Process for preparing asymmetric carbonates

Abstract

The invention relates to a process for preparing a carbonate compound (C), comprising: (a) reacting in a first reactor (V1), a first phenolic compound with phosgene in presence of a first solvent and sodium hydroxide, to obtain an intermediate product stream (P) comprising a chloroformate compound (CF); (b) passing the product stream (P) to a second reactor (V2) through a conduit, wherein the second reactor (V2) contains a reaction mixture (RM) comprising a second phenolic compound, a second solvent and a tertiary amine compound; and (c) reacting the second phenolic compound with the chloroformate compound (CF) to obtain the carbonate compound (C); wherein the product stream (P) upon formation, has a residence time of < 1.0 hour, in the first reactor (V1) prior to passing to the second reactor (V2).

Description

PROCESS FOR PREPARING ASYMMETRIC CARBONATESFIELD OF INVENTION

[0001] The invention relates to an in-situ process for preparing asymmetric carbonates having high purity content while being produced at high yield and throughput rate.BACKGROUND

[0002] Residual or unreacted Bis-phenol A (BP A) present in polycarbonate material is a serious health and an environmental hazard. One possible approach to control residual BPA is to add an asymmetric carbonate during the last stage(s) of the melt polymerization during polycarbonate synthesis. Asymmetric carbonates such as phenyl methyl salicylate (abbreviated as PMSC) can help reduce the formation of residual BPA.

[0003] However, asymmetric carbonates in general are difficult to synthesize. For example, transesterification route to synthesize asymmetric carbonate, results in one or more byproducts, which are difficult to separate and purify. An alternate approach is to use commercially available chloroformates, which can be reacted with activated phenols, such as methyl salicylate to form PMSC. Chloroformates for example can be prepared by the process described in US 6,103,855A. WO 2005 / 023204 discloses prodrugs of propofol, methods of making prodrugs of propofol, pharmaceutical compositions of prodrugs of propofol and methods of using prodrugs of propofol and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting. The article HOEFLAKE J.M.: "La Nitration des Carbonates Phenyliques", RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS, vol. 40, no. 8, 1 January 1921 (1921-01-01), pages 488-518, discloses nitration of phenolic carbonates.

[0004] However, the handling of chloroformate compounds is not easy as chloroformates are moisture sensitive and tend to hydrolyze to form diphenyl carbonates, and phenolic compounds. Often the presence of impurities in commercial samples affect the purity of the asymmetric carbonates and in turn the final polycarbonate product. The presence of diphenyl carbonates not only reduces the selectivity and yield to form the intended asymmetric carbonates but such compounds may also end up in the final polycarbonate material as impurities, which can affect the processability and molecular weight buildup of the polycarbonate material.

[0005] Therefore, it is an object of the present invention to provide a method of producing asymmetric carbonates such as phenyl methyl salicylate at high throughput rate with the maintaining the desired purity and yield.DESCRIPTION

[0006] Accordingly, the objective of the present invention is achieved by a process for preparing a carbonate compound (C), comprising:(a) reacting in a first reactor (VI), a first phenolic compound with phosgene in presence of a first solvent and an alkali metal hydroxide, preferably sodium hydroxide, to obtain an intermediate product stream (P) comprising a chloroformate compound (CF);(b) passing the product stream (P) to a second reactor (V2) through a conduit wherein the second reactor (V2) contains a reaction mixture (RM) comprising a second phenolic compound, a second solvent and a tertiary amine compound; and(c) reacting the second phenolic compound with the chloroformate compound (CF) to obtain the carbonate compound (C); wherein the intermediate product stream (P) upon formation, has a residence time of < 1.0 hour, preferably < 0.5 hour, preferably < 1.0 minute, preferably < 30.0 seconds in the first reactor (VI) prior to passing to the second reactor (V2); wherein the first phenolic compound has a structure represented by the formula (I):wherein ‘Z’ is a substituent selected from the group consisting of hydrogen, halogen group, hydrocarbyl group having 1-20 carbon atoms optionally comprising oxygen as a hetero-atom, and an amine group; Substituent ‘Z’may form a ring structure optionally including one or more oxygen atoms as heteroatoms. Preferably ‘Z’ is a substituent selected from the group consisting of hydrogen, halogen group, hydrocarbyl group having 1-20 carbon atoms and an amine group. Morepreferably ‘Z’ is a substituent selected from the group consisting of hydrogen, halogen group and hydrocarbyl group having 1-20 carbon atoms. wherein the second phenolic compound has a structure represented by the formula (II):wherein ‘G’ is a substituent selected from the group consisting of R1(C=O)-, halogen group, cyano group, and nitro group, and wherein the substituent R1is independently selected from the group consisting of optionally substituted alkoxy group, optionally substituted phenoxy group, optionally substituted benzyloxy group, and optionally substituted phenyl group; wherein the first phenolic compound and the second phenolic compound are chemically different.

