Method for preparing pentamethylene diisocyanate

Abstract

Provided are a method for preparing bio-based pentanediamine hydrochloride, and a method for using the pentanediamine hydrochloride and phosgene to prepare pentamethylene diisocyanate by means of a liquid phase method.

Description

Process for preparing piperidinediyl isocyanate TECHNICAL FIELD

[0001] The present application belongs to the field of chemical industry, and in particular, relates to a method for obtaining piperidinediyl mono-hydrochloride and a method for preparing piperidinediyl isocyanate by liquid phase method using piperidinediyl mono-hydrochloride and phosgene. BACKGROUND

[0002] The preparation methods of piperidinediyl isocyanate (PDI) are divided into liquid phase method and gas phase method. The gas phase method is to prepare PDI by directly reacting piperidinediyl amine (PDA) gasified with gaseous phosgene. Since the gas phase reaction speed is extremely fast, it is easy to produce by-products such as urea to block the reaction pipeline, and the requirement for the entire set of equipment is extremely high. The reaction speed of the liquid phase method is relatively slow, and it is similar to the synthesis of isocyanate by phosgenation reaction of other amine raw materials, which may involve three main chemical reactions. The first reaction is the reaction of diamine and phosgene to generate carbamoyl chloride and carbamoyl chloride amine hydrochloride, the second reaction is the continuous reaction of carbamoyl chloride amine hydrochloride with phosgene to generate carbamoyl chloride, and the third reaction is the further reaction of carbamoyl chloride to generate isocyanate and hydrogen chloride.

[0003] In actual production of PDI by liquid phase method, the raw material PDA can be pure piperidinediyl amine or piperidinediyl amine salt. When pure PDA is used as raw material for preparation, the PDA salt solution is first prepared by fermentation method, and then the basic substance is added to the PDA salt solution to form a free PDA solution, and then distillation or cation resin adsorption elution or solvent extraction is used to obtain PDA. This purification process will inevitably bring the disadvantages of by-product salt, large energy consumption and increased production cost. When PDA salt (for example, piperidinediyl mono-hydrochloride) is used as raw material for preparation, the purified PDA is introduced into excess acid (for example, hydrochloric acid) to form PDA salt (for example, piperidinediyl mono-hydrochloride), and then dissolved in a solvent and reacted with phosgene. In addition to the above-mentioned deficiency of needing to purify PDA first, the PDA salt has reduced flowability compared to PDA, and is easily attached to the stirred reactor, so that a large amount of solvent and strong stirring of the reaction kettle are required for improvement.

[0004] Therefore, it is still necessary to develop a more economical and efficient method for preparing PDI from PDA, and a method for obtaining high yield and high purity PDI. SUMMARY

[0005] To overcome the deficiencies of the prior art, the present inventors surprisingly found that in the process of preparing PDI by liquid phase method, by controlling the amount of HCl in the fermentation process, the generated PDA·XHCl is in a state close to piperidinediyl mono-hydrochloride, and the solid piperidinediyl mono-hydrochloride obtained as raw material directly performs phosgenation reaction, the amount of solvent required is small, the flowability of the slurry is good, the reaction speed is controllable, the generated product has low hydrolysis chlorine, less tar impurities, and the product purity is as high as and the yield is high.

[0006] In one aspect, the present application provides a method for preparing pentamethylene diamine X hydrochloride, comprising the following steps:

[0007] (1) adding a hydrochloric acid solution to a lysine solution to form a lysine X hydrochloride solution;

[0008] (2) adding a lysine decarboxylase to convert the lysine X hydrochloride solution obtained in step (1) into a pentamethylene diamine X hydrochloride solution;

[0009] (3) concentrating the pentamethylene diamine X hydrochloride obtained in step (2);

[0010] wherein X is in the range of 0.8-1.2. In some embodiments, X is 1.

[0011] In some embodiments, the method for preparing pentamethylene diamine X hydrochloride provided by the present application, the concentration of the lysine X hydrochloride solution is in the range of 400-650 g / L, and the pentamethylene diamine X hydrochloride obtained after the concentration step has a content of 98.5% or more.

[0012] In another aspect, the present application provides a method for preparing pentamethylene diisocyanate, comprising the following steps:

[0013] (a) mixing pentamethylene diamine X hydrochloride (wherein X is in the range of 0.8-1.2) with a solvent to form a first mixed solution;

[0014] (b) passing phosgene into the first mixed solution obtained in step (a), adjusting the heating temperature to 80-150°C, and incubating for 1-6 hours until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is generated, to form a second solution;

[0015] (c) adjusting the temperature of the second solution obtained in step (b) to 150-180°C, and incubating for 6-24 hours until the reaction is completed when there is no solid, and stopping the passage of phosgene.

[0016] In some embodiments, the solvent in step (a) is selected from the group consisting of dichloromethane, chlorobenzene, o-dichlorobenzene, benzene, toluene, xylene, hexane, tetrahydrofuran, chloronaphthalene, and any combination thereof. In some embodiments, the pentamethylene diamine X hydrochloride in step (a) is prepared by the method described in the present application. In some embodiments, the mass ratio of the pentamethylene diamine X hydrochloride to the solvent in step (a) is 1:2-1:10.

