is divided into three stages of low, medium and high temperature. The product obtained from lepidolite is almost pure. The melting point is 80-83 ℃, and the yield is over 90%. In this process, the reaction between BTC and methanol is used to generate DMC again. From the perspective of the entire reaction process, only methanol and chlorine are consumed, and DMC can be prepared as needed, so this process is an ideal process for triphosgene synthesis. However, the research on recycling technology has not been reported so far, let alone industrialized production. The main reason is that the reaction between triphosgene and methanol is too complex and the reaction time is too long. Therefore, the task of preparing triphosgene through a recycling method is still very arduous.

Triphosgene [Application]

1. Synthesis of isocyanate

The carbonylation reaction between phosgene and primary amines can produce various isocyanates. However, because phosgene is difficult to accurately measure, side reactions often occur. Triphosgene is a solid and can be measured accurately, and using triphosgene instead of phosgene greatly improves its safety, so it can safely replace phosgene. The reaction between triphosgene and amine compounds is a widely used field. This reaction has strong selectivity. Some functional groups do not require protection and can be directly used.��Generates isocyanate, urea and other compounds. Triphosgene and various primary amines undergo a carbonylation reaction to synthesize various isocyanates. The reaction only needs to accurately control the ratio of triphosgene and amines to obtain the target product without the appearance of by-products. For example, triphosgene reacts with 2,4-diaminodiphenylmethane to synthesize 2,4-dimethyldiisocyanate (TDI); triphosgene reacts with 4,4′-diaminodiphenylmethane to produce 4,4′-diisocyanate. Phenylmethane diisocyanate (MDI); triphosgene and hexamethylenediamine can generate sodium hexamethylene diisocyanate (HDI). BTC can also undergo cyclization and condensation reactions during the carbonylation reaction of thienopyridine. In this type of reaction, triphosgene is widely used. It can be used not only to prepare N-carbonyl anhydride, but also to prepare various important heterocyclic compounds and cyclic carbonate compounds. The former can be used to prepare active amino acids and polypeptide compounds, and the latter can be used to prepare various pharmaceutical and pesticide intermediates.

2. Synthetic polycarbonate

The traditional process for synthesizing polycarbonate is to use phosgene and bisphenol A as raw materials and dichloromethane as the solvent. The current synthesis method of polycarbonate is to use acid diphenyl ester and monomer bisphenol for transesterification, which replaces the conventional phosgene synthesis route and achieves two green goals at the same time: first, no toxic and harmful raw materials are used; Second, because the reaction is carried out in a molten state, suspected carcinogens (methyl chloride) are not used as solvents. For example: triphosgene and 1,4-hydroquinone can react to prepare thermally denatured polycarbonate; 4,4′-dihydroxybiphenyl, 4,4′-dihydroxydiphenyl ether, 4,4′-dihydroxydiphenyl Dihydric phenols such as hydroxybenzophenone, bisphenol A and 4,4′-dihydroxydiphenylsulfone can generate thermotropic liquid crystal polycarbonate in the presence of triphosgene; using triphosgene and 0,0′ of bisphenol A The solution condensation polymerization of -methylene-bridged dimer can generate bisphenol A polycarbonate copolymer; using triphosgene and bisphenol A as monomers, high molecular weight polycarbonate is synthesized by interfacial condensation polymerization; using triphosgene The gas can also be used to prepare thermoplastic polycarbonate and polycarbonate-styrene-acrylonitrile terpolymers and other high molecular polymers, functional polymerized styrene, etc.

3. Synthesis of chloroformate

Using triphosgene and alcohol or secondary amine as raw materials, they react in the presence of solvent to generate chloroformate. Eckert used tertiary alcohols and functionalized amides as solvents to synthesize chloroformates in high yields. It first reacts with a nucleophile to form an unstable intermediate, which then reacts with a hydroxyl compound to form a chloroformate. Triphosgene chloroformylation reaction can be used in organic synthesis to prepare various important chemical intermediates. Such as: synthesis of β-lactam antibiotic precursors, synthesis of cationic lipid compounds, synthesis of active carbamates, etc.

4. Synthesis of acid chlorides and acid anhydrides

Due to the high chlorine content in triphosgene molecules, it is a good chlorinating agent and can be used in chlorination reactions. The reaction of triphosgene and carboxylic acid can produce various acid chlorides and acid anhydrides, especially aromatic acid chlorides and acid anhydrides. Using triphosgene to synthesize acid chlorides and acid anhydrides has mild reaction, convenient post-processing, less pollution and high yield.

5. Synthetic medicines and pharmaceutical intermediates

Triphosgene can be used to replace phosgene and diphosgene in the synthesis of drugs and pharmaceutical intermediates. For example, triphosgene is used instead of trichloromethyl chloroformate to react with triphenylazepine to synthesize formamide benzene, which is used for the synthesis of antidepressant and analgesic drug carbamazepine; triphosgene is used to react with N-ethyloxypiperazine Synthesis of N-ethyloxypiperazine acid chloride, used for the synthesis of oxypiperazine penicillin side chain intermediates; triphosgene is used to replace phosgene and trichloromethyl chloroformate interacts with anthranilamide for the antihypertensive drug quinazole Synthesis of linodiones.

6. Synthetic pesticides

Triphosgene reacts with alcohol to prepare chloroformate, which can then be further reacted with the corresponding amine to prepare a series of carbamate pesticides. Triphosgene reacts with secondary amines to obtain aminoacyl chloride, which can then react with another amine molecule to produce many urea herbicides, such as linuron. The corresponding acyl isocyanate can be prepared by reacting triphosgene with 2,6-difluorobenzamide, which can then be reacted with a suitable amine to prepare a series of benzoyl urea pesticides. Similarly, triphosgene and sulfonamide can also be used to prepare sulfonylurea herbicides. In addition, triphosgene reacts with 1,2-bifunctional compounds such as 1,2-diamine, diol (thiol), aminoalcohol, amino acid, aminoamide, o-aminophenol and catechol to form five-membered heterocyclic compounds , which is an important intermediate for many pesticides. Another example is the cyclization reaction of triphosgene and 2-amino-5-methoxyphenol to synthesize the natural product 6-methoxy-2,3-dihydrobenzothiazole with fungicidal activity.

Triphosgene [Main Reference Material]

[1] Wang Zhengping, Liu Tiancai. Synthesis and application of triphosgene[J]. Journal of Harbin Engineering University, 2001, 22(2): 74-77.

[2] Ji Bao, Zhai Xianming, Xu Yi. Reaction mechanism and application of triphosgene[J]. Science and Technology Information Development and Economics, 2009 (10): 136-137.

[3] Xue Jian, Mo Weimin, Sun Nan, et al. Properties and preparation of triphosgene[J]. Journal of Liaocheng University: Natural Science Edition, 2003, 16(4): 107-110.