Improved process for producing 1,5-pentamethylene diisocyanate from cadaverine salts.

Abstract

Described herein is an improved method for producing 1,5-pentamethylene diisocyanate (PDI) from cadaverine salts. The method generally involves providing a solution containing a cadaverine salt dissolved in an inert solvent in the presence of a tertiary amine base, and subjecting the solution to a liquid-phase phosgenation reaction to convert the cadaverine to PDI. The phosgenation reaction involves maintaining the reaction at a temperature of 100°C to 120°C for a time sufficient to achieve a desired threshold yield of PDI. The method described herein allows for a reduction in the amount of reactants consumed, the reaction temperature, and / or the overall reaction time compared to conventional phosgenation reactions. Because subjecting cadaverine to high temperatures can result in the formation of certain cyclic compounds that are carried over into the PDI produced, it can prove advantageous to employ biobased cadaverine salts that have not previously been subjected to distillation.

Description

[Technical Field]

[0001] This description relates to the production of 1,5-pentamethylene diisocyanate. More particularly, described herein is an improved phosgenation process for producing 1,5-pentamethylene diisocyanate from a cadaverine salt in the presence of a tertiary amine, which can be carried out at temperatures lower than those employed in conventional phosgenation reactions. [Background technology]

[0002] Isocyanates are typically produced from amines by phosgenation via a carbamoyl chloride intermediate. In particular, 1,5-pentamethylene diisocyanate (PDI), typically produced from the phosgenation of cadaverine, is a key component used in advanced coatings and polyurethane manufacturing. In such applications, the purity of the PDI monomer is crucial, as the presence of certain cyclic compounds significantly impacts downstream performance. Furthermore, due to the hazards of phosgene and the toxic gases associated with cadaverine, special equipment and precautions are required to safely produce PDI on an industrial scale. Therefore, improved, less hazardous methods for producing PDI on an industrial scale are highly desirable. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] European Patent Application No. 14908171.3 Summary of the Invention [Means for solving the problem]

[0004] In a first aspect, described herein is a method for producing 1,5-pentamethylene diisocyanate (PDI) from a cadaverine salt, comprising the steps of: (a) providing a phosgene source; (b) providing a solution comprising a cadaverine salt dissolved in an inert solvent in the presence of a tertiary amine base; and (c) subjecting the solution to a liquid-phase phosgenation reaction to convert the cadaverine to PDI, wherein the phosgenation reaction comprises maintaining the reaction at a temperature range of 100° C. to 120° C. for a time sufficient to achieve a desired threshold yield of PDI, wherein the tertiary amine base is present in an amount sufficient to allow the phosgenation reaction to occur to completion at said temperature range.

[0005] In some embodiments, the phosgenation reaction of (c) is a multi-step phosgenation reaction comprising at least a first stage in which the solution is heated to a first temperature so that the cadaverine reacts with phosgene from the phosgene source to produce a dicarbamoyl chloride intermediate, and a subsequent second stage in which the solution is further heated to a second temperature higher than the first temperature to subject the dicarbamoyl chloride intermediate to dehydrochlorination, the second stage comprising maintaining the reaction at a temperature between 100° C. and 120° C. for a time sufficient to achieve a threshold yield of PDI.

[0006] In some embodiments, the amount of phosgene source and / or tertiary amine base reactant employed in the multi-stage phosgenation reaction is less than the amount required to achieve the same PDI yield as the corresponding single-stage phosgenation reaction occurring only at the second temperature.

[0007] In some embodiments, the cadaverine salt (e.g., cadaverine dihydrochloride) is a biobased cadaverine salt obtained from fermentation and / or enzymatic conversion, preferably via an immobilized whole (intact) cell biocatalyst to reduce cyclic compounds from cell lysate components. In some embodiments, the provided cadaverine salt was produced without distillation or otherwise not subjected to temperatures that promote the formation of cyclic compounds.

[0008] In some embodiments, the tertiary amine base is a heterocyclic amine or a tertiary amine base with an sp2 hybridized N atom, such as pyridine, and the inert solvent is a solvent or solvent mixture with a boiling point of at least 120°C.

[0009] In further aspects, described herein are compositions having a THP or other cyclic compound content of less than 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt%. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the phosgenation reaction of cadaverine dihydrochloride to produce PDI. [Figure 2] FIG. 1 shows a gas chromatograph from the PDI production method of Example 14. [Figure 3] FIG. 1 shows a gas chromatograph from the PDI production method of Example 16. [Figure 4] FIG. 1 shows a gas chromatograph from the PDI production method of Example 38. [Figure 5] FIG. 1 shows a gas chromatograph from the PDI production method of Example 39. [Figure 6] FIG. 1 shows a gas chromatograph from the PDI production method of Example 41. [Figure 7] FIG. 1 shows a gas chromatograph from the PDI production method of Example 44. DETAILED DESCRIPTION OF THE INVENTION

[0011] General definition Headings and other identifiers, e.g., (a), (b), (i), (ii), etc., are provided solely to facilitate the reading of the specification and claims. The use of headings or other identifiers in the specification or claims does not necessarily require the steps or elements to be presented in alphabetical or numerical order or in the order in which they are presented.

[0012] In the claims and / or specification, the use of the words "a" or "an," when used in conjunction with the term "comprising," may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one."

[0013] The term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. Generally, the term "about" is meant to indicate a possible variation of up to 10%. Thus, variations in values ​​of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% are encompassed by the term "about." Unless otherwise indicated, the use of the term "about" before a range applies to both ends of the range.

[0014] As used herein, the terms "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or process / method steps.

[0015] Sequence Listing This application contains a sequence listing in computer readable form, created on September 28, 2020, having a size of approximately 12 kb. The computer readable form is incorporated herein by reference.

[0016] [Table 1]

[0017] Industrial-scale production of 1,5-pentamethylene diisocyanate (PDI) from biobased cadaverine (1,5-pentanediamine, pentamethylenediamine, PDA) using conventional methods requires significant labor and large amounts of hazardous phosgene gas. As summarized in paragraphs

[0003] and

[0004] of European Patent Application No. 14908171.3 (published as EP3235804), conventional industrial cadaverine production methods involve obtaining a cadaverine salt solution through fermentation or enzymatic conversion, treating the salt solution with alkali, followed by extraction, evaporation, and finally completing a distillation purification step to obtain cadaverine in its free base form. The cadaverine free base is then subjected to a conventional phosgenation reaction to obtain PDI. Conventional processes involve the production of toxic gases from treating cadaverine in its free base form, utilize relatively large amounts of hazardous phosgene gas, and require high temperatures (e.g., greater than 170° C.) to obtain reasonable yields. The process described herein relates to the production of PDI by liquid-phase phosgenation of a cadaverine salt solution in the presence of a sufficient amount of a tertiary amine base to drive the phosgenation reaction to completion at temperatures substantially lower than those conventionally employed.

