Improved process for the preparation of 1,5-pentamethylene diisocyanate from 1,5-pentanediamine salt

Abstract

This application describes an improved method for preparing 1,5-pentamethylene diisocyanate (PDI) from 1,5-pentanediamine salts. The method generally includes: providing a solution containing a 1,5-pentanediamine salt dissolved in an inert solvent in the presence of a tertiary amine; and subjecting the solution to a liquid-phase phosgenation reaction to convert 1,5-pentanediamine to PDI. The phosgenation reaction includes the step of maintaining the reaction at a temperature of 100°C to 120°C for a sufficient time to achieve the desired threshold yield of PDI. The method described in this application enables a reduction in the amount of reactants consumed, a lower reaction temperature, and / or a shorter total reaction time compared to conventional phosgenation reactions. It has been found advantageous to use bio-based 1,5-pentanediamine salts that have not been previously distilled, as subjecting 1,5-pentanediamine to high temperatures leads to the formation of certain cyclic compounds that may remain in the resulting PDI.

Description

Technical Field

[0001] This application relates to the production of 1,5-pentamethylene diisocyanate. More specifically, this application describes an improved phosgenation method for the production of 1,5-pentamethylene diisocyanate from 1,5-pentanediamine salts in the presence of a tertiary amine, which can be carried out at a lower temperature than that used in conventional phosgenation reactions. Background Technology

[0002] Isocyanates are typically produced from amines via the phosgenation reaction of carbamoyl chloride intermediates. In particular, 1,5-pentamethylene diisocyanate (PDI) is commonly generated by the phosgenation of 1,5-pentanediamine and is a crucial component in the production of advanced coatings and polyurethanes. For such applications, the purity of the PDI monomer is critical, as the presence of certain cyclic compounds can significantly impact downstream performance. Furthermore, due to the hazardous nature of phosgene and the harmful fumes associated with 1,5-pentanediamine, special facilities and precautions are required for the safe industrial-scale production of PDI. Therefore, there is a strong need for an improved method for the industrial-scale production of less hazardous PDI. Summary of the Invention

[0003] In a first aspect, this application describes a method for preparing 1,5-pentamethylene diisocyanate (PDI) from a 1,5-pentanediamine salt, the method comprising: (a) providing a phosgene source; (b) providing a solution containing a 1,5-pentanediamine 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 1,5-pentanediamine into PDI, the phosgenation reaction comprising the step of: maintaining the reaction at a temperature range of 100°C to 120°C for a sufficient time to achieve a desired PDI threshold yield, wherein the presence of the tertiary amine base is sufficient to allow the phosgenation reaction to complete within the temperature range.

[0004] In some embodiments, the phosgenation reaction in (c) is a multi-stage phosgenation reaction comprising at least a first stage and a subsequent second stage, wherein in the first stage the solution is heated to a first temperature to cause 1,5-pentanediamine to react with phosgene from a phosgene source to generate a dicarbamoyl chloride intermediate, wherein in the subsequent second stage the solution is further heated to a second temperature above the first temperature to cause the dicarbamoyl chloride intermediate to undergo a dehydrochlorination reaction, wherein the second stage comprises the step of maintaining the reaction at a temperature of 100°C to 120°C for a sufficient time to achieve the threshold yield of PDI.

[0005] In some embodiments, the amount of phosgene source and / or tertiary amine base reactant used in the multi-stage phosgenation reaction is less than the amount required to achieve the same PDI yield as a single-stage phosgenation reaction that occurs only at the second temperature.

[0006] In some embodiments, the 1,5-pentanediamine salt (e.g., 1,5-pentanediamine dihydrochloride) is a bio-based 1,5-pentanediamine salt obtained from fermentation and / or enzymatic conversion, preferably occurring via immobilized whole-cell biocatalysts to reduce substances from cell lysis components. In some embodiments, the provided 1,5-pentanediamine salt is produced without distillation or otherwise subjected to temperatures conducive to the formation of cyclic compounds.

[0007] In some embodiments, the tertiary amine base is a heterocyclic amine, or has sp... 2 - A tertiary amine base with hybridized N atoms, such as pyridine; the inert solvent is a solvent or mixture of solvents with a boiling point of at least 120 °C.

[0008] In other respects, this application describes compositions comprising less than 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt% of THP or other cyclic compounds. Attached Figure Description

[0009] In the attached diagram:

[0010] Figure 1 This illustrates the phosgenation reaction of 1,5-pentanediamine dihydrochloride used to prepare PDI.

[0011] Figure 2 Gas chromatography showing the PDI production method from Example 14.

[0012] Figure 3 Gas chromatography is shown from the PDI production method of Example 16.

[0013] Figure 4 Gas chromatography showing the PDI production method from Example 38.

[0014] Figure 5 Gas chromatography is shown from the PDI production method of Example 39.

[0015] Figure 6 Gas chromatography is shown from the PDI production method of Example 41.

[0016] Figure 7 Gas chromatography is shown for the PDI production method from Example 44. Detailed Implementation

[0017] definition

[0018] Titles and other identifiers, such as (a), (b), (i), (ii), etc., are provided solely for ease of reading the specification and claims. The use of titles or other identifiers in the specification or claims does not necessarily require that steps or elements be performed in alphabetical or numerical order or in the order in which they are presented.

[0019] When used in conjunction with the term "comprising" in the claims and / or description, the words "a" or "an" may mean "one," but also have the same meaning as "one or more," "at least one," and "one or more."

[0020] The term "about" is used to indicate the standard deviation of a numerical value, including the error of the apparatus or method used to determine the value. Typically, the term "about" is intended to indicate a possible variation of up to 10%. Therefore, variations of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% of a value are included in the term "about." Unless otherwise stated, the term "about" used before a range also applies to both ends of that range.

[0021] The terms “comprising” (and any form of inclusion), “having” (and any form of having), “including” (and any form of including), or “containing” (and any form of containing) as used in this application are inclusive or open-ended and do not exclude additional undescribed elements or process / method steps.

[0022] sequence list

[0023] This application contains a sequence list in a computer-readable form created on September 28, 2020, which is approximately 12kb in size. This computer-readable form is incorporated herein by reference.

[0024]

[0025] The industrial-scale production of 1,5-pentamethylene diisocyanate (PDI) from bio-based 1,5-pentanediamine (pentamethylenediamine, PDA) using conventional methods is labor-intensive and requires large quantities of harmful phosgene gas. As described in paragraphs

[0003] and

[0004] of European Patent Application No. 14908171.3 (published as EP 3235804), the conventional industrial 1,5-pentanediamine production process includes: obtaining a solution of 1,5-pentanediamine salt by fermentation or enzymatic conversion, treating the salt solution with alkali, followed by extraction and evaporation, and finally obtaining 1,5-pentanediamine in the form of a free alkali in a distillation purification step. The free 1,5-pentanediamine alkali is then subjected to a conventional phosgenation reaction to obtain PDI. Conventional methods are associated with the generation of harmful fumes from the production of 1,5-pentanediamine using the free alkali form, the use of relatively large quantities of harmful phosgene gas, and the requirement of high temperatures (e.g., above 170°C) to achieve reasonable yields. The method described in this application relates to the production of PDI by liquid-phase phosgenation of a 1,5-pentanediamine salt solution in the presence of a sufficient amount of tertiary amine base to allow the phosgenation reaction to be completed at a temperature significantly lower than that conventionally used.

[0026] In a first aspect, this application describes a method for producing PDI from a 1,5-pentanediamine salt. The method generally involves preparing a solution containing a 1,5-pentanediamine 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 1,5-pentanediamine to PDI, wherein the phosgenation reaction includes the following steps: maintaining the reaction at a temperature of 100°C to 120°C for a sufficient time to achieve the desired threshold yield of PDI. In addition to promoting the dissolution of the 1,5-pentanediamine salt in the inert solvent, the presence of the tertiary amine base in the liquid-phase phosgenation reaction enables the phosgenation reaction to occur at a significantly lower temperature (e.g., 100 to 120°C) than would be possible without the tertiary amine base.

[0027] In some embodiments, the phosgenation reaction temperature in the methods described in this application does not exceed about 119°C, 118°C, 117°C, 116°C, 115°C, 114°C, 113°C, 112°C, 111°C, or 110°C. Higher temperatures have been found to offer no benefit to the yield and / or purity of PDI and are associated with a faster accumulation of insoluble, dark-colored polymeric materials in the reaction solution. Furthermore, the ability to implement the methods described in this application at temperatures significantly lower than conventional phosgenation reaction temperatures can result in substantial energy cost savings over time. In some embodiments, the phosgenation reaction temperature in the method described in this application is not lower than the following temperatures: 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C. In some embodiments, lower temperatures are disadvantageous to the method described in this application, for example, in terms of the initial dissolution of reactants in inert solvents and / or the formation of monocarbamoyl chloride and / or dicarbamoyl chloride intermediates. In some embodiments, the phosgenation reaction in the method described in this application includes the following steps: maintaining the reaction within the following temperature range or maintaining the temperature for a sufficient time to achieve a threshold yield of PDI: 100 to 115°C, 105 to 115°C, 110 to 115°C, or 100 to 110°C; or at approximately 110°C. In some embodiments, the total temperature range of the method described in this application may be approximately 20 to 125°C, 20 to 120°C, 20 to 115°C, 25 to 115°C, 30 to 115°C, 35 to 115°C, 40 to 115°C, 45 to 115°C, or 50 to 115°C.