[0007] Preferably, wherein the substituent ‘G’ is R1(C=O)- and wherein the substituent R1is an optionally substituted alkoxy group having 1-10 carbon atoms, preferably 1-3 carbon atoms.

[0008] The expression “the first phenolic compound and the second phenolic compound are chemically different” means that the first phenolic compound is a different compound or a molecule compared to that of the second phenolic compound or a molecule such that the chemical moieties on either side of the carbonate group of the carbonate compound (C) are different thereby rendering the carbonate compound (C) to be asymmetric. Preferably the present invention is not directed at carbonate compounds (C) that contain nitrogen atoms. In other words, preferably carbonate compound (C) does not comprise nitrogen atoms.First phenolic Compound and the Second Phenolic Compound

[0009] Preferably, the first phenolic compound is a compound selected from:phenolic compound is preferably phenol.

[0011] Preferably, the second phenolic compound is a compound selected from:and , where ‘X’ represents an halogen element.

[0012] Preferably, the halogen element is selected from chlorine, bromine, iodine, fluorine. Preferably the halogen element is chlorine.

[0013] Preferably, the second phenolic compound is methyl salicylate as represented bythe formula:

[0014] It is preferred that the first phenolic compound is phenol, the second phenolic compound is methyl salicylate, the chloroformate compound (CF) is phenyl chloroformate, andthe carbonate compound (C) is phenyl methyl salicylyl carbonate (PMSC). Preferably the first and / or second phenolic compounds do not contain nitrogen atoms.First rector (VI) and Product stream (P) comprising the chloroformate compound (CF)

[0015] The first phenolic compound reacts with phosgene to form the product stream (P) comprising the chloroformate compound (CF). It is preferred that the molar ratio of phosgene to the first phenolic compound ranges from > 1.0 and < 1.5, preferably from > 1.05 and < 1.2. It is preferred that the first phenolic compound is reacted with phosgene at any temperature ranging from 20°C to 30°C, preferably at any temperature from 22°C to 27°C.

[0016] Preferably, the product stream (P) comprises at least 90.0 wt.%, preferably at least 95.0 wt.%, preferably at least 99.0 wt.%, preferably 100.0 wt.%, based on the total weight of the intermediate product stream (P), of the chloroformate compound (CF).

[0017] The reaction is carried out in presence of the first solvent and an alkali metal hydroxide, preferably sodium hydroxide. The reaction condition is kept alkaline to facilitate the neutralization of any hydrochloric acid that is formed as a byproduct and thereby drive the reaction forward.

[0018] It is preferred that the first solvent is free of nitrogen containing compounds. Preferably, the first solvent is free of amine containing compounds. The presence of nitrogen containing compounds such as amine, for example primary, secondary or tertiary amine, can interfere with the reaction and also react with the chloroformates to form undesirable byproducts.

[0019] It is particularly preferred that the first solvent comprises less than 10.0 parts per million (ppm) by weight, preferably less than 5.0 parts per million (ppm) by weight, preferably the first solvent has 0.0 parts per million by weight, of the tertiary amine compound.

[0020] The first solvent accordingly can be a suitable organic solvent substantially free of impurities as described herein. It is preferred that the first solvent is methylene chloride.

[0021] The intermediate product stream (P) upon its formation, has a residence time of < 1.0 hour, preferably < 0.5 hour, preferably < 1.0 minute in the first reactor (VI) prior to passing to the second reactor (V2). Preferably the intermediate product stream (P) upon its formation, has a residence time of < 20.0 seconds and > 5.0 second, preferably < 15.0 seconds and > 10.0 seconds, in the first reactor (VI) prior to passing to the second reactor (V2)

[0022] The expression “residence time” as used herein means the time that the product stream (P) is stored in the first reactor (VI) after its formation. The low residence time after formation, prevents the reaction of the chloroformate present in the product stream (P) with the first phenolic compound to form diaryl carbonates and other phenolic byproducts including monohydric phenols.

[0023] Preferably the intermediate product stream (P) comprises less than 1.0 wt.%, preferably less than 0.5 wt.%, preferably less than 0.01 wt.%, based on the total weight of the intermediate product stream (P), of compounds selected from phenolic compounds, diaryl carbonate compounds and combinations thereof. An example of a diaryl carbonate compound can be diphenyl carbonate.