[0018] In a first aspect, described herein is a method for producing PDI from a cadaverine salt. The method generally involves preparing a solution containing a cadaverine salt dissolved in an inert solvent in the presence of a tertiary amine base. The solution is then subjected to liquid-phase phosgenation to convert the cadaverine to PDI, and the phosgenation reaction involves maintaining the reaction at a temperature of 100°C to 120°C for a time sufficient to achieve a desired threshold yield of PDI. In addition to promoting the dissolution of the cadaverine salt in the inert solvent, the presence of the tertiary amine base in the liquid-phase phosgenation reaction allows the phosgenation reaction to occur at significantly lower temperatures (e.g., 100°C to 120°C) than would be possible in the absence of the tertiary amine base.

[0019] In some embodiments, the phosgenation reaction temperature in the processes described herein does not exceed about 119, 118, 117, 116, 115, 114, 113, 112, 111, or 110° C. Higher temperatures have been found to be less beneficial in terms of PDI yield and / or purity and are associated with a more rapid accumulation of insoluble dark polymeric material in the reaction solution. Furthermore, the ability to carry out the processes described herein at temperatures much lower than those employed in conventional phosgenation reactions translates into significant savings in energy costs over time. In some embodiments, the phosgenation reaction temperature in the processes described herein does not decrease below 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50° C. In some embodiments, lower temperatures were not beneficial to the methods described herein, for example, in terms of initial dissolution of the reactants in the inert solvent and / or formation of mono- and / or dicarbamoyl chloride intermediates. In some embodiments, the phosgenation reaction in the methods described herein includes maintaining the reaction at a temperature of 100-115, 105-115, 110-115, or 100-110°C, or at about 110°C, for a time sufficient to achieve a threshold yield of PDI. In some embodiments, the overall temperature range for the methods described herein can be about 20-125, 20-120, 20-115, 25-115, 30-115, 35-115, 40-115, 45-115, or 50-115°C.

[0020] The phosgenation reactions described herein are preferably carried out for the minimum time necessary to achieve the desired PDI yield while maintaining an acceptable level of purity. In some embodiments, the phosgenation reactions described herein involve maintaining the reaction at a temperature of 100°C to 120°C for at least 1.5, 2, 2.5, or 3 hours. In some embodiments, the phosgenation reactions described herein involve maintaining the reaction at a temperature of 100°C to 120°C for no more than 6, 7, 8, 9, 10, 11, or 12 hours. In some embodiments, the phosgenation reactions described herein involve maintaining the reaction at a temperature of 100°C to 120°C for 1.5 to 6, 2 to 6, 2 to 5.5, 2.5 to 5.5, 2.5 to 6, or 3 to 5 hours.

[0021] In some embodiments, the phosgenation reaction described herein employs a multi-stage phosgenation reaction comprising at least a first stage and a second stage. In the first stage, the reaction mixture is heated to a first temperature (or maintained at a first temperature range) to allow cadaverine to react with phosgene from a phosgene source to produce a carbamoyl chloride intermediate (e.g., a mono- and / or di-carbamoyl chloride intermediate). In the second stage, the reaction mixture is further heated to a second temperature higher than the first temperature to subject the carbamoyl chloride intermediate to dehydrochlorination, thereby producing PDI. For clarity, the second stage includes the steps described herein of maintaining the reaction at a temperature between 100°C and 120°C for a time sufficient to achieve a threshold yield of PDI. In general, multi-stage phosgenation reactions have been found to provide beneficial results in terms of PDI yield and / or purity compared to corresponding phosgenation reactions carried out at only a single elevated temperature range (e.g., only the second-stage temperature). In some embodiments, the amount of phosgene source and / or tertiary amine base reactant employed in a multi-stage phosgenation reaction may be less than the amount required to achieve the same PDI yield as a corresponding single-stage phosgenation reaction occurring only at a second temperature. In some embodiments, the first temperature may be about 30-65°C, 35-65°C, 35-60°C, 40-60°C, 35-55°C, 40-55°C, or 45-55°C. In some embodiments, the first temperature may be about 50°C. The reaction times employed during the first and second stages may be varied and / or optimized depending on the particular reaction conditions to optimize PDI yield and / or purity. In some embodiments, the first stage may include maintaining the solution at the first temperature for at least 0.5, 1, or 2 hours, or for 0.5-3, 0.5-2.5, 0.5-2, 1-2.5, or 1-2 hours. In some embodiments, the second stage may include maintaining the solution at the second temperature for at least 1.5, 2, 2.5, or 3 hours, or for 1.5 to 6, 2 to 6, 2 to 5.5, 2.5 to 5.5, 2.5 to 6, or 3 to 5 hours.

[0022] In some embodiments, the phosgenation reactions described herein allow for reduced amounts of reactants consumed compared to corresponding conventional processes. Such reductions significantly reduce operating costs. In some embodiments, the phosgenation reactions described herein may employ 3 to 30, 4 to 29, 4 to 27, 4 to 24, 4 to 18, or 4.5 to 18 moles of phosgene per mole of cadaverine salt. While larger amounts or stoichiometric ratios of phosgene may be employed, minimal beneficial effects in terms of PDI yield and / or purity have been observed. Furthermore, due to the toxicity of phosgene, reducing the amount of phosgene reactant in industrial-scale processes is advantageous from the perspective of safety and regulatory concerns. As used herein, moles of phosgene refer to the number of moles of phosgene added and / or consumed in the phosgenation reaction, regardless of the source of the phosgene. For example, one mole of triphosgene is expected to be converted to three moles of phosgene during the phosgenation reactions described herein. Thus, one mole of triphosgene as the phosgene source corresponds to three moles of phosgene in the stoichiometries and ratios described herein.

[0023] Adding a tertiary amine (e.g., pyridine or TMEDA) to the phosgenation reaction described herein, either neat or diluted with an inert solvent, reduced the temperature required for PDI production. In some embodiments, the phosgenation reaction described herein may employ a sufficient amount of tertiary amine to allow the phosgenation reaction to proceed to or near completion at a temperature range of 100-120°C. In some embodiments, the phosgenation reaction described herein may employ at least 4, 4.5, 5, 5.5, or 6 moles of tertiary amine per mole of cadaverine salt. Employing greater amounts of tertiary amine base offered minimal benefit in terms of PDI yield and / or purity. Conversely, employing excess tertiary amine base (which would be too costly on an industrial scale) was found herein to be associated with an increase in the proportion of soluble by-products in the final reaction solution, observable by GC analysis, thereby reducing the overall purity of the PDI produced. In some embodiments, such soluble by-products may be difficult to remove by subsequent distillation if their boiling points are similar to that of PDI.