[0028] The phosgenation reaction described in this application is preferably carried out for the shortest duration required to achieve the desired PDI yield while maintaining acceptable purity. In some embodiments, the phosgenation reaction described in this application includes the step of maintaining the reaction at a temperature of 100°C to 120°C for at least 1.5 hours, 2 hours, 2.5 hours, or 3 hours. In some embodiments, the phosgenation reaction described in this application includes the step of maintaining the reaction at a temperature of 100°C to 120°C for no more than 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, the phosgenation reaction described in this application includes the step of maintaining the reaction at a temperature of 100°C to 120°C for 1.5 to 6 hours, 2 to 6 hours, 2 to 5.5 hours, 2.5 to 5.5 hours, 2.5 to 6 hours, or 3 to 5 hours.

[0029] In some embodiments, the phosgenation reaction described in this application employs a multi-stage phosgenation reaction comprising at least a first stage and a second stage. In the first stage, the reactants are heated to a first temperature (or maintained within a first temperature range) to cause 1,5-pentanediamine to react with phosgene from a phosgene source to generate a carbamoyl chloride intermediate (e.g., monocarbamoyl chloride and / or dicarbamoyl chloride intermediate). In the second stage, the reactants are further heated to a second temperature above the first temperature to cause the carbamoyl chloride intermediate to dehydrochlorinate, thereby generating PDI. For clarity, the second stage includes the step described in this application below: maintaining the reaction at a temperature of 100°C to 120°C for a sufficient time to achieve a threshold yield of PDI. It has generally been found that multi-stage phosgenation reactions produce beneficial results in terms of PDI yield and / or purity compared to corresponding phosgenation reactions carried out only in a higher temperature range (e.g., only at the temperature of the second stage). In some embodiments, the amount of phosgene source and / or tertiary amine base reactant used in the 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 the second temperature. In some embodiments, the first temperature may be about 30 to 65°C, 35 to 65°C, 35 to 60°C, 40 to 60°C, 35 to 55°C, 40 to 55°C, or 45 to 55°C. In some embodiments, the first temperature may be about 50°C. The reaction time used during the first and second stages may be varied and / or optimized depending on the specific reaction conditions in order to optimize the 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 hours, 1 hour, or 2 hours; or maintaining it for 0.5 to 3 hours, 0.5 to 2.5 hours, 0.5 to 2 hours, 1 to 2.5 hours, or 1 to 2 hours. In some embodiments, the second stage may include: maintaining the solution at a second temperature for at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours; or maintaining it for 1.5 to 6 hours, 2 to 6 hours, 2 to 5.5 hours, 2.5 to 5.5 hours, 2.5 to 6 hours, or 3 to 5 hours.

[0030] In some embodiments, the phosgenation reaction described herein allows for a reduction in the amount of reactants consumed compared to corresponding conventional methods. This reduction significantly lowers operating costs. In some embodiments, the phosgenation reaction described herein can use 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 1,5-pentanediamine salt. Although higher amounts or stoichiometric ratios of phosgene can be used, it has been observed that doing so produces minimal beneficial effects in terms of PDI yield and / or purity. Furthermore, due to the toxicity of phosgene, reducing the amount of phosgene reactants in industrial-scale methods is advantageous from safety and regulatory perspectives. The mole count of phosgene used herein refers to the number of moles of phosgene added and / or consumed in the phosgenation reaction, regardless of the source of the phosgene. For example, in the phosgenation reaction described herein, one mole of triphosgene is expected to be converted into three moles of phosgene. Therefore, in the stoichiometric values ​​and ratios described herein, one mole of triphosgene as a phosgene source can correspond to three moles of phosgene.

[0031] Adding either undiluted or diluted tertiary amines (e.g., pyridine or TMEDA) to the phosgenation reaction described in this application lowers the temperature required for PDI production. In some embodiments, the phosgenation reaction described in this application may use a sufficient amount of tertiary amine to allow the phosgenation reaction to occur completely or nearly completely in a temperature range of 100 to 120°C. In some embodiments, the phosgenation reaction described in this application may use at least 4, 4.5, 5, 5.5, or 6 moles of tertiary amine per mole of 1,5-pentanediamine salt. Using higher amounts of tertiary amine base shows minimal benefit in terms of PDI yield and / or purity. Conversely, this application has found that using high excesses of tertiary amine base (which is costly on an industrial scale) is associated with a higher proportion of soluble byproducts in the final reaction solution (observable by gas chromatography-GC analysis), thereby reducing the overall purity of the obtained PDI. In some embodiments, if the boiling points of these soluble byproducts are similar to those of PDI, it may be difficult to remove these soluble byproducts by subsequent distillation.

[0032] In some embodiments, the 1,5-pentanediamine salt used in the phosgenation reaction described in this application is preferably a bio-based 1,5-pentanediamine salt derived from fermentation (e.g., fermentation of microorganisms engineered to produce 1,5-pentanediamine) and / or enzymatic conversion (e.g., enzymatic conversion from lysine or lysine-HCl salt, preferably purified lysine-HCl salt). In some embodiments, the enzymatic conversion preferably occurs via immobilized whole-cell biocatalysts (e.g., whole cells expressing lysine decarboxylase) to reduce cyclic compounds from cell lysis components. In some embodiments, the 1,5-pentanediamine salt is 1,5-pentanediamine dihydrochloride. During the preparation of 1,5-pentanediamine by conventional methods, cyclic compounds containing unsaturated bonds, such as 2,3,4,5-tetrahydropyridine (THP or 1-piperidine), are also generated, and these cyclic compounds must then be removed to avoid interfering with downstream polymerization applications (e.g., in nylon production) (EP 3235804). The PDI production method described in this application is at least partly due to the following finding of this application: that such cyclic compounds are produced by exposure of 1,5-pentanediamine to high temperatures, for example, when the 1,5-pentanediamine solution is exposed to high temperatures during a distillation step. Therefore, in some embodiments, the 1,5-pentanediamine salt used in this application can be obtained without a distillation step, or without being subjected to sufficiently high temperatures in other ways to facilitate the formation of cyclic compounds (e.g., 2,3,4,5-tetrahydropyridine [THP]; piperidine; 2-(aminomethyl)-3,4,5,6-tetrahydropyridine; 1-piperidine carbonyl chloride; or 1(2H)-pyridine carbonyl chloride). Any cyclic compounds present in the 1,5-pentanediamine salt reactants can undergo the phosgenation reaction described in this application, reducing the overall purity and / or performance of the final PDI.

[0033] In some embodiments, the cyclic compounds and / or other components described herein may include: THP, piperidine; 2-(aminomethyl)-3,4,5,6-tetrahydropyridine; 1-piperidine carbonyl chloride; 1(2H)-pyridine carbonyl chloride, or polymer (insoluble) components that impart a darker color to the resulting PDI. As used herein, the term "cyclic compound" refers to any of the following compounds or materials present in the raw materials (e.g., 1,5-pentanediamine salt) and / or the final product (e.g., PDI) that may have some effect on the performance of the final product for its intended commercial purpose. For example, any cyclic compound or material that is thought to have some effect on the performance of PDI in a polymerization reaction (e.g., in polyurethane production) is considered a cyclic compound. In some embodiments, the content of THP or other cyclic compounds in the 1,5-pentanediamine salt described in this application may be less than 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt%.

[0034] In some embodiments, the PDI obtained by the phosgenation reaction described in this application may have a content of less than 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt% of THP or other cyclic compounds before undergoing one or more distillation purification steps. The reduced content of cyclic compounds (especially the soluble cyclic compounds described in this application with boiling points similar to PDI) may be more difficult to remove from the PDI reaction solution by distillation, or may require more than one distillation purification step. Therefore, reducing the content of cyclic compounds upstream of any PDI distillation purification step is advantageous.

[0035] In some embodiments, the phosgene source used in the phosgenation reaction described in this application can be phosgene gas or triphosgene. The former is advantageous for large-scale industrial methods, while the latter is advantageous for laboratory-scale or smaller-scale methods due to practicality and safety reasons. In some embodiments, the phosgene source is triphosgene, and a tertiary amine base reacts with triphosgene to release phosgene for the phosgenation reaction. In some embodiments, the phosgene source is triphosgene, and the tertiary amine base is used to promote the dissolution of 1,5-pentanediamine salt, to react with triphosgene to release phosgene, and to catalyze the subsequent phosgenation reaction within the phosgenation temperature range. In some embodiments, it is advantageous to carry out the phosgenation reaction described in this application at a temperature below about 200°C, because phosgene has been reported to begin to undergo some thermal degradation at this temperature, thus requiring more reactants. In some embodiments, it is advantageous to carry out the phosgenation reaction described herein at a temperature below about 170°C, since triphosgene has been reported to degrade at this temperature into a mixture of CO2, phosgene and carbon tetrachloride (CCl4), thus requiring more reactants (Cotarca et al., 2017).