[0024] It is preferred that the first reaction reactor (VI) is a tubular flow reactor. The tubular flow reactor for example has an upstream end and a downstream end and at least one input and at least one output. Preferably, the tubular flow reactor has an L / D ratio of greater than 5.0, preferably greater than 10.0, or preferably greater than 20.0 and less than 30.0. The intermediate product stream (P) may be conveyed through the tubular reactor, under turbulent flow conditions characterized by a Reynolds number of about 200 to about 100,000. As the residence time of the intermediate product stream (P) is kept low the overall throughput rate of the entire production process is high.Second rector (V2) and the formation of carbonate compound (C)

[0025] The product stream (P) once formed is passed to a second reactor (V2) through a conduit. The second reactor (V2) contains a reaction mixture (RM) comprising the second phenolic compound, the second solvent and the tertiary amine compound. It is preferred that the second reactor (V2) is a batch reactor.

[0026] It is preferred that the intermediate product stream (P) is introduced into the second reactor (V2) at a flow rate of greater than 10.0 ml / sec, preferably greater than 15.0 ml / sec, preferably greater than 25.0 ml / sec.

[0027] In second reactor (V2) the chloroformate present in the intermediate product stream (P) is reacted with the second phenolic compound. The reaction condition is kept alkaline to facilitate the neutralization of any hydrochloric acid that is formed as a byproduct and thereby drive the reaction forward.

[0028] It is preferred that the reaction of the second phenolic compound with the chloroformate compound (CF), is carried out in the second reactor, at a pH of 8.5 to 11.0, preferably at a pH of 9.0-10.5, in presence of 20.0 wt.% to 40.0 wt.% of aqueous alkali metal hydroxide, preferably aqueous sodium hydroxide, and the second solvent. It is preferred that the second solvent is methylene chloride.

[0029] It is preferred that the molar ratio of the second phenolic compound to the chloroformate compound (CF) ranges from 3: 1 to 1 :3, preferably from 2:1 to 1 :2. It is particularly preferred that the molar ratio of the second phenolic compound to the chloroformate compound (CF) is 1 : 1.

[0030] It is preferred that wherein the reaction mixture (RM) prior to the reaction of the second phenolic compound with the chloroformate compound (CF), is maintained at a pH in the range of 8.5 to 11.0, preferably in the range of 9.0-10.5. The reaction mixture (RM) comprising the second phenolic compound, the second solvent and the tertiary amine compound is maintained at a pH in the range of 8.5 to 11.0, preferably in the range of 9.0-10.5, which is sufficient to initiate the reaction with the intermediate product stream as it enters the second reactor (V2). The reaction mixture (RM) contains a catalytic amount of tertiary amine compound sufficient to catalyze the reaction of the chloroformate with that of the second phenolic compound.

[0031] Preferably, the tertiary amine compound is present in an amount of not greater than 0.1 wt.%, preferably not greater than 0.08 wt.%, preferably 0.05 wt.%, based on the total weight of the reaction mixture (RM). Preferably, the tertiary amine is selected from tri-ethylamine, tripropylamine, tri-butylamine, and combinations thereof. It preferred that the tertiary amine compound is tri-ethylamine.

[0032] The carbonate compound (C) obtained from the process described in this application has low impurity content and can be produced at high yield and throughput rate.

[0033] In an embodiment of the invention, phenol (first phenolic compound) is dissolved in methylene chloride (first solvent) in a stirred tank reactor. The phenol solution containing methylene chloride is introduced into a tubular flow reactor (first reactor) together with phosgene. Dilute caustic (20% solution) is added as an acid neutralizing agent. A product stream (intermediate product stream) containing phenyl chloroformate (PCF) is obtained.

[0034] The phenyl chloroformate (PCF), generated at the exit of tubular flow reactor, is removed within twenty seconds after formation and introduced into a batch reactor (second reactor) containing methyl salicylate (second phenolic compound) pre-dissolved in methylene chloride (second solvent) and caustic (20% NaOH) containing 5% Triethyl amine (TEA) (tertiary amine). The pH of the solution is maintained at 10.1 during the reaction of the reactants. The product obtained is isolated and purified to obtain the phenyl methyl salicylic carbonate (carbonate compound (C)). The phenyl methyl salicylic carbonate is obtained at a purity of greater than 99.1 wt.% and at a yield of 82%.