[0024] In some embodiments, the cadaverine salt employed in the phosgenation reaction described herein is preferably a biobased cadaverine salt obtained from fermentation (e.g., of a microorganism engineered to produce cadaverine) and / or enzymatic conversion (e.g., from lysine or lysine-HCl salt, preferably purified lysine-HCl salt). In some embodiments, the enzymatic conversion preferably occurs via an immobilized whole (intact) cell biocatalyst (e.g., whole cells expressing lysine decarboxylase) to reduce cyclic compounds from cell lysate components. In some embodiments, the cadaverine salt is cadaverine dihydrochloride. During the preparation of cadaverine by conventional methods, cyclic compounds containing unsaturated bonds, such as 2,3,4,5-tetrahydropyridine (THP or 1-piperidine), are also produced, which must then be removed to prevent interference with downstream polymerization applications (e.g., nylon production) (EP 3235804). The PDI production methods described herein are motivated, at least in part, by the discovery herein that such cyclic compounds result from exposure of cadaverine to high temperatures, such as when a cadaverine solution is subjected to a distillation process. Accordingly, in some embodiments, the cadaverine salts utilized herein may be produced without a distillation process or otherwise not subjected to a temperature high enough to promote the formation of cyclic compounds (e.g., 2,3,4,5-tetrahydropyridine [THP], piperidine, 2-(aminomethyl)-3,4,5,6-tetrahydropyridine, 1-piperidinecarbonyl chloride, or 1(2H)-pyridinecarbonyl chloride). The presence of cyclic compounds in the cadaverine salt reactants may result in the phosgenation reaction described herein being carried out, ultimately reducing the overall purity and / or performance of the PDI produced.

[0025] In some embodiments, the cyclic compounds and / or other components described herein can include THP, piperidine, 2-(aminomethyl)-3,4,5,6-tetrahydropyridine, 1-piperidinecarbonyl chloride, 1(2H)-pyridinecarbonyl chloride, or polymeric (insoluble) components that impart a dark color to the resulting PDI. As used herein, the term "cyclic compound" refers to any compound or material present in the raw materials (e.g., cadaverine salts) and / or the final product (e.g., PDI) that may have an impact on the performance of the final product for its intended commercial purpose. For example, any ring-containing compound or material that may have an impact on the performance of PDI in a polymerization reaction (e.g., polyurethane production) is considered a cyclic compound. In some embodiments, the content of THP or other cyclic compounds in the cadaverine salts described herein can be less than 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt%.

[0026] In some embodiments, the PDI produced by the phosgenation reaction described herein may have a THP or other cyclic compound content of less than 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt.% before undergoing one or more distillation purification steps. Reducing the level of cyclic compounds, particularly the soluble cyclic compounds described herein with boiling points similar to those of PDI, may make them more difficult to remove from the PDI reaction solution via distillation or may require more than one distillation purification step. Therefore, reducing the level of cyclic compounds upstream of any PDI distillation purification step is advantageous.

[0027] In some embodiments, the phosgene source employed in the phosgenation reactions described herein may be phosgene gas or triphosgene. The former is advantageous for large-scale industrial processes, while the latter is advantageous for laboratory or small-scale processes for practicality and safety reasons. In some embodiments, the phosgene source is triphosgene, and a tertiary amine base reacts with the triphosgene to release phosgene for the phosgenation reaction. In some embodiments, the phosgene source is triphosgene, and the tertiary amine base serves to promote dissolution of the cadaverine salt, react with the triphosgene to release phosgene, and catalyze the subsequent phosgenation reaction in the phosgenation temperature range. In some embodiments, conducting the phosgenation reactions described herein at temperatures below about 200° C. is advantageous because phosgene has been reported to begin to undergo some thermal decomposition at this temperature, thereby requiring more reactants. In some embodiments, conducting the phosgenation reactions described herein at temperatures below about 170° C. is advantageous because triphosgene has been reported to decompose at this temperature into a mixture of CO, phosgene, and carbon tetrachloride (CCl), thereby requiring more reactants (Cotarca et al., 2017).

[0028] In some embodiments, a tertiary amine base suitable for the phosgenation reactions described herein may be a heterocyclic amine or a tertiary amine base having an sp2 hybridized N atom. In some embodiments, the tertiary amine base may be pyridine, TMEDA, or a mixture thereof. In some embodiments, the phosgenation reactions described herein may employ the hydrochloride salt of cadaverine, thereby generating the chloride salt of the tertiary amine base as a by-product. This tertiary amine hydrochloride (e.g., pyridine hydrochloride) may be isolated from the reaction solution and recycled.

[0029] In some embodiments, an inert solvent suitable for the phosgenation reactions described herein may comprise or consist of chlorobenzene, dichlorobenzene, toluene, nitrobenzene, or any mixture thereof. Other inert solvents conventionally used in phosgenation reactions may also be considered. In some embodiments, the inert solvent may be a solvent or solvent mixture having a boiling point of at least 120, 125, or 130° C.

[0030] In some embodiments, the desired threshold yield of PDI for the phosgenation reactions described herein may be at least 50, 55, 60, 65, 70, 75, or 80%.

[0031] In some aspects, described herein are compositions comprising PDI produced by the methods described herein, having a THP or other cyclic compound content of less than 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt%.

[0032] In some aspects, described herein are compositions comprising a PDI, wherein the PDI contains less than 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt% THP or other cyclic compounds.

[0033] In some embodiments, the methods described herein may take the form of a one-pot synthesis in which a cadaverine salt and a phosgene source are slowly combined in a single vessel in an inert solvent in the presence of a tertiary amine base, followed by heating to initiate the phosgenation reaction.

[0034] In some embodiments, the PDI produced by the methods described herein may be subjected to a distillation purification step.

[0035] In some embodiments, the PDI produced by the methods described herein may be used (or may be of sufficient purity to be used) in a variety of applications, such as in polyurethane production, coatings, resins, sealants, and textiles. [Example]

[0036] Example 1 General Materials and Methods The following reference materials are used in the examples: Recombinant DNA manipulations generally follow the methods described in Sambrook et al., 2001. Restriction enzymes, T4 DNA ligase, Rapid DNA Ligation Kit, SanPrep Column DNA Gel Extraction Kit, Plasmid Mini-Prep Kit, and agarose are purchased from Sangon Biotech Co., Ltd. (Shanghai, China). TE buffer contains 10 mM Tris-HCl (pH 8.0) and 1 mM Na2EDTA (pH 8.0). TAE buffer contains 40 mM Tris-acetate (pH 8.0) and 2 mM Na2EDTA.

[0037] In Example 2, restriction enzyme digestion was performed in buffer provided by Sangon Biotech. A typical restriction enzyme digest contained 0.8 μg of DNA in 8 μL of TE, 2 μL of restriction enzyme buffer (10x concentration), 1 μL of bovine serum albumin (0.1 mg / mL), 1 μL of restriction enzyme, and 8 μL of TE. The reaction was incubated at 37°C for 1 hour and analyzed by agarose gel electrophoresis. DNA used in cloning experiments was digested and stopped by heating at 70°C for 15 minutes, after which DNA was extracted using a SanPrep Column DNA Gel Extraction Kit. The concentration of DNA in the sample was determined as follows: An aliquot of DNA (10 μL) was diluted to 1 mL with TE, and the absorbance at 260 nm was measured relative to the absorbance of TE. DNA concentration was calculated based on an absorbance of 1.0 at 260 nm for 50 μg / mL double-stranded DNA.