[0036] In some embodiments, the tertiary amine base suitable for the phosgenation reaction described in this application may be a heterocyclic amine or have sp... 2 - A tertiary amine base with hybridized N atoms. In some embodiments, the tertiary amine base may be pyridine, TMEDA, or a mixture thereof. In some embodiments, the phosgenation reaction described herein may use 1,5-pentanediamine hydrochloride, which produces a chloride salt of the tertiary amine base as a byproduct. The tertiary amine hydrochloride (e.g., pyridine hydrochloride) can be separated from the reaction solution and recycled.

[0037] In some embodiments, the inert solvent suitable for the phosgenation reaction described in this application may include or consist of the following solvents: 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 with a boiling point of at least 120°C, 125°C, or 130°C.

[0038] In some embodiments, the desired threshold yield of PDI for the phosgenation reaction described in this application can be at least 50%, 55%, 60%, 65%, 70%, 75%, or 80%.

[0039] In some aspects, this application describes compositions comprising PDI prepared by the methods described herein, wherein the content of THP or other cyclic compounds is less than 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt%.

[0040] In some aspects, this application describes compositions comprising PDI, wherein the content of THP or other cyclic compounds in the PDI is less than 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt%.

[0041] In some embodiments, the method described in this application can be a one-pot synthesis in which a 1,5-pentanediamine salt and a phosgene source are slowly mixed in an inert solvent in the presence of a tertiary amine base in a single container, and then heated to initiate a phosgenation reaction.

[0042] In some embodiments, the PDI prepared by the method described in this application may be subjected to a distillation purification step.

[0043] In some embodiments, the PDI obtained by the method described in this application can be used (or can have sufficient purity for use) in a variety of applications, such as in polyurethane production, coatings, resins, sealants and textiles.

[0044] Example

[0045] Example 1: General Materials and Methods

[0046] The following reference materials were used in the examples: Recombinant DNA manipulation generally followed 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 were purchased from Sangon Biotech (Shanghai, China). TE buffer contained 10 mM Tris-HCl (pH 8.0) and 1 mM Na2EDTA (pH 8.0). TAE buffer contained 40 mM Tris-acetate (pH 8.0) and 2 mM Na2EDTA.

[0047] In Example 2, restriction enzyme digestion was performed in a buffer solution provided by Sangon Biotech.

[0048] A typical restriction enzyme digestion solution contains: 0.8 μg DNA in 8 μL TE, 2 μL restriction enzyme buffer (10x concentration), 1 μL bovine serum albumin (0.1 mg / mL), 1 μL restriction enzyme, and 8 μL TE. The reaction is incubated at 37°C for 1 hour and analyzed by agarose gel electrophoresis. DNA for cloning experiments is digested by terminating the reaction at 70°C for 15 minutes, and then the DNA is extracted using the SanPrep Column DNA Gel Extraction Kit. The concentration of DNA in the sample is determined as follows: an aliquot of DNA (10 μL) is diluted to 1 mL in TE, and the absorbance relative to TE is measured at 260 nm. The DNA concentration is calculated based on the fact that the absorbance of 50 μg / mL double-stranded DNA at 260 nm is 1.0.

[0049] 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 UV light. The agarose gel is then subjected to electrophoresis in TAE buffer. The size of the DNA fragments is determined using two sets of 1kb Plus DNA Ladders purchased from Sangon Biotech.

[0050] Example 2: Cloning, expression, and activity assay of lysine decarboxylase expressed in Escherichia coli

[0051] 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 from *E. coli* strain BW25113 (EC4.1.1.18) is represented by SEQ ID NO:1, and the amino acid sequence is represented by SEQ ID NO:2, labeled as lysine decarboxylase.

[0052] The plasmid containing the kdc gene was transformed into BL21(DE3) *E. coli* cells. The empty plasmid pET21a was also transformed into a negative control. For enzyme expression and characterization experiments, flasks containing 40 mL of TB were inoculated at 5% from overnight culture and shaken. The flasks were incubated at 30 °C with shaking at 250 rpm for 2 hours, then protein production was induced with 0.2 mM isopropyl β-D-1-thiogalactopyranoside (IPTG) and incubated again at 30 °C with shaking for 4 hours. Cells were collected by centrifugation, and aggregates were stored at -80 °C.

[0053] KDC enzyme activity was assessed using a pH-based in vitro assay. Enzyme activity was tested using commercially available lysine-HCl salt. All chemicals were purchased from Sigma-Aldrich Chemical Company (St. Louis, Missouri, USA) unless otherwise specified. First, cells were lysed using a benchtop sonicator according to the manufacturer's instructions. Cell lysates were partially clarified by centrifugation (14,000 g, 5 min). Protein concentrations of the clarified lysates were measured using a Bradford Protein Assay Kit (Sangon Biotech) according to the manufacturer's instructions. Lysates were normalized to protein concentration by dilution in 10 mM Tris buffer. The normalized lysates were then diluted 1:5 in 10 mM Tris buffer. 20 μL of lysate was added to each well for multi-well plate analysis. Each condition was repeated three times.

[0054] The reaction mixture contained 15% lysine-HCl and 0.04% pyridoxal-5'-phosphate (PLP). The pH of each reaction mixture was adjusted to approximately pH 6.5 by adding 1M H₂SO₄ and 1N NaOH. The lysate was then added to the reaction mixture while maintaining the pH at 6.5 by adding 1M H₂SO₄. The amount of H₂SO₄ used was recorded and used to calculate enzyme activity. The reaction was considered complete when no further addition of H₂SO₄ was needed to maintain the pH at 6.5.

[0055] Example 3: Fermentation of transformed E. coli overexpressing KDC

[0056] For embodiments of the present invention, the growth medium was prepared as follows: all solutions were prepared in distilled deionized water. LB medium (1L) contained: Bacto™ tryptone (i.e., the enzymatic digest of casein) (10g), Bacto™ yeast extract (i.e., the water-soluble fraction of autolysed yeast extract) (5g), and NaCl (10g). LB-glucose medium (1L) contained: glucose (10g), MgSO4 (0.12g), and thiamine hydrochloride (0.001g). LB-freeze buffer (1L) contained: K2HPO4 (6.3g), KH2PO4 (1.8g), MgSO4 (1.0g), (NH4)2SO4 (0.9g), sodium citrate dihydrate (0.5g), and glycerol (44mL). M9 salt (1L) contains: Na₂HPO₄ (6g), KH₂PO₄ (3g), NH₄Cl (1g), and NaCl (0.5g). M9 basal medium in 1L of M9 salt contains: D-glucose (10g), MgSO₄ (0.12g), and thiamine hydrochloride (0.001g). Antibiotics were added as appropriate to the following final concentrations: ampicillin (Ap), 50 μg / mL; chloramphenicol (Cm), 20 μg / mL; kanamycin (Kan), 50 μg / mL; tetracycline (Tc), 12.5 μg / mL. Antibiotic stock solutions were prepared in water, except for chloramphenicol prepared in 95% ethanol and tetracycline prepared in 50% ethanol aqueous solution. Aqueous stock solutions of IPTG were prepared at various concentrations.

[0057] The standard fermentation medium (1L) contained: K₂HPO₄ (7.5g), ferric ammonium citrate (III) (0.3g), citrate monohydrate (2.1g), and concentrated H₂SO₄ (1.2mL). Prior to autoclaving, the pH of the fermentation medium was adjusted to 7.0 by adding concentrated NH₄OH. The following supplements were added just before fermentation began: D-glucose; MgSO₄ (0.24g); potassium; and trace minerals, including (NH₄)₆(Mo₇O₂). 24The following ingredients were added: ZnSO4·7H2O (0.0037 g), ZnSO4·7H2O (0.0029 g), H3BO3 (0.0247 g), CuSO4·5H2O (0.0025 g), and MnCl2·4H2O (0.0158 g). If necessary (e.g., when the optical density at 600 nm is between 15 and 20), add IPTG stock solution to the indicated final concentration. The glucose feed solution and MgSO4 (1 M) solution were autoclaved separately. The glucose feed solution (650 g / L) was prepared by mixing 300 g of glucose with 280 mL of H2O. The solution of trace minerals and IPTG was sterilized through a 0.22 μm membrane. An antifoaming agent (Sigma 204) was added to the fermentation broth as needed. A typical wet E. coli cell density was achieved at 120 g / L.

[0058] Example 4: Using whole-cell expression of lysine decarboxylase to convert lysine hydrochloride to PDA hydrochloride

[0059] To produce pentamethylenediamine (PDA)-HCl, 2 g of wet-engineered *E. coli* containing lysine decarboxylase was added to 1 L of a 200 g / L lysine hydrochloride solution containing 0.1 g / L PLP. The pH was maintained at 6.5 with HCl. The solution temperature was raised to 37 °C. The reaction was then initiated and continued for 10 hours while maintaining the pH at 6.5. At the end of the reaction (<0.5% w / v), the lysine content was measured by high-performance liquid chromatography (HPLC).