Claims

CLAIMS1. A process for preparing a carbonate compound (C), comprising:(a) reacting in a first reactor (VI), a first phenolic compound with phosgene in presence of a first solvent and an alkali metal hydroxide, preferably sodium hydroxide, to obtain an intermediate product stream (P) comprising a chloroformate compound (CF);(b) passing the product stream (P) to a second reactor (V2) through a conduit, wherein the second reactor (V2) contains a reaction mixture (RM) comprising a second phenolic compound, a second solvent and a tertiary amine compound; and(c) reacting the second phenolic compound with the chloroformate compound (CF) to obtain the carbonate compound (C); wherein the intermediate product stream (P) upon formation, has a residence time of < 1.0 hour, preferably < 0.5 hour, preferably < 1.0 minute, preferably < 30.0 seconds in the first reactor (VI) prior to passing to the second reactor (V2); wherein the first phenolic compound has a structure represented by the formula (I):wherein ‘Z’ is a substituent selected from the group consisting of hydrogen, halogen group, hydrocarbyl group having 1-20 carbon atoms optionally comprising oxygen as a hetero-atom, and an amine group; wherein the second phenolic compound has a structure represented by the formula (II):wherein ‘G’ is a substituent selected from the group consisting of R1(C=O)-, halogen group, cyano group, and nitro group, and wherein the substituent R1is independently selected from the group consisting of optionally substituted alkoxy group, optionally substituted phenoxy group, optionally substituted benzyloxy group, and optionally substituted phenyl group; and further wherein the first phenolic compound and the second phenolic compound are chemically different.

2. The process of claim 1 , wherein the substituent ‘ G’ is R1(C=O)- and wherein the substituent R1is an optionally substituted alkoxy group having 1-10 carbon atoms, preferablyl-3 carbon atoms.

3. The process according to any one of claims 1 -2, wherein the molar ratio of phosgene to the first phenolic compound ranges from > 1.0 and < 1.5; and / or wherein the first phenolic compound is reacted with phosgene at any temperature ranging from 20°C to 30°C4. The process according to any one of claims 1-3, wherein the first solvent is free of nitrogen containing compounds, preferably free of amine containing compounds.

5. The process according to any one of claims 1-4, wherein the first solvent is methylene chloride.

6. The process according to any one of claims 1-5, wherein the first solvent comprises less than 10.0 parts per million (ppm) by weight, preferably less than 5.0 parts per million (ppm) by weight, preferably the first solvent has 0.0 parts per million by weight, of the tertiary amine compound.

7. The process to any one of claims 1-6, wherein the intermediate product stream (P) comprises less than 1.0 wt.%, preferably less than 0.5 wt.%, preferably less than 0.01 wt.%, based on the total weight of the intermediate product stream (P), of compounds selected from phenolic compounds, diaryl carbonate compounds and combinations thereof.

8. The process according to any one of claims 1-7, wherein the reaction mixture (RM) prior to the reaction of the second phenolic compound with the chloroformate compound (CF), is maintained at a pH in the range of 8.5 to 11.0, preferably in the range of 9.0-10.5.

9. The process according to any one of claims 1-8, wherein reaction mixture (RM) contains a catalytic amount of tertiary amine compound sufficient to catalyze the reaction of thechloroformate with that of the second phenolic compound, preferably wherein the tertiary amine compound is present in an amount of not greater than 0.1 wt.%, based on the total weight of the reaction mixture (RM).

10. The process according to claim 9, wherein the tertiary amine compound is tri-ethylamine.

11. The process according to any one of claims 1-10, wherein the reaction of the second phenolic compound with the chloroformate compound (CF) is carried out in the second reactor, at a pH of 8.5 to 11.0, preferably at a pH of 9.0-10.5, in presence of 20.0 wt.% to 40.0 wt.% of aqueous alkali metal hydroxide, preferably aqueous sodium hydroxide and the second solvent, preferably wherein the second solvent is methylene chloride.

12. The process according to any one of claims 1-11, wherein the molar ratio of the second phenolic compound to the chloroformate compound (CF) ranges from 3 : 1 to 1 :3, preferably from 2: 1 to 1 :2, preferably wherein the molar ratio of the second phenolic compound to the chloroformate compound (CF) is 1 : 1.

13. The process according to any one of claims 1-12, wherein the first phenolic compound is a compound selected from:

14. The process according to any one of claims 1-13, wherein the second phenolic compound is a compound selected from:and , where ‘X’ represents an halogen element.

15. The process according to any one of claims 1-14, wherein the first phenolic compound is phenol, the second phenolic compound is methyl salicylate, the chloroformate compound (CF) is phenyl chloroformate, and the carbonate compound (C) is phenyl methyl salicylyl carbonate (PMSC).

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