[0038] Agarose gels typically contain 0.7% agarose (w / v) in TAE buffer. Ethidium bromide (0.5 μg / ml) is added to the agarose to allow visualization of DNA fragments under a UV lamp. Agarose gels were run in TAE buffer. DNA fragment sizes were determined using two sets of 1 kb Plus DNA Ladder from Sangon Biotech.

[0039] Example 2 Cloning, expression and activity testing of lysine decarboxylase expressed in Escherichia coli. The E. coli lysine decarboxylase kdc (2-keto acid decarboxylase) gene was synthesized and cloned into pET21a (Millipore Sigma, formerly Novagen). The wild-type kdc nucleic acid sequence (EC 4.1.1.18) from E. coli BW25113 strain is represented by SEQ ID NO: 1, and the amino acid sequence is represented by SEQ ID NO: 2, annotated as lysine decarboxylase.

[0040] The kdc gene-containing plasmid was transformed into BL21(DE3) E. coli cells. As a negative control, the empty plasmid pET21a was also transformed. For enzyme expression and characterization experiments, flasks containing 40 mL of TB were inoculated with 5% of the overnight culture and shaken. The flasks were incubated at 30°C with shaking at 250 rpm for 2 hours, after which protein production was induced with 0.2 mM isopropyl β-D-1-thiogalactopyranoside (IPTG) and incubated for an additional 4 hours at 30°C with shaking. The cells were harvested by centrifugation, and the pellets were stored at -80°C.

[0041] KDC enzyme activity was assessed using a pH-based in vitro assay. Enzyme activity was tested using commercially available lysine-HCl salt. Unless otherwise specified, all chemicals were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). First, cells were lysed using a benchtop sonicator according to the manufacturer's instructions. The cell lysate was partially clarified by centrifugation (14,000 g, 5 min). The protein concentration of the resulting clarified lysate was measured using a Bradford Protein Assay Kit (Sangon Biotech) according to the manufacturer's instructions. Lysates were normalized by protein concentration by diluting with 10 mM Tris buffer. The normalized lysate was then diluted 1:5 with 10 mM Tris buffer. For multiple-well plate assays, 20 μL of lysate was added to each well. Each condition was performed in triplicate.

[0042] The reaction mixture contained 15% lysine-HCl, 0.04% pyridoxal 5'-phosphate (PLP). The pH of each reaction mixture was adjusted to approximately pH 6.5 by adding 1 M H2SO4 and 1 N NaOH. The lysate was then added to the reaction mixture, constantly maintaining the pH at 6.5 by adding 1 M H2SO4. The amount of H2SO4 used was recorded and used to calculate the enzyme activity. The assay reaction was complete when no more H2SO4 additions were required to maintain the pH at 6.5.

[0043] Example 3 Fermentation of transformed E. coli overexpressing KDC In this example, growth media were prepared as follows: all solutions were prepared with distilled, deionized water. LB medium (1 L) contained Bacto™ tryptone (i.e., an enzymatic digest of casein) (10 g), Bacto™ yeast extract (i.e., the water-soluble portion of autolyzed yeast cells) (5 g), and NaCl (10 g). LB-glucose medium contained glucose (10 g), MgSO (0.12 g), and thiamine hydrochloride (0.001 g) per 1 L of LB medium. LB freezing buffer contained K2HPO4 (6.3 g), KH2PO4 (1.8 g), MgSO4 (1.0 g), (NH4)2SO4 (0.9 g), sodium citrate dihydrate (0.5 g), and glycerin (44 mL) per 1 L of LB medium. M9 salts (1 L) contained 6 g of NaHPO, 3 g of KHPO, 1 g of NHCl, and 0.5 g of NaCl. M9 minimal medium contained 10 g of D-glucose, 0.12 g of MgSO, and 0.001 g of thiamine hydrochloride in 1 L of M9 salts. Antibiotics were added as needed to the following final concentrations: ampicillin (Ap), 50 μg / mL; chloramphenicol (Cm), 20 μg / mL; kanamycin (Kan), 50 μg / mL; and tetracycline (Tc), 12.5 μg / mL. Antibiotic stock solutions were prepared in water, except for chloramphenicol, which was prepared in 95% ethanol, and tetracycline, which was prepared in 50% aqueous ethanol. Aqueous IPTG stock solutions were prepared at various concentrations.

[0044] Standard fermentation medium (1 L) contained KHPO (7.5 g), ammonium iron(III) citrate (0.3 g), citric acid monohydrate (2.1 g), and concentrated HSO (1.2 mL). The fermentation medium was adjusted to pH 7.0 by adding concentrated NHOH before autoclaving. The following supplements were added immediately before the start of fermentation: D-glucose, MgSO (0.24 g), potassium, and (NH)(MoO). 24Trace minerals included ZnSO₄·4H₂O (0.0037 g), ZnSO₄·7H₂O (0.0029 g), H₃BO₃ (0.0247 g), CuSO₄·5H₂O (0.0025 g), and MnCl₂·4H₂O (0.0158 g). IPTG stock solution was added as needed (e.g., when the optical density at 600 nm reached 15–20) to the indicated final concentrations. The glucose feed solution and MgSO₄ (1 M) solution were autoclaved separately. The glucose feed solution (650 g / L) was prepared by combining 300 g of glucose and 80 mL of H₂O. The trace mineral and IPTG solutions were sterilized through a 0.22 μm membrane. Antifoam (Sigma 204) was added to the fermentation broth as needed. A typical wet E. coli cell density of 120 g / L was achieved.

[0045] Example 4 Conversion of lysine hydrochloride to PDA hydrochloride using whole cells expressing lysine decarboxylase To produce pentamethylenediamine (PDA)-HCl, 2 g of engineered wet E. coli containing lysine decarboxylase was added to 1 L of a 200 g / L lysine hydrochloride solution containing 0.1 g / L PLP. HCl was used to maintain the pH at 6.5. The temperature of the solution was brought to 37°C. The reaction was then initiated and continued for 10 hours while maintaining the pH at 6.5. The lysine content was determined by high-performance liquid chromatography (HPLC) at the end of the reaction (<0.5% w / v).