[0060] The reaction mixture was passed through a 0.2-micrometer microfiltration membrane (to remove large particles such as cells, bacterial debris, and aggregates) and a 10 kDa ultrafiltration membrane (to remove proteins and other soluble macromolecules from the culture medium). The filtrate was concentrated to 1 / 4 of its original volume under reduced pressure. Twice the volume of methanol was added to the mixture, and crystallization was then carried out at 15°C. The solid was then collected and dried. The white solid product weighed 174.67 g, and its PDA-HCl content was analyzed. 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.

[0061] Example 5: Converting lysine hydrochloride to PDA hydrochloride using a lysine decarboxylase from cell lysates

[0062] PDA hydrochloride (PDA-HCl) was produced using the same method as in Example 4, however, instead of whole cells, 2 g of lysate from engineered *E. coli* cells containing lysine decarboxylase was added. To obtain the soluble cell extract, 2 g of engineered *E. coli* cells were added to 10 mL of phosphate buffer (pH 7.0) and stirred thoroughly. The cells were then crushed by autoclaving and centrifuged to obtain the soluble cell extract. The remaining white solid from the reaction weighed 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 steps.

[0063] Example 6: Crystallization of PDA hydrochloride with ethanol

[0064] PDA-HCl was produced using the same method as in Example 4, but ethanol was added at 15°C instead of methanol for crystallization. The remaining white solid from the reaction weighed 177.35 g. The PDA-HCl purity was found to be 99.2%, with a yield of 92.5%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0065] Example 7: Crystallization of PDA hydrochloride using isopropanol

[0066] PDA-HCl was produced using the same method as in Example 4, but with 3 times the volume of isopropanol added instead of methanol at 15°C for crystallization. The remaining white solid from the reaction weighed 171.2 g. The PDA-HCl purity was found to be 99.4%, with a yield of 89.3%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0067] Example 8: Increased lysine hydrochloride concentration and adjustment of pH to 7

[0068] PDA-HCl was produced using the same method as in Example 4, except that: the lysine hydrochloride concentration was 300 g / L and the pH was maintained at 7, while the non-lysine hydrochloride concentration was 200 g / L and the pH was maintained at 6.5; 4 g of engineered wet E. coli was added instead of 2 g; 0.15 g / L of PLP was added instead of 0.1 g / L; and the reaction time was 13 hours instead of 10 hours. The remaining white solid from the reaction weighed 223.4 g. The PDA-HCl purity was found to be 99.3%, with a yield of 91.5%. The PDA-HCl salt was not subjected to further distillation purification steps.

[0069] Example 12: Analysis of diisocyanates by gas chromatography

[0070] Subsequent examples typically involve the production of diisocyanates (1,5-pentamethylene diisocyanate [PDI]) from a diamine free base (PDA; Example 13) or a diamine salt (PDA-HCl; Examples 14-46). When indicated, the PDI prepared in the subsequent examples was analyzed using gas chromatography with the following settings / parameters: column: DB-5 30m*0.25mm*0.25μm, inlet temperature: 160°C, detector: detector temperature 280°C, carrier gas flow rate: 2mL / 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: 1μL.

[0071] Example 13: Production of PDI from PDA free alkali at a temperature of up to 170°C

[0072] 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 h. The mixture was then dissolved in approximately 100 g of water under reduced pressure. Subsequently, 200 g of ethanol was added at 20 °C and stirred until the solid completely precipitated. After filtration, the mother liquor was desolventized under reduced pressure and dried under a high vacuum of 1,000 Pa to obtain 51 g of free PDA base.

[0073] In a 2-liter three-necked flask, 51 g (0.5 mol; 1 equivalent) of free PDA base and 1050 g of dichlorobenzene were mixed and heated to 60 °C to begin exposure to phosgene. The aeration rate was 2.5 g / min, and the exhaust gas was absorbed by a 10% sodium hydroxide solution. After 40 minutes, the temperature was increased to 80 °C while maintaining the aeration rate. After 1 hour, the temperature was increased to 170 °C. After 12 hours of aeration, a total of 2050 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.

[0074] After being transferred to a distillation 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 collect 49 g of a colorless liquid, namely pentamethylene diisocyanate (PDI), with a yield of 63.6% and a GC purity of 99.5%.

[0075] - 1 H-NMR (CDCl3, 400MHz) δ: 3.32~3.35 (t, 4H, OCN-CH2-H), 1.62~1.67 (m, 4H), 1.45~1.51 (m, 2H)

[0076] - 13 C NMR (400MHz, CDCl3) δ: 23.68, 30.63, 42.81, 122.06

[0077] - Elemental analysis: Theoretical values: C, 54.54; H, 6.54; N, 18.17; Measured values: C, 54.55; H, 6.48; N, 18.42.

[0078] PDI production from PDA-HCl salt

[0079] Although Example 13 describes a method for producing PDI from PDA free base, the following examples relate to the production of PDI from PDA-HCl salt via a phosgenation reaction. Figure 1 More specifically, Examples 14-37 and Figure 2 , 3 Table 1 describes the production of PDI from PDA-HCl using phosgene gas directly as the phosgene source. For safety and practical reasons, other experiments used triphosgene instead of phosgene. Therefore, Examples 38-46 and... Figure 4-7 Table 2 relates to the production of PDI from PDA-HCl using triphosgene as an indirect phosgene source. However, it is desirable that the results obtained using triphosgene also apply to phosgene (and vice versa), provided that one mole of triphosgene is expected to be converted to three moles of phosgene in the phosgenation reaction described in this application. Tables 1 and 2 provide a summary table for easy comparison of the reaction conditions in Examples 14-46, and Example 47 provides an overview of the results.

[0080] Table 1

[0081]

[0082]

[0083]

[0084] Total purity of the crude reaction solution; **** to *: maximum to minimum amount of insoluble dark polymer material found at the bottom of the flask; +++++ to +: maximum to minimum purity of the reaction solution as determined by gas chromatography; "Clarity": no insoluble dark polymer material found at the bottom of the flask, but yield less than 10%.

[0085] Table 2

[0086]

[0087]

[0088] Total purity of the crude reaction solution; **** to *: maximum to minimum amount of insoluble dark polymer material found at the bottom of the flask; +++++ to +: maximum to minimum purity of the reaction solution as determined by gas chromatography; "Clarity": no insoluble dark polymer material found at the bottom of the flask, but yield less than 10%.

[0089] Example 14: Production of PDI from PDA-HCl using phosgene at temperatures up to 170°C

[0090] 87.5 g (0.5 mol) of PDA-HCl and 1050 g of dichlorobenzene were mixed in a 2 L three-necked flask and heated to 60 °C. Phosgene was initiated at a rate of 2.5 g / min, and the tail 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 allowed to proceed for another 12 hours. A total of 2050 g (20.7 mol) of phosgene was introduced and sampled. The reaction yield was 88.1%. Gas chromatography results are shown in [data missing]. Figure 2 .

[0091] Example 15: Production of PDI from PDA-HCl using phosgene at a temperature of up to 210°C

[0092] 87.5 g (0.5 mol) of PDA-HCl and 1050 g of nitrobenzene were mixed in a 2 L three-necked flask and heated to 60 °C. Phosgene was initiated at a rate of 2.5 g / min, and the tail 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 aeration rate unchanged. After another 1 hour, the temperature was raised to 210 °C, allowing the reaction to proceed for another 11 hours. A total of 2,050 g (20.7 mol) of phosgene was introduced. The reaction yield was 56.2%, but a relatively large amount of insoluble, dark-colored polymer material was observed at the bottom of the flask.

[0093] Example 16: Production of PDI from PDA-HCl using phosgene at temperatures up to 130°C

[0094] 87.5 g (0.5 mol) of PDA-HCl and 612.5 g of chlorobenzene were mixed in a 2 L three-necked flask and heated to 60 °C. Phosgene was initiated at a rate of 2.5 g / min, and the tail 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 allowed to proceed for another 5 hours. A total of 1,000 g (10.1 mol) of phosgene was introduced and sampled. The reaction yield was 2.4%. Gas chromatography results are shown in [data missing]. Figure 3 .

[0095] Example 17: Production of PDI from PDA-HCl using phosgene at temperatures up to 130°C

[0096] 87.5 g (0.5 mol) of PDA-HCl and 1050 g of chlorobenzene were mixed in a 2 L three-necked flask and heated to 60 °C. Phosgene was initiated at a rate of 2.5 g / min, and the tail 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 allowed to proceed for another 5 hours. A total of 1,000 g (10.1 mol) of phosgene was introduced, and a sample was taken. The reaction yield was 3.0%.

[0097] Example 18: Production of PDI from PDA-HCl using phosgene at temperatures up to 130°C

[0098] 87.5 g (0.5 mol) of PDA-HCl and 1050 g of chlorobenzene were mixed in a 2 L three-necked flask and heated to 60 °C. Phosgene was initiated at a rate of 2.5 g / min, and the tail 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 allowed to proceed for another 12 hours. A total of 2,050 g (20.7 mol) of phosgene was introduced and sampled. The reaction yield was 9.4%.

[0099] Example 19: Production of PDI from PDA-HCl using phosgene at temperatures up to 130°C in the presence of aniline.

[0100] 87.5 g (0.5 mol) of PDA-HCl and 612.5 g of chlorobenzene were mixed in a 2 L three-necked flask, and aniline (6 mL) was added as a catalyst. The mixture was heated to 60 °C to initiate phosgenation at a rate of 2.5 g / min. The tail 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, allowing the reaction to continue for another 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%.

[0101] Example 20: Production of PDI from PDA-HCl using phosgene at 100°C with TMEDA as solvent

[0102] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl and 875 g TMEDA was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with a 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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-colored polymeric material was found at the bottom of the flask.

[0103] Example 21: Production of PDI from PDA-HCl using phosgene at 100°C with pyridine as solvent

[0104] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl and 875 g pyridine was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with a 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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-colored polymeric material was found at the bottom of the flask.

[0105] Example 22: Production of PDI from PDA-HCl using phosgene at 100°C with TMEDA / chlorobenzene as solvent

[0106] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 116 g (1 mol) TMEDA was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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%.

[0107] Example 23: Production of PDI from PDA-HCl using phosgene at 100°C with TMEDA / toluene as solvent

[0108] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g toluene, and 116 g (1 mol) TMEDA was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with a 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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-colored polymeric material was found at the bottom of the flask.

[0109] Example 24: Production of PDI from PDA-HCl using phosgene at 100°C with pyridine / chlorobenzene as solvent

[0110] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 79 g (1 mol) pyridine was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with a 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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-colored polymeric material was found at the bottom of the flask.

[0111] Example 25: Production of PDI from PDA-HCl using phosgene at 100°C with pyridine / toluene as solvent

[0112] In a 2-liter three-necked flask, a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g toluene, and 79 g (1 mol) pyridine was heated to 100 °C to initiate phosgenation at a rate of 1.2 g phosgene / min. The tail gas was quenched with a 10% sodium hydroxide solution. After 1,000 minutes, the phosgenation reaction was complete, 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-colored polymeric material was found at the bottom of the flask.

[0113] Example 26: Production of PDI from PDA-HCl using phosgene at 80°C with TMEDA as solvent

[0114] The phosgenation reaction was carried out as described in Example 20, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 16.3%.

[0115] Example 27: Production of PDI from PDA-HCl using phosgene at 80°C with pyridine as solvent

[0116] The phosgenation reaction was carried out as described in Example 21, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 22.3%.

[0117] Example 28: Production of PDI from PDA-HCl using phosgene at 80°C with TMEDA / chlorobenzene as solvent

[0118] The phosgenation reaction was carried out as described in Example 22, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 16.5%.

[0119] Example 29: Production of PDI from PDA-HCl using phosgene at 80°C with TMEDA / toluene as solvent

[0120] The phosgenation reaction was carried out as described in Example 23, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 8.2%.

[0121] Example 30: Production of PDI from PDA-HCl using phosgene at 80°C with pyridine / chlorobenzene as solvent

[0122] The phosgenation reaction was carried out as described in Example 24, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 21.9%.

[0123] Example 31: Production of PDI from PDA-HCl using phosgene at 80°C with pyridine / toluene as solvent

[0124] The phosgenation reaction was carried out as described in Example 25, except that the temperature was raised to 80°C instead of 100°C. The reaction yield was 9.9%.

[0125] Example 32: Production of PDI from PDA-HCl using phosgene at 50°C and then at 80°C using TMEDA as a solvent.

[0126] The phosgenation reaction was carried out as described in Example 20, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 16.4%.

[0127] Example 33: Production of PDI from PDA-HCl using phosgene at 50°C and then at 80°C using pyridine as a solvent.

[0128] The phosgenation reaction was carried out as described in Example 21, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 21.5%.

[0129] Example 34: Production from PDA-HCl using phosgene at 50°C and then at 80°C using TMEDA / chlorobenzene as a solvent. PDI

[0130] The phosgenation reaction was carried out as described in Example 22, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 17.1%.

[0131] Example 35: Production from PDA-HCl using phosgene at 50°C and then at 80°C using TMEDA / toluene as a solvent. PDI

[0132] The phosgenation reaction was carried out as described in Example 23, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 7.9%.

[0133] Example 36: Production from PDA-HCl using phosgene at 50°C and then at 80°C using pyridine / chlorobenzene as a solvent. PDI

[0134] The phosgenation reaction was carried out as described in Example 24, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 22.3%.

[0135] Example 37: Production from PDA-HCl using phosgene at 50°C and then at 80°C using pyridine / toluene as a solvent. PDI

[0136] The phosgenation reaction was carried out as described in Example 25, except that the temperature was maintained at 50°C for 4 hours and then at 80°C for 12.7 hours (instead of 100°C). The reaction yield was 8.6%.

[0137] Example 38: Production of PDI from PDA-HCl salt using triphosgene at temperatures up to 170°C

[0138] 87.5 g (0.5 mol) of PDA-HCl and 100 g of dichlorobenzene were mixed in a 2 L three-necked flask. 3,000 g (10.1 mol) of triphosgene was dissolved in 900 g of dichlorobenzene and slowly added to the flask at 170 °C. The tail gas was quenched with 10% sodium hydroxide solution. The total reaction time was 6 hours. A sample was taken; the reaction yield was 68%. Gas chromatography results are shown in [data missing]. Figure 5 .

[0139] Example 39: Using triphosgene at 100°C, TMEDA / chlorobenzene / dichlorobenzene was used as a solvent to produce PDA-HCl salt. PDI production

[0140] In a 5-liter three-necked flask, 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 generated phosgene gas was bubbled into another three-necked flask containing 87.5 g (0.5 mol) of PDA-HCl and 875 g of TMEDA at 100 °C. The tail gas was quenched with 10% sodium hydroxide solution. After the reaction was complete, the flasks were cooled to 25 °C and samples were taken. The reaction yield was 15.2%. Gas chromatographic results are shown in [Figure number missing]. Figure 6 .

[0141] Example 40: Using triphosgene at 100°C, TMEDA / chlorobenzene / dichlorobenzene was used as a solvent to produce PDA-HCl salt. PDI production

[0142] In a 5-liter three-necked flask, a solution of 116 g (1 mol) 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) triphosgene in 3,000 g of dichlorobenzene at 50 °C. The generated phosgene gas was bubbled into another three-necked flask containing a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g of chlorobenzene, and 116 g (1 mol) TMEDA at 100 °C. The tail gas was quenched with 10% sodium hydroxide solution. After the reaction was complete, the flasks were cooled to 25 °C and samples were taken. The reaction yield was 16.3%.

[0143] Example 41: Production of PDA-HCl salt using triphosgene at 100°C with pyridine / chlorobenzene / dichlorobenzene as solvent PDI

[0144] In a 5-liter three-necked flask, a solution of 79 g (1 mol) pyridine in 500 g chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) triphosgene in 3,000 g dichlorobenzene at 50 °C. The generated phosgene gas was bubbled into another three-necked flask containing a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 79 g (1 mol) pyridine at 100 °C. The tail gas was quenched with 10% sodium hydroxide solution. After the reaction was complete, the flasks were cooled to 25 °C and samples were taken. The reaction yield was 31.4%. Gas chromatographic results are shown in... Figure 7 .

[0145] Example 42: Production of PDI from PDA-HCl salt using triphosgene at 100°C with pyridine / chlorobenzene as solvent

[0146] In a 5-liter three-necked flask, a solution of 79 g (1 mol) pyridine in 500 g chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) triphosgene in 3,000 g chlorobenzene at 50 °C. The generated phosgene gas was bubbled into another three-necked flask containing 87.5 g (0.5 mol) PDA-HCl and 875 g pyridine at 100 °C. The tail gas was quenched with 10% sodium hydroxide solution. After the reaction was complete, the flasks were cooled to 25 °C and samples were taken. The reaction yield was 55.6%.

[0147] Example 43: Production from PDA-HCl salt using triphosgene at 80°C with pyridine / chlorobenzene / dichlorobenzene as solvent PDI

[0148] In a 5-liter three-necked flask, a solution of 79 g (1 mol) pyridine in 500 g chlorobenzene was added dropwise at a rate of 5 g / min to a solution of 1,483 g (5 mol) triphosgene in 3,000 g dichlorobenzene at 50 °C. The generated phosgene gas was bubbled into another three-necked flask containing a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 79 g (1 mol) pyridine at 80 °C. The tail gas was quenched with 10% sodium hydroxide solution. After the reaction was complete, the flasks were cooled to 25 °C and samples were taken. The reaction yield was 20.3%.

[0149] Example 44: The process involved directly adding triphosgene at 50°C and then using pyridine / chlorobenzene as a solvent at 80°C. PDA-HCl salt for PDI production

[0150] In a 5-liter three-necked flask, a solution of 741.5 g (2.5 mol) triphosgene in 1,500 g chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 79 g (1 mol) pyridine at 30–35 °C. After the addition, the reaction mixture was heated to 50 °C and maintained for 1 hour. Then, the reaction temperature was raised to 80 °C and maintained for another 3 hours. After the reaction, the flask was cooled to 25 °C and a sample was taken. The reaction yield was 20.9%. The gas chromatographic results are shown in Table 1.