[0046] The reaction mixture was passed through a 0.2 micron microfiltration membrane (to remove large particles such as cells, bacterial fragments, and aggregates) and a 10 kDa ultrafiltration membrane (to remove proteins and other soluble macromolecules in the culture medium). The filtrate was concentrated under reduced pressure to one-quarter of its original volume. Two volumes of methanol were added to the mixture, which was then crystallized at 15°C. The solid was then collected and dried. The white solid product weighed 174.67 g and was analyzed for PDA-HCl content. The PDA-HCl content was found to be 99.3%, with a yield of 91.1%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0047] Example 5 Conversion of lysine hydrochloride to PDA hydrochloride using lysine decarboxylase from cell lysates A similar method to that used in Example 4 was used to prepare PDA hydrochloride (PDA-HCl), except that 2 g of lysine decarboxylase-containing engineered E. coli cells was added instead of whole cells. To obtain a soluble cell extract, 2 g of engineered E. coli cells were added to 10 mL of phosphate buffer solution (pH 7.0) and mixed well. The cells were then disrupted by high-pressure homogenization and then centrifuged to obtain the soluble cell extract. The weight of the white solid remaining from the reaction was 172.9 g. The PDA-HCl content was found to be 99.5%, with a yield of 90.2%. The PDA-HCl salt was not subjected to further distillation purification.

[0048] Example 6 Crystallization of PDA hydrochloride from ethanol The same method as in Example 4 was used to prepare PDA-HCl, except that ethanol was added instead of methanol for crystallization at 15°C. The weight of the white solid remaining from the reaction was 177.35 g. The PDA-HCl content was found to be 99.2%, with a yield of 92.5%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0049] Example 7 Crystallization of PDA hydrochloride from isopropanol The same method as in Example 4 was used to prepare PDA-HCl, except that three times the amount of isopropyl alcohol was added instead of methanol for crystallization at 15°C. The weight of the white solid remaining from the reaction was 171.2 g. The PDA-HCl content was found to be 99.4%, with a yield of 89.3%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0050] Example 8 Increased lysine hydrochloride concentration and adjusted pH to 7 The same method as in Example 4 was used to prepare PDA-HCl, except that the lysine hydrochloride concentration was 300 g / L with the pH maintained at 7 instead of 200 g / L at pH 6.5, 4 g of engineered wet E. coli was added instead of 2 g, PLP was 0.15 g / L instead of 0.1 g / L, and the reaction time was 13 hours instead of 10 hours. The weight of the white solid remaining from the reaction was 223.4 g. The PDA-HCl content was found to be 99.3%, with a yield of 91.5%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0051] Example 12 Diisocyanate analysis by gas chromatography The following examples generally relate to the preparation of diisocyanates (1,5-pentamethylene diisocyanate [PDI]) from diamine free base (PDA, Example 13) or diamine salts (PDA-HCl, Examples 14-46). Where indicated, the PDI prepared in the following examples was analyzed by gas chromatograph with the following settings / parameters: Column: DB-5 30 m x 0.25 mm x 0.25 μm; Inlet Temperature: 160°C; Detector: Detector Temperature 280°C; Carrier Gas Flow Rate: 2 mL / min; Split Ratio: 36:1; Column Oven: Initial temperature 40°C, hold for 5 minutes, ramp to 250°C at 20°C / min, hold for 5 minutes; Injection Volume: 1 μL.

[0052] Example 13 PDI production from PDA free base at temperatures up to 170°C 87.5 g (0.5 mol) of PDA-HCl salt was mixed with 200 g (1 mol) of 20% sodium hydroxide solution and stirred at room temperature for 1 hour. The mixture was then dissolved in approximately 100 g of water under reduced pressure. 200 g of ethanol was then added at 20°C and stirred until the solid was completely precipitated. After filtration, the mother liquor was desolvated under reduced pressure and dried under high vacuum at 1,000 Pa to obtain 51 g of PDA free base.

[0053] 51 g (0.5 mol, 1 equivalent) of PDA free base and 1,050 g of dichlorobenzene were mixed in a 2 L three-neck flask and heated to 60°C. Phosgene was initiated. The aeration rate was 2.5 g / min, and the tail gas was absorbed with 10% sodium hydroxide solution. After 40 minutes, the temperature was increased to 80°C, with the aeration rate unchanged. After 1 hour, the temperature was increased to 170°C. After 12 hours of aeration, a total of 2,050 g (20.7 mol, 41.4 equivalents) of phosgene was introduced and a sample was taken. The reaction yield was calculated to be 72.2% by GC normalization.

[0054] After transferring to a rectification apparatus, the solvent dichlorobenzene was removed at 46°C under a pressure of 200 Pa, and the temperature was raised to 65-66°C to recover 49 g of a colorless liquid, which was pentamethylene diisocyanate (PDI), with a yield of 63.6% and a GC purity of 99.5%. - 1 H-NMR (CDCl3, 400 MHz) δ: 3.32~3.35 (t, 4H,OCN-CH2-H), 1.62~1.67 (m, 4H), 1.45~1.51 (m, 2H) - 13 C NMR (400 MHz, CDCl3) δ: 23.68, 30.63, 42.81, 122.06 - Elemental analysis: theoretical C, 54.54; H, 6.54; N, 18.17; found C, 54.55; H, 6.48; N, 18.42.

[0055] PDI production from PDA-HCl salt While Example 13 described a method for the preparation of PDI from PDA free base, subsequent examples relate to the preparation of PDI from PDA-HCl salt via a phosgenation reaction ( FIG. 1 ). More specifically, Examples 14-37, FIGS. 2 and 3, and Table 1 relate to the preparation of PDI from PDA-HCl using phosgene gas directly as the phosgene source. For safety and practical reasons, further experiments were performed using triphosgene instead of phosgene. Thus, Examples 38-46, FIGS. 4-7, and Table 2 relate to the preparation of PDI from PDA-HCl using triphosgene as an indirect phosgene source. Nevertheless, given that one mole of triphosgene is expected to be converted to three moles of phosgene during the phosgenation reaction described herein, it is believed that the results obtained with triphosgene are applicable to phosgene (and vice versa). Tables 1 and 2 provide summary tables to facilitate comparisons between the reaction conditions of Examples 14-46, and Example 47 provides a summary of the results.

[0056] [Table 2A]

[0057] [Table 2B]

[0058] [Table 3]

[0059] Example 14 PDI production from PDA-HCl using phosgene at temperatures up to 170°C 87.5 g (0.5 mol) of PDA-HCl and 1,050 g of dichlorobenzene were mixed in a 2-L three-neck flask and heated to 60°C. Phosgenation was initiated at a rate of 2.5 g / min, and the off-gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 170°C, and the reaction was continued for an additional 12 hours. A total of 2,050 g (20.7 mol) of phosgene was introduced, and samples were collected. The reaction yield was 88.1%. The gas chromatography results are shown in Figure 2.