[0151] Example 45: Pyridine (2 when...) was added directly to triphosgene at 50°C and then used at 80°C, 110°C, and 120°C. PDI is produced from PDA-HCl salt using chlorobenzene as a solvent (by amount).

[0152] In a 5-liter three-necked flask, a solution of 222 g (0.75 mol) triphosgene in 1,500 g chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 79 g (1 mol) pyridine at 30–35 °C. After the addition, the reaction mixture was heated to 50 °C and maintained for 1 hour. GC analysis showed no reaction occurred. The reaction temperature was then increased to 80 °C and maintained for another 3 hours. The yield was 12.1%. The reaction temperature was further increased to 110 °C and maintained for another 3 hours. The yield was 22.6%. Finally, the reaction temperature was increased to 120 °C and maintained for another 3 hours. The yield was 22.7%. A dark polymer material began to appear at 90 °C.

[0153] Example 46: Pyridine (6-times) was added directly to triphosgene at 50°C and then used at 80°C, 110°C, and 120°C. PDI is produced from PDA-HCl salt using chlorobenzene as a solvent (by amount).

[0154] In a 5-liter three-necked flask, a solution of 222 g (0.75 mol) triphosgene in 1,500 g chlorobenzene was added dropwise to a solution of 87.5 g (0.5 mol) PDA-HCl, 1,050 g chlorobenzene, and 237 g (3 mol) 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 occurred. Subsequently, the reaction temperature was raised to 80 °C and held for another 3 hours. The yield was 18.1%. Then, the reaction temperature was further raised to 110 °C and held for another 3 hours. The yield was 80.2%. Finally, the reaction temperature was raised to 120 °C and held for another 3 hours. The yield was 80.2%. A dark polymer material began to appear at 90 °C.

[0155] Example 47: Overview of Examples 13-46

[0156] Example 13 reproduces a conventional industrial method for producing PDI, which involves many labor-intensive steps, generates harmful fumes from the production of PDA using the form of free alkali, utilizes relatively large amounts of hazardous phosgene gas, and requires high temperatures (e.g., above 170°C) to obtain a reasonable yield.

[0157] Example 14 describes a phosgenation reaction similar to the conventional method described in Example 13, except that it begins with a PDA salt solution (PDA-HCl) instead of free PDA base. Referring to Table 1, although the PDI production in Example 14 achieved a yield of 88.1% and an acceptable high purity (+++++), the entire method consumed a relatively large amount of phosgene (41.4 equivalents), required maintaining a high reaction temperature (170°C) for an extended period (12 hours), with the entire reaction occurring for more than 13 hours, and produced an undesirable dark-colored insoluble polymeric material (**) at the bottom of the flask. The experiments described in Examples 15-46 explored different methods to improve the production of PDI from PDA-HCl, as discussed below. More specifically, the objectives included maintaining reasonably high yields and purity while seeking to: reduce the amount of phosgene consumed, lower the maximum temperature required in the method, reduce the overall reaction time, and / or reduce the amount of dark-colored insoluble polymeric material byproducts.

[0158] Referring to Table 1, Example 15 shows that increasing the maximum temperature to 210°C results in a significant decrease in yield (from 88.1% to 56.2%), reduced purity (+++), and a higher amount of dark-colored polymer material (***). Despite the presence of a primary amine base (aniline) as a potential catalyst (Example 19), initial attempts to reduce the maximum reaction temperature to 130°C resulted in yields below 10% (Examples 16-19).

[0159] Examples 20-37 and 39-45 show that, with phosgene amounts ranging from 4.5 to 30 equivalents, the reaction in the presence of undiluted or diluted tertiary amines (TMEDA or pyridine) with an inert solvent lowers the temperature required for PDI production. However, yields are mostly below 50%, and overall purity is compromised, with numerous byproducts from undesirable side reactions visible via GC analysis of the reaction solution (see Tables 1 and 2). Interestingly, comparisons of Examples 20 and 22, Examples 21 and 24, Examples 26 and 28, Examples 27 and 30, Examples 32 and 34, and Examples 33 and 36 show that using excess tertiary amine generally offers no benefit in terms of yield or purity.

[0160] Comparison of Examples 43 and 44 shows that if the reaction is initially carried out at a lower temperature (50°C), which favors the formation of intermediates (confirmed by GC), similar yields can be obtained with reduced amounts of phosgene and pyridine. Comparison of Examples 44 and 45 shows that reducing the amount of phosgene in Example 45 to only 4.5 equivalents reduces the yield at 80°C from 20.9% to 12.1%, 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, as observed in Example 46.

[0161] Example 46 differs from Example 45 only in that the amount of pyridine is increased from 2 equivalents to 6 equivalents. Notably, as shown in Table 2, changing this single reaction parameter significantly increases the yield (80.2%), increases the purity (+++++), and results in minimal accumulation of insoluble dark polymeric material in the reaction solution (*). These results indicate that: (1) the equivalent of the tertiary amine must be sufficient, otherwise the yield and total purity will be low; (2) in the presence of a sufficient equivalent of the tertiary amine, the yield increases with increasing temperature, and the yield does not change significantly above 110°C; and (3) for 1 equivalent of PDA-HCl, 1.5 equivalents of triphosgene (or 4.5 equivalents of phosgene) is sufficient to produce PDI.

[0162] Therefore, the PDI production method described in Example 46 achieves similar yields and purities to the more conventional method in Example 14, but requires nearly 90% less phosgene (from 41.4 equivalents to 4.5 equivalents), the maximum temperature is reduced by 60°C (from 170°C to 110°C), the total reaction time is reduced by about 50% (from 13.7 hours to 7 hours), and the amount of insoluble dark polymer material byproducts is reduced (**to*).

[0163] References

[0164] Cotarca et al., "Bis(trichloromethyl)carbonate(BTC,Triphosgene): ASafer Alternative to Phosgene?", Organic Process Research & Development (2017), 21: 1439-1446.

[0165] Qin et al., "Method for Purifying 1,5-Pentanediamine and 1,5-Pentanediamine", European patent application No.14908171.3 published as EP3235804.