[0060] Example 15 PDI production from PDA-HCl using phosgene at temperatures up to 210°C 87.5 g (0.5 mol) of PDA-HCl and 1,050 g of nitrobenzene were mixed in a 2-L three-neck flask and heated to 60°C. Phosgenation was initiated at a rate of 2.5 g / min, and the off-gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 130°C, with the ventilation rate unchanged. After 1 hour, the temperature was raised to 210°C, and the reaction was continued for an additional 11 hours. A total of 2,050 g (20.7 mol) of phosgene was passed through. The reaction yield was 56.2%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0061] Example 16 PDI production from PDA-HCl using phosgene at temperatures up to 130°C 87.5 g (0.5 mol) of PDA-HCl and 612.5 g of chlorobenzene were mixed in a 2 L three-neck flask and heated to 60°C. Phosgenation was initiated at a rate of 2.5 g / min, and the off-gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 130°C, and the reaction was continued for an additional 5 hours. A total of 1,000 g (10.1 mol) of phosgene was introduced, and samples were collected. The reaction yield was 2.4%. The results of gas chromatography are shown in Figure 3.

[0062] Example 17 PDI production from PDA-HCl using phosgene at temperatures up to 130°C 87.5 g (0.5 mol) of PDA-HCl and 1,050 g of chlorobenzene were mixed in a 2 L three-neck flask and heated to 60°C. Phosgenation was initiated at a rate of 2.5 g / min, and the exhaust gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 130°C, and the reaction was continued for an additional 5 hours. A total of 1,000 g (10.1 mol) of phosgene was introduced, and samples were collected. The reaction yield was 3.0%.

[0063] Example 18 PDI production from PDA-HCl using phosgene at temperatures up to 130°C 87.5 g (0.5 mol) of PDA-HCl and 1,050 g of chlorobenzene were mixed in a 2-L three-neck bottle and heated to 60°C. Phosgenation was initiated at a rate of 2.5 g / min, and the off-gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 130°C, and the reaction was continued for an additional 12 hours. A total of 2,050 g (20.7 mol) of phosgene was introduced and sampled. The reaction yield was 9.4%.

[0064] Example 19 Production of PDI from PDA-HCl using phosgene in the presence of aniline at temperatures up to 130°C 87.5 g (0.5 mol) of PDA-HCl and 612.5 g of chlorobenzene were mixed in a 2 L three-neck flask, and aniline (6 mL) was added as a catalyst. The mixture was heated to 60°C and phosgenation was initiated at a rate of 2.5 g / min. The exhaust gas was quenched with 10% sodium hydroxide solution. After 40 minutes, the temperature was raised to 80°C. After 1 hour, the temperature was raised to 130°C and the reaction was continued for an additional 5 hours. A total of 1,000 g (10.1 mol) of phosgene was introduced. A sample was taken and the reaction yield was 3.8%.

[0065] Example 20 PDI production from PDA-HCl using phosgene at 100°C with TMEDA as a solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl and 875 g of TMEDA was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 36.1%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0066] Example 21 PDI production from PDA-HCl using phosgene at 100°C with pyridine as a solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl and 875 g of pyridine was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 43.1%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0067] Example 22 PDI production from PDA-HCl using phosgene at 100°C with TMEDA / chlorobenzene as a solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 116 g (1 mol) of TMEDA was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 37.6%.

[0068] Example 23 PDI production from PDA-HCl using phosgene at 100°C using TMEDA / toluene as a solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of toluene, and 116 g (1 mol) of TMEDA was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 15.2%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0069] Example 24 PDI production from PDA-HCl using phosgene at 100°C with pyridine / chlorobenzene as solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 79 g (1 mol) of pyridine was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 44.2%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0070] Example 25 PDI production from PDA-HCl using phosgene at 100°C with pyridine / toluene as solvent In a 2 L three-neck flask, a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of toluene, and 79 g (1 mol) of pyridine was heated to 100°C, and phosgenation was initiated at 1.2 g of phosgene per minute. The off-gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was terminated, and the mixture was cooled to 25°C. A total of 1,200 g (12.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 20.3%, but a relatively large amount of insoluble dark polymeric material was observed at the bottom of the flask.

[0071] Example 26 Production of PDI from PDA-HCl with phosgene at 80°C using TMEDA as a solvent The phosgenation reaction was carried out as described in Example 20, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 16.3%.

[0072] Example 27 Preparation of PDI from PDA-HCl using phosgene at 80°C with pyridine as a solvent The phosgenation reaction was carried out as described in Example 21, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 22.3%.

[0073] Example 28 PDI production from PDA-HCl using phosgene at 80°C using TMEDA / chlorobenzene as a solvent The phosgenation reaction was carried out as described in Example 22, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 16.5%.

[0074] Example 29 PDI production from PDA-HCl using phosgene at 80°C using TMEDA / toluene as a solvent The phosgenation reaction was carried out as described in Example 23, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 8.2%.

[0075] Example 30 PDI production from PDA-HCl using phosgene at 80°C using pyridine / chlorobenzene as a solvent The phosgenation reaction was carried out as described in Example 24, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 21.9%.

[0076] Example 31 PDI production from PDA-HCl using phosgene at 80°C using pyridine / toluene as solvent The phosgenation reaction was carried out as described in Example 25, except that the temperature was heated to 80° C. instead of 100° C. The reaction yield was 9.9%.

[0077] Example 32 PDI production from PDA-HCl with phosgene using TMEDA as a solvent at 50°C and then 80°C The phosgenation reaction was carried out as described in Example 20, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 16.4%.

[0078] Example 33 Preparation of PDI from PDA-HCl with phosgene at 50°C and then 80°C using pyridine as a solvent The phosgenation reaction was carried out as described in Example 21, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 21.5%.

[0079] Example 34 PDI production from PDA-HCl with phosgene using TMEDA / chlorobenzene as solvent at 50°C and then 80°C The phosgenation reaction was carried out as described in Example 22, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 17.1%.

[0080] Example 35 PDI production from PDA-HCl with phosgene using TMEDA / toluene as solvent at 50°C and then 80°C The phosgenation reaction was carried out as described in Example 23, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 7.9%.

[0081] Example 36 PDI production from PDA-HCl with phosgene at 50°C and then 80°C using pyridine / chlorobenzene as solvent The phosgenation reaction was carried out as described in Example 24, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 22.3%.

[0082] Example 37 PDI production from PDA-HCl with phosgene at 50°C and then 80°C using pyridine / toluene as solvent The phosgenation reaction was carried out as described in Example 25, except that the temperature was held at 50° C. for 4 hours, then at 80° C. for 12.7 hours (instead of 100° C.). The reaction yield was 8.6%.

[0083] Example 38 PDI production from PDA-HCl salt using triphosgene at temperatures up to 170 °C 87.5 g (0.5 mol) of PDA-HCl and 100 g of dichlorobenzene were mixed in a 2 L three-neck flask. 3,000 g (10.1 mol) of triphosgene was dissolved in 900 g of dichlorobenzene and slowly added to the three-neck flask at 170 °C. The off-gas was quenched with 10% sodium hydroxide solution, and the total reaction time was 6 hours. A sample was taken, and the reaction yield was 68%. The gas chromatography results are shown in Figure 5.