[0166] Sambrook et al. (2001). Molecular Cloning: ALaboratory Manual, Third Edition, Sambrook and Russell, Cold Spring Harbor Laboratory Press, 3 rd Edition. sequence list <110> Guang'an Mojia Biotechnology Co., Ltd. Liu Wenjie Lu Chengliang Qiu Guisen <120> An Improved Method for Preparing 1,5-Pentamethylene Diisocyanate from 1,5-Pentamethylene Diamine Salt <130> 19597-10 <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 2148 <212> DNA <213> Escherichia coli BW25113 <400> 1 atgaacgtta ttgcaatatt gaatcacatg ggggtttat ttaaagaaga acccatccgt 60 gaacttcatc gcgcgcttga acgtctgaac ttccagattg tttacccgaa cgaccgtgac 120 gacttattaa aactgatcga aaacaatgcg cgtctgtgcg gcgttatatttt tgactggggat 180 aaatataatc tcgagctgtg cgaagaaatt agcaaaatga acgagaacct gccgttgtac 240 gcgttcgcta atacgtattc cactctcgat gtaagcctga atgacctgcg tttacagatt 300 agcttctttg aatatgcgct gggtgctgct gaagatattg ctaataagat caagcagacc 360 actgacgaat atatcaacac tattctgcct ccgctgacta aagcactgtt taaatatgtt 420 cgtgaaggta aatatacttt ctgtactcct ggtcacatgg gcggtactgc attccagaaa 480 agcccggtag gtagcctgtt ctatgatttc tttggtccga atacatgaa atctgatatt 540 tccatttcag tatctgaact gggttctctg ctggatcaca gtggtccaca caaagaagca 600 gaacagtata tcgctcgcgt ctttaacgca gaccgcagct acatggtgac caacggtact 660 tccactgcga acaaaattgt tggtatgtac tctgctccag caggcagcac cattctgatt 720 gaccgtaact gccacaaatc gctgacccac ctgatgatga tgagcgatgt tacgccaatc 780 tatttccgcc cgacccgtaa cgcttacggt attcttggtg gtatcccaca gagtgaattc 840 cagcacgcta ccattgctaa gcgcgtgaaa gaaacaccaa acgcaacctg gccggtacat 900 gctgtaatta ccaactctac ctatgatggt ctgctgtaca acaccgactt catcaagaaa 960 acactggatg tgaaatccat ccactttgac tccgcgtggg tgccttacac caacttctca 1020 ccgatttacg aaggtaaatg cggtatgagc ggtggccgtg tagaagggaa agtgatttac 1080 gaaacccagt ccactcacaa actgctggcg gcgttctctc aggcttccat gatccacgtt 1140 aaaggtgacg taaacgaaga aacctttaac gaagcctaca tgatgcacac caccacttct 1200 ccgcactacg gtatcgtggc gtccactgaa accgctgcgg cgatgatgaa aggcaatgca 1260 ggtaagcgtc tgatcaacgg ttctattgaa cgtgcgatca aattccgtaa agagatcaaa 1320 cgtctgagaa cggaatctga tggctggttc tttgatgtat ggcagccgga tcatatcgat 1380 acgactgaat gctggccgct gcgttctgac agcacctggc acggcttcaa aaacatcgat 1440 aacgagcaca tgtatcttga cccgatcaaa gtcaccctgc tgactccggg gatggaaaaa 1500 gacggcacca tgagcgactt tggtattccg gccagcatcg tggcgaaata cctcgacgaa 1560 catggcatcg ttgttgagaa aaccggtccg tataacctgc tgttcctgtt cagcatcggt 1620 atcgataaga ccaaagcact gagcctgctg cgtgctctga ctgactttaa acgtgcgttc 1680 gacctgaacc tgcgtgtgaa aaacatgctg ccgtctctgt atcgtgaaga tcctgaattc 1740 tatgaaaaca tgcgtattca ggaactggct cagaatatcc acaaactgat tgttcaccac 1800 aatctgccgg atctgatgta tcgcgcattt gaagtgctgc cgacgatggt aatgactccg 1860 tatgctgcat tccagaaaga gctgcacggt atgaccgaag aagtttacct cgacgaaatg 1920 gtaggtcgta ttaacgccaa tatgatcctt ccgtacccgc cgggagttcc tctggtaatg 1980 ccgggtgaaa tgatcaccga agaagccgt ccggttctgg agttcctgca gatgctgtgt 2040 gaaatcggcg ctcactatcc gggctttgaa accgatattc acggtgcata ccgtcaggct 2100 gatggccgct ataccgttaa ggtattgaa gagaaagca aaaataa 2148 <210> 2 <211> 715 <212> PRT <213> Escherichia coli BW25113 <400> 2 Met Asn Val Ile Ala Ile Leu Asn His Met Gly Val Tyr Phe Lys Glu 1 5 10 15 Glu Pro With Arg Glu Leu His Arg Ala Leu Glu Arg Leu Asn Phe Gln 20 25 30 Ile Val Tyr Pro Asn Asp Arg Asp Asp Leu Lys Leu Ile Glu Asn 35 40 45 Asn Ala Arg Leu Cys Gly Val Ile Phe Asp Trp Asp Lys Tyr Asn Leu 50 55 60 Leu Glu Cys Glu Glu Ile Ser Lys Met Asn Leu Glu Pro Leu Tyr 65 70 75 80 Ala Phe Ala Asn Thr Tyr Ser Thr Leu Asp Val Ser Leu Asn Asp Leu 85 90 95 Arg Leu Gln Ile Ser Phe Phe Glu Tyr Ala Leu Gly Ala Ala Glu Asp 100 105 110 Ile Ala Asn Lys Ile Lys Gln Thr Thr Asp Glu Tyr Ile Asn Thr Ile 115 120 125 Leu Pro Pro Leu Thr Lys Ala Leu Phe Lys Tyr Val Arg Glu Gly Lys 130 135 140 Tyr Thr Phe Cys Thr Pro Gly His Met Gly Gly Thr Ala Phe Gln Lys 145 150 155 160 Ser Pro Val Gly Ser Leu Phe Tyr Asp Phe Phe Gly Pro Asn Thr Met 165 170 175 Lys Ser Asp Ile Ser Ile Ser Val Ser Glu Leu Gly Ser Leu Leu Asp 180 185 190 His Ser Gly Pro His Lys Glu Ala Glu Gln Tyr Ile Ala Arg Val Phe 195 200 205 Asn Ala Asp Arg Ser Tyr Met Val Thr Asn Gly Thr Ser Thr Ala Asn 210 215 220 Lys Ile Val Gly Met Tyr Ser Ala Pro Ala Gly Ser Thr Ile Leu Ile 225 230 235 240 Asp Arg Asn Cys His Lys Ser Leu Thr His Leu Met Met Met Ser Asp 245 250 255 Val Thr Pro Ile Tyr Phe Arg Pro Thr Arg Asn Ala Tyr Gly Ile Leu 260 265 270 Gly Gly Ile Pro Gln Ser Glu Phe Gln His Ala Thr Ile Ala Lys Arg 275 280 285 Val Lys Glu Thr Pro Asn Ala Thr Trp Pro Val His Ala Val Ile Thr 290 295 300 Asn Ser Thr Tyr Asp Gly Leu Leu Tyr Asn Thr Asp Phe Ile Lys Lys 305 310 315 320 Thr Leu Asp Val Lys Ser Ile His Phe Asp Ser Ala Trp Val Pro Tyr 325 330 335 Thr Asn Phe Ser Pro Ile Tyr Glu Gly Lys Cys Gly Met Ser Gly Gly 340 345 350 Arg Val Glu Gly Lys Val Ile Tyr Glu Thr Gln Ser Thr His Lys Leu 355 360 365 Leu Ala Ala Phe Ser Gln Ala Ser Met Ile His Val Lys Gly Asp Val 370 375 380 Asn Glu Glu Thr Phe Asn Glu Ala Tyr Met Met His Thr Thr Thr Ser 385 390 395 400 Pro His Tyr Gly Ile Val Ala Ser Thr Glu Thr Ala Ala Ala Met Met 405 410 415 Lys Gly Asn Ala Gly Lys Arg Leu Ile Asn Gly Ser Ile Glu Arg Ala 420 425 430 Ile Lys Phe Arg Lys Glu Ile Lys Arg Leu Arg Thr Glu Ser Asp Gly 435 440 445 Trp Phe Phe Asp Val Trp Gln Pro Asp His Ile Asp Thr Thr Glu Cys 450 455 460 Trp Pro Leu Arg Ser Asp Ser Thr Trp His Gly Phe Lys Asn Ile Asp 465 470 475 480 Asn Glu His Met Tyr Leu Asp Pro Ile Lys Val Thr Leu Leu Thr Pro 485 490 495 Gly Met Glu Lys Asp Gly Thr Met Ser Asp Phe Gly Ile Pro Ala Ser 500 505 510 Ile Val Ala Lys Tyr Leu Asp Glu His Gly Ile Val Val Glu Lys Thr 515 520 525 Gly Pro Tyr Asn Leu Leu Phe Leu Phe Ser Ile Gly Ile Asp Lys Thr 530 535 540 Lys Ala Leu Ser Leu Leu Arg Ala Leu Thr Asp Phe Lys Arg Ala Phe 545 550 555 560 Asp Leu Asn Leu Arg Val Lys Asn Met Leu Pro Ser Leu Tyr Arg Glu 565 570 575 Asp Pro Glu Phe Tyr Glu Asn Met Arg Ile Gln Glu Leu Ala Gln Asn 580 585 590 Ile His Lys Leu Ile Val His His Asn Leu Pro Asp Leu Met Tyr Arg 595 600 605 Ala Phe Glu Val Leu Pro Thr Met Val Met Thr Pro Tyr Ala Ala Phe 610 615 620 Gln Lys Glu Leu His Gly Met Thr Glu Glu Val Tyr Leu Asp Glu Met 625 630 635 640 Val Gly Arg Ile Asn Ala Asn Met Ile Leu Pro Tyr Pro Pro Gly Val 645 650 655 Pro Leu Val Met Pro Gly Glu Met Ile Thr Glu Glu Ser Arg Pro Val 660 665 670 Leu Glu Phe Leu Gln Met Leu Cys Glu Ile Gly Ala His Tyr Pro Gly 675 680 685 Phe Glu Thr Asp Ile His Gly Ala Tyr Arg Gln Ala Asp Gly Arg Tyr 690 695 700 Thr Val Lys Val Leu Lys Glu Glu Ser Lys Lys 705 710 715

Claims

1. A method of preparing 1,5-pentamethylene diisocyanate (PDI) from a 1,5-pentanediamine salt, the method comprising: (a) providing a source of phosgene, wherein the source of phosgene is phosgene or triphosgene; (b) providing a solution comprising a 1,5-pentanediamine 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 1,5-pentanediamine to PDI, the phosgenation reaction comprising the step of maintaining the reaction at a temperature range of 100 °C to 120 °C for a sufficient time to achieve a desired threshold yield of PDI, wherein the tertiary amine base is pyridine, wherein the tertiary amine base is present in an amount sufficient for the phosgenation reaction to be completed at the temperature range; wherein the method uses from 4 moles of tertiary amine base per mole of 1,5-pentanediamine salt to 24 moles of tertiary amine base per mole of 1,5-pentanediamine salt, and from 4.5 to 30 moles of phosgene per mole of 1,5-pentanediamine salt, or from 1.5 to 10 moles of triphosgene per mole of 1,5-pentanediamine salt.

2. The method of claim 1, wherein the phosgenation reaction in step (c) comprises the step of maintaining the reaction at a temperature range of 100 to 115 °C for a sufficient time to achieve a threshold yield of PDI.

3. The method of claim 1 or 2, wherein the sufficient time in (c) is at least 1.5 hours.

4. The method of claim 1 or 2, wherein the phosgenation reaction in (c) is a multi-stage phosgenation reaction comprising at least a first stage and a subsequent second stage, wherein in the first stage the solution is heated to a first temperature to allow the 1,5-pentanediamine to react with phosgene from the phosgene source to generate a biscarbamoyl chloride intermediate, wherein in the subsequent second stage the solution is further heated to a second temperature higher than the first temperature to allow the biscarbamoyl chloride intermediate to undergo a dehydrochlorination reaction, wherein the second stage comprises the steps of: maintaining the reaction at a temperature of 100 °C to 120 °C for a sufficient time to achieve a threshold yield of PDI.