[0084] Example 39 PDI production from PDA-HCl salt using triphosgene at 100°C using TMEDA / chlorobenzene / dichlorobenzene as solvent In a 5-L three-neck flask, a solution of 116 g (1 mol) of TMEDA in 500 g of chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) of triphosgene in 3,000 g of dichlorobenzene at 50 °C. The evolved phosgene gas was bubbled into another three-neck flask containing 87.5 g (0.5 mol) of PDA-HCl and 875 g of TMEDA at 100 °C. The off-gas was quenched with 10% sodium hydroxide solution. After the reaction was completed, the flask was cooled to 25 °C and a sample was taken. The reaction yield was 15.2%. The gas chromatography results are shown in Figure 6.

[0085] Example 40 PDI production from PDA-HCl salt using triphosgene at 100°C using TMEDA / chlorobenzene / dichlorobenzene as solvent In a 5-L three-neck flask, a solution of 116 g (1 mol) of TMEDA in 500 g of chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) of triphosgene in 3,000 g of dichlorobenzene at 50°C. The evolved phosgene gas was bubbled into another three-neck flask containing 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 116 g (1 mol) of TMEDA at 100°C. The off-gas was quenched with 10% sodium hydroxide solution. After the reaction was completed, the flask was cooled to 25°C and a sample was taken. The reaction yield was 16.3%.

[0086] Example 41 PDI production from PDA-HCl salt using triphosgene at 100°C using pyridine / chlorobenzene / dichlorobenzene as solvent In a 5-L three-neck flask, a solution of 79 g (1 mol) of pyridine in 500 g of chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) of triphosgene in 3,000 g of dichlorobenzene at 50 °C. The evolved phosgene gas was bubbled into another three-neck flask containing 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 79 g (1 mol) of pyridine at 100 °C. The off-gas was quenched with 10% sodium hydroxide solution. After the reaction was completed, the flask was cooled to 25 °C and a sample was taken. The reaction yield was 31.4%. The gas chromatography results are shown in Figure 7.

[0087] Example 42 PDI production from PDA-HCl salt using triphosgene at 100°C using pyridine / chlorobenzene as a solvent In a 5-L three-neck flask, a solution of 79 g (1 mol) of pyridine in 500 g of chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) of triphosgene in 3,000 g of chlorobenzene at 50°C. The evolved phosgene gas was bubbled into another three-neck flask containing 87.5 g (0.5 mol) of PDA-HCl and 875 g of pyridine at 100°C. The off-gas was quenched with 10% sodium hydroxide solution. After the reaction was completed, the flask was cooled to 25°C and a sample was taken. The reaction yield was 55.6%.

[0088] Example 43 PDI production from PDA-HCl salt using triphosgene at 80°C using pyridine / chlorobenzene / dichlorobenzene as solvent In a 5-L three-neck flask, a solution of 79 g (1 mol) of pyridine in 500 g of chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) of triphosgene in 3,000 g of dichlorobenzene at 50°C. The evolved phosgene gas was bubbled into another three-neck flask containing 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 79 g (1 mol) of pyridine at 80°C. The off-gas was quenched with 10% sodium hydroxide solution. After the reaction was completed, the flask was cooled to 25°C and a sample was taken. The reaction yield was 20.3%.

[0089] Example 44 Preparation of PDI from PDA-HCl salt by direct addition of triphosgene using pyridine / chlorobenzene as solvent at 50°C and then 80°C In a 5 L three-neck flask, a solution of 741.5 g (2.5 mol) of triphosgene in 1,500 g of chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 79 g (1 mol) of pyridine at 30-35°C. After the addition, the reaction mixture was heated to 50°C and maintained for 1 hour. The reaction temperature was then increased to 80°C and maintained for an additional 3 hours. After the reaction, the reaction flask was cooled to 25°C and a sample was taken. The reaction yield was 20.9%. The gas chromatography results are shown in Table 1.

[0090] Example 45 Preparation of PDI from PDA-HCl salt by direct addition of triphosgene using pyridine (2 equivalents) / chlorobenzene as solvent at 50°C, followed by 80°C, 110°C, and 120°C In a 5 L three-neck flask, a solution of 222 g (0.75 mol) of triphosgene in 1,500 g of chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 79 g (1 mol) of pyridine at 30–35°C. After the addition, the reaction mixture was heated to 50°C and held for 1 hour. No reaction occurred, as indicated by GC analysis. The reaction temperature was then increased to 80°C and held for an additional 3 hours. The reaction yield was 12.1%. The reaction temperature was further increased to 110°C and held for an additional 3 hours. The reaction yield was 22.6%. Finally, the reaction temperature was increased to 120°C and held for an additional 3 hours. The reaction yield was 22.7%. A dark polymeric material began to appear at 90°C.

[0091] Example 46 Preparation of PDI from PDA-HCl salt by direct addition of triphosgene using pyridine (6 equivalents) / chlorobenzene as solvent at 50°C, followed by 80°C, 110°C, and 120°C In a 5 L three-neck flask, a solution of 222 g (0.75 mol) of triphosgene in 1,500 g of chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) of PDA-HCl, 1,050 g of chlorobenzene, and 237 g (3 mol) of pyridine at 30–35°C. After the addition, the reaction mixture was heated to 50°C and held for 1 hour. GC analysis showed no reaction had occurred. The reaction temperature was then raised to 80°C and held for an additional 3 hours. The reaction yield was 18.1%. The reaction temperature was then further raised to 110°C and held for an additional 3 hours. The reaction yield was 80.2%. Finally, the reaction temperature was raised to 120°C and held for an additional 3 hours. The reaction yield was 80.2%. A dark polymeric material began to appear at 90°C.

[0092] Example 47 Overview of Examples 13 to 46 Example 13 replicates conventional industrial processes for producing PDI, which involve many laborious steps, involve the production of toxic gases from handling PDI in its free base form, utilize relatively large amounts of hazardous phosgene gas, and require high temperatures (e.g., above 170°C) to obtain reasonable yields.

[0093] Example 14 describes a phosgenation reaction similar to the conventional method described in Example 13, except starting with a PDA salt solution (PDA-HCl) instead of PDA free base. Referring to Table 1, the yield of Example 14 was 88.1%, producing PDI of acceptable purity (+++++). However, the overall process consumed a relatively large amount of phosgene (41.4 equivalents), required a high reaction temperature (170°C) to be maintained for an extended period (12 hours), and the entire reaction took over 13 hours, producing undesirable dark, insoluble polymeric material at the bottom of the flask (**). The experiments described in Examples 15-46 explore different approaches to improving the production of PDI starting from PDA-HCl, as described below. More specifically, the objectives included maintaining reasonably high yields and purity while attempting to reduce phosgene consumption, reduce the maximum temperature required in the process, reduce the overall reaction time, and / or reduce the amount of dark, insoluble polymeric material by-product.

[0094] Referring to Table 1, Example 15 shows that increasing the maximum reaction temperature to 210°C resulted in a significant decrease in yield (from 88.1% to 56.2%), a decrease in purity (+++), and a higher amount of dark polymeric material (***). Initial attempts to reduce the maximum reaction temperature to 130°C resulted in less than 10% yield (Examples 16-19), despite the presence of a primary amine base (aniline) as a potential catalyst (Example 19).

[0095] Examples 20-37 and 39-45 demonstrate that, when the phosgene amount ranged from 4.5 to 30 equivalents, the reaction temperature required for PDI production was reduced when carried out in the presence of a tertiary amine (TMEDA or pyridine), either neat or diluted with an inert solvent. However, yields were often less than 50%, overall purity was poor, and many by-products resulting from unwanted side reactions were visible in GC analysis of the reaction solution (see Tables 1 and 2). Interestingly, comparisons of Examples 20 and 22, 21 and 24, 26 and 28, 27 and 30, 32 and 34, and 33 and 36 suggest that using an excess of tertiary amine was generally not beneficial in terms of yield or purity.

[0096] A comparison of Examples 43 and 44 suggests that similar yields can be obtained with reduced amounts of phosgene and pyridine if the reaction is initially carried out at a lower temperature (50°C) (as confirmed by GC) that favors intermediate formation. A comparison of Examples 44 and 45 shows that reducing the amount of phosgene to only 4.5 equivalents in Example 45 reduces the yield from 20.9% to 12.1% at 80°C, but increasing the maximum temperature to 110°C increases the yield to 22.6%. Example 45 also shows that increasing the temperature to 120°C does not further improve the yield, an observation also made in Example 46.

[0097] Example 46 differs from Example 45 only in that the amount of pyridine was increased from 2 to 6 equivalents. Remarkably, as shown in Table 2, this single reaction parameter change dramatically increased yield (80.2%), increased purity (++++++), and minimized the accumulation of insoluble dark polymeric material in the reaction solution. (*) These results suggest that (1) sufficient equivalents of tertiary amine must be present, otherwise both yield and overall purity will be low; (2) in the presence of sufficient equivalents of tertiary amine, yield increases with increasing temperature and does not change significantly above 110 °C; and (3) 1.5 equivalents of triphosgene (or 4.5 equivalents of phosgene) per equivalent of PDA-HCl is sufficient to produce PDI.

[0098] Thus, the PDI production process described in Example 46 achieved similar yields and purity to the more conventional process of Example 14, but required approximately 90% less phosgene (from 40.4 equivalents to 4.5 equivalents), a 60°C reduction in maximum temperature (from 170°C to 110°C), an approximately 50% reduction in overall reaction time (from 13.7 hours to 7 hours), and a reduction in the amount of insoluble dark polymeric by-product (from ** to *). (References) TIFF0007780518000005.tif50168

Claims

1. 1. A process for producing 1,5-pentamethylene diisocyanate (PDI) from a cadaverine salt, comprising: (a) providing a source of phosgene; (b) providing a solution comprising a cadaverine salt dissolved in an inert solvent in the presence of a tertiary amine base; and (c) subjecting the solution to a liquid phase phosgenation reaction to convert the cadaverine to PDI, comprising maintaining the phosgenation reaction at a temperature range of 100°C to 120°C to achieve a desired threshold yield of PDI. Including, A process wherein the tertiary amine base allows the phosgenation reaction to occur to completion in said temperature range.

2. 10. The process of claim 1, wherein the phosgenation reaction temperature of step (c) does not exceed 119°C and does not decrease below 30°C.

3. 3. The method according to claim 1 or 2, wherein the phosgenation reaction in (c) comprises maintaining the reaction at a temperature of 100 to 115°C.

4. 4. The method of claim 1, further comprising maintaining the phosgenation reaction of (c) in the temperature range for at least 1.5 hours.

5. 5. The process of claim 1, wherein the phosgenation reaction of (c) is a multi-step phosgenation reaction comprising at least a first stage in which the solution is heated to a first temperature so that the cadaverine reacts with phosgene from a phosgene source to produce a dicarbamoyl chloride intermediate, and a subsequent second stage in which the solution is further heated to a second temperature higher than the first temperature to subject the dicarbamoyl chloride intermediate to dehydrochlorination, the second stage comprising maintaining the reaction at a temperature of from 100°C to 120°C to achieve a threshold yield of PDI, wherein the amount of phosgene source and / or tertiary amine base reactant employed in the multi-step phosgenation reaction is less than the amount required to achieve the same PDI yield as a corresponding single-step phosgenation reaction occurring only at the second temperature.

6. 6. The method of claim 5, wherein the first temperature is 30 to 65°C, and the first stage comprises maintaining the solution at the first temperature for at least 0.5 hours.

7. 7. The method of claim 5 or 6, wherein the second temperature is at least 10°C higher than the first temperature.

8. (a) employing 3 to 30 moles of phosgene per mole of cadaverine salt; (b) employing at least 4 moles of a tertiary amine base per mole of cadaverine salt; or (c) Both (a) and (b); 8. The method according to any one of claims 1 to 7.

9. 9. The method of claim 1, wherein the cadaverine salt is a bio-based cadaverine salt obtained from fermentation and / or enzymatic conversion, the fermentation being of a microorganism engineered to produce cadaverine, and the enzymatic conversion is from lysine.

10. 10. The method of claim 1, wherein the provided cadaverine salt is produced without distillation or otherwise subjected to temperatures that promote the formation of cyclic compounds, the cyclic compounds being selected from one or more of the group consisting of 2,3,4,5-tetrahydropyridine [THP], piperidine, 2-(aminomethyl)-3,4,5,6-tetrahydropyridine, 1-piperidinecarbonyl chloride, or 1(2H)-pyridinecarbonyl chloride, and the content of cyclic compounds in the cadaverine salt is less than 0.1% by weight.

11. 11. The method of any one of claims 1 to 10, wherein the cadaverine salt is cadaverine dihydrochloride.

12. 12. The method according to any one of claims 1 to 11, wherein the tertiary amine base is pyridine, a heterocyclic amine with an sp2 hybridized N atom or a tertiary amine base.

13. 13. The process according to any one of claims 1 to 12, wherein the inert solvent comprises or consists of chlorobenzene, dichlorobenzene, toluene, nitrobenzene, or any mixture thereof, and / or the inert solvent is a solvent or solvent mixture having a boiling point of at least 120°C.

14. 14. The process of any one of claims 1 to 13, wherein the process is a one-pot synthesis in which the cadaverine salt and the phosgene source are slowly combined in a single vessel in an inert solvent in the presence of a tertiary amine base, followed by heating to initiate the phosgenation reaction.

15. 15. The method of any one of claims 1 to 14, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.1% by weight before being subjected to one or more distillation steps.

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