5. The method of claim 4, wherein the first temperature is from 30 to 65 °C.

6. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for at least 0.5 hours.

7. The method of claim 4, wherein the second temperature is at least 10 °C higher than the first temperature.

8. The method of claim 4, wherein the amount of the source of phosgene and / or tertiary amine base reactants used in the multi-stage phosgenation reaction is lower than the amount required to achieve the same PDI yield as a corresponding single-stage phosgenation reaction conducted at only the second temperature.

9. The method of claim 1 or 2, wherein the 1,5-pentanediamine salt is a biobased 1,5-pentanediamine salt derived from fermentation and / or enzymatic conversion, preferably by an immobilized whole-cell biocatalyst to reduce cyclic compounds from cell lysate components.

10. The method of claim 9, wherein the fermentation is a fermentation of a microorganism engineered to produce 1,5-pentanediamine, and the enzymatic conversion is an enzymatic conversion from lysine.

11. The method of claim 1 or 2, wherein the provided 1,5-pentanediamine salt is made without distillation, or otherwise subjected to temperatures that contribute to the formation of cyclic compounds.

12. The method of claim 11, wherein the cyclic compounds are selected from one or more of: 2,3,4,5-tetrahydropyridine [THP]; piperidine; 2-(aminomethyl)-3,4,5,6-tetrahydropyridine; 1-piperidine carbonyl chloride; or 1(2H)-pyridine carbonyl chloride.

13. The process of claim 1 or 2, wherein the THP or other cyclic compound content of the 1,5-pentanediamine salt is less than 0.1 wt%.

14. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt is 1,5- pentanediamine dihydrochloride.

15. The process of claim 1, wherein the source of phosgene is triphosgene, and the tertiary amine base reacts with the triphosgene to release phosgene for the phosgenation reaction.

16. The process of claim 15, wherein the source of phosgene is triphosgene, and the tertiary amine base is used to facilitate dissolution of the 1,5-pentanediamine salt, to react with the triphosgene to release phosgene, and to catalyze the subsequent phosgenation reaction at the phosgenation temperature range.

17. The method of claim 1 or 2, wherein the inert solvent comprises or consists of: chlorobenzene, dichlorobenzene, toluene, nitrobenzene, or any mixture thereof.

18. The process of claim 1 or 2, wherein the inert solvent is a solvent or solvent mixture having a boiling point of at least 120 °C.

19. The process of claim 1 or 2, wherein the process is a one-pot synthesis process, wherein the 1,5-pentanediamine salt and source of phosgene are slowly mixed in the presence of the tertiary amine base in the inert solvent in a single vessel, which is then heated to initiate the phosgenation reaction.

20. The process of claim 1 or 2, wherein the PDI produced has a THP or other cyclic compound content of less than 0.1 wt% prior to performing one or more distillation steps.

21. The process of claim 1 or 2, wherein the desired PDI threshold yield is at least 50%.

22. The process of claim 1, wherein the phosgenation reaction in step (c) comprises the step of maintaining the reaction at a temperature range of 105 to 115 °C for a sufficient time to achieve a PDI threshold yield.

23. The process of claim 1, wherein the phosgenation reaction in step (c) comprises the step of maintaining the reaction at a temperature range of 110 to 115 °C for a sufficient time to achieve a PDI threshold yield.

24. The process of claim 1, wherein the phosgenation reaction in step (c) comprises the step of maintaining the reaction at a temperature range of 100 to 110 °C for a sufficient time to achieve a PDI threshold yield.

25. The process of claim 1, wherein the phosgenation reaction in step (c) comprises the step of maintaining the reaction at a temperature of 110 °C for a sufficient time to achieve a PDI threshold yield.

26. The process of claim 1 or 2, wherein the sufficient time in (c) is at least 2 hours.

27. The process of claim 1 or 2, wherein the sufficient time in (c) is at least 2.5 hours.

28. The process of claim 1 or 2, wherein the sufficient time in (c) is at least 3 hours.

29. The process of claim 1 or 2, wherein the sufficient time in (c) is 1.5 to 6 hours.

30. The method of claim 1 or 2, wherein the sufficient time in (c) is 2 to 6 hours.

31. The method of claim 1 or 2, wherein the sufficient time in (c) is 2 to 5.5 hours.

32. The method of claim 1 or 2, wherein the sufficient time in (c) is 2.5 to 5.5 hours.

33. The method of claim 1 or 2, wherein the sufficient time in (c) is 2.5 to 6 hours.

34. The method of claim 1 or 2, wherein the sufficient time in (c) is 3 to 5 hours.

35. The method of claim 4, wherein the first temperature is 35 to 65 °C.

36. The method of claim 4, wherein the first temperature is 35 to 60 °C.

37. The method of claim 4, wherein the first temperature is 40 to 60 °C.

38. The method of claim 4, wherein the first temperature is 35 to 55 °C.

39. The method of claim 4, wherein the first temperature is 40 to 55 °C.

40. The method of claim 4, wherein the first temperature is 45 to 55 °C.

41. The method of claim 4, wherein the first temperature is 50 °C.

42. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for at least 1 hour.

43. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for at least 2 hours.

44. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for 0.5 to 3 hours.

45. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for 0.5 to 2.5 hours.

46. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for 0.5 to 2 hours.

47. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for 1 to 2.5 hours.

48. The method of claim 4, wherein the first phase comprises: maintaining the solution at the first temperature for 1 to 2 hours.

49. The method of claim 4, wherein the second temperature is at least 15 °C higher than the first temperature.

50. The method of claim 4, wherein the second temperature is at least 20 °C higher than the first temperature.

51. The method of claim 4, wherein the second temperature is at least 25 °C higher than the first temperature.

52. The method of claim 4, wherein the second temperature is at least 30 °C higher than the first temperature.

53. The method of claim 4, wherein the second temperature is at least 35 °C higher than the first temperature.

54. The method of claim 4, wherein the second temperature is at least 40 °C higher than the first temperature.

55. The method of claim 4, wherein the second temperature is at least 45 °C higher than the first temperature.

56. The method of claim 4, wherein the second temperature is at least 50 °C higher than the first temperature.

57. The method of claim 4, wherein the second temperature is at least 55 °C higher than the first temperature.

58. The method of claim 4, wherein the second temperature is at least 60 °C higher than the first temperature.

59. The process of claim 1 or 2, wherein the process uses 4.5 to 29 moles of phosgene per mole of 1,5-pentanediamine salt.

60. The process of claim 1 or 2, wherein the process uses 4.5 to 27 moles of phosgene per mole of 1,5-pentanediamine salt.

61. The process of claim 1 or 2, wherein the process uses 4.5 to 24 moles of phosgene per mole of 1,5-pentanediamine salt.

62. The process of claim 1 or 2, wherein the process uses 4.5 to 18 moles of phosgene per mole of 1,5-pentanediamine salt.

63. The process of claim 1 or 2, wherein the process uses at least 5 moles of tertiary amine base per mole of 1,5-pentanediamine salt.

64. The process of claim 1 or 2, wherein the process uses at least 5.5 moles of tertiary amine base per mole of 1,5-pentanediamine salt.

65. The process of claim 1 or 2, wherein the process uses at least 6 moles of tertiary amine base per mole of 1,5-pentanediamine salt.

66. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.09 wt%.

67. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.08 wt%.

68. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.07 wt%.

69. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.06 wt%.

70. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.05 wt%.

71. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.04 wt%.

72. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.03 wt%.

73. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.02 wt%.

74. The process of claim 1 or 2, wherein the 1,5-pentanediamine salt has a THP or other cyclic compound content of less than 0.01 wt%.

75. The process of claim 1 or 2, wherein the inert solvent is a solvent or solvent mixture having a boiling point of at least 125 °C.

76. The process of claim 1 or 2, wherein the inert solvent is a solvent or solvent mixture having a boiling point of at least 130 °C.

77. The process of claim 1 or 2, wherein the PDI produced has a THP or other cyclic compound content of less than 0.09 wt% prior to performing one or more distillation steps.

78. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.08 wt% prior to performing one or more distillation steps.

79. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.07 wt% prior to performing one or more distillation steps.

80. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.06 wt% prior to performing one or more distillation steps.

81. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.05 wt% prior to performing one or more distillation steps.

82. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.04 wt% prior to performing one or more distillation steps.

83. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.03 wt% prior to performing one or more distillation steps.

84. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.02 wt% prior to performing one or more distillation steps.

85. The process of claim 1 or 2, wherein the PDI produced has a content of THP or other cyclic compounds of less than 0.01 wt% prior to performing one or more distillation steps.

86. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 55%.

87. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 60%.

88. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 65%.

89. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 70%.

90. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 75%.

91. The process of claim 1 or 2, wherein the threshold yield of PDI desired is at least 80%.

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