[0017] In certain embodiments, the flow rate of the phosgene introduced in step (b) is 0.1-5 L / min; or the molar ratio of the phosgene introduced in step (b) to the amino group of the pentamethylene diamine X hydrochloride in step (a) is 1.1:1-28:1. In certain embodiments, the second solution obtained in step (b) contains aminoacyl chlorides.

[0018] In certain embodiments, after the phosgene introduction is stopped in step (c), the temperature is decreased to room temperature. In certain embodiments, an inert gas is introduced while the temperature is decreasing in step (c). In certain embodiments, the inert gas is selected from the group consisting of nitrogen, carbon dioxide, carbon monoxide, helium, argon, and any combination thereof. In certain embodiments, the room temperature in step (c) is in the range of -10 °C to 40 °C.

[0019] In certain embodiments, the method for preparing penta-methylene diisocyanate provided by the present application further comprises step (d): collecting the penta-methylene diisocyanate prepared in step (c).

[0020] In another aspect, the present application provides a method for preparing penta-methylene diisocyanate, comprising the following steps:

[0021] (i). adding a hydrochloric acid solution to a lysine solution to form lysine X hydrochloride (wherein X is in the range of 0.8-1.2), and then allowing the lysine X hydrochloride to react with lysine decarboxylase to generate a mixture containing pentamethylene diamine X hydrochloride;

[0022] (ii). concentrating (e.g., to a content of 98.5% or more) the mixture containing pentamethylene diamine X hydrochloride obtained in step (i) to obtain pentamethylene diamine X hydrochloride;

[0023] (iii). mixing the pentamethylene diamine X hydrochloride obtained in step (ii) with a solvent to form a first mixed solution;

[0024] (iv). introducing phosgene into the first mixed solution obtained in step (iii), adjusting the heating temperature to 80 °C-150 °C, and maintaining heating for 1-6 hours until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is generated, to form a second solution;

[0025] (v). adjusting the temperature of the second solution obtained in step (iv) to 150 °C or more (e.g., 150 °C-180 °C), and maintaining heating for 6-24 hours until the reaction is completed when there is no solid, stopping the phosgene introduction, and decreasing the temperature to room temperature; and

[0026] (vi). collecting the penta-methylene diisocyanate prepared in step (v). DETAILED DESCRIPTION

[0027] The specific embodiments and illustrative embodiments described in the claims are not intended to be limiting. Other embodiments and variations may be adopted without departing from the spirit or scope of the subject matter of this application. It is understood that various different configurations, substitutions, combinations, and designs can be made to the various aspects of the content of this application generally described herein, all of which explicitly constitute part of the content of this application.

[0028] Method for preparing pentanediamine X hydrochloride

[0029] In one aspect, this application provides a method for preparing pentanediamine X hydrochloride, comprising the following steps:

[0030] (1) Add hydrochloric acid solution to lysine solution to form lysine X hydrochloride solution;

[0031] (2) Add lysine decarboxylase to convert the lysine X hydrochloride solution obtained in step (1) into a pentanediamine X hydrochloride solution;

[0032] (3) Concentrate the pentanediamine X hydrochloride obtained in step (2);

[0033] The value of X ranges from 0.8 to 1.2.

[0034] In this application, "pentanediamine X hydrochloride," "PDA·X hydrochloride," or "PDA·XHCl" refers to a salt of pentanediamine having an average of X associated hydrochloric acid molecules. For example, "pentanediamine monohydrochloride," "PDA·monohydrochloride," or "PDA·1HCl" refers to a salt of pentanediamine having an average of 1 associated hydrochloric acid molecule. As another example, "pentanediamine 0.5 hydrochloride," "PDA·0.5 hydrochloride," or "PDA·0.5HCl" refers to a salt of pentanediamine having an average of 0.5 associated hydrochloric acid molecules. In some embodiments, pentanediamine X hydrochloride is a mixture; for example, a mixture formed by 1 mole of unassociated hydrochloric acid molecules of pentanediamine and 1 mole of pentanediamine monohydrochloride can be called pentanediamine 0.5 hydrochloride. Those skilled in the art will understand that all subtle variations in the number of associated hydrochloric acid molecules are contemplated within the scope of this application. Unless otherwise stated, the value of X in "pentanediamine X hydrochloride", "PDA·X hydrochloride" or "PDA·XHCl" mentioned in this application ranges from 0.8 to 1.2 (e.g., any specific value within the range of 0.8, 0.9, 1, 1.1, 1.2 or any two of the above values). In some embodiments, pentanediamine X hydrochloride is pentanediamine monohydrochloride (also known as "pentanediamine monohydrochloride"), that is, X is 1.

[0035] In certain embodiments, the concentration of the lysine X hydrochloride solution formed in step (1) ranges from 400 g / L to 650 g / L, for example, 400 g / L, 450 g / L, 500 g / L, 510 g / L, 520 g / L, 530 g / L, 540 g / L, 550 g / L, 560 g / L, 570 g / L, 580 g / L, 590 g / L, 600 g / L, 610 g / L, 620 g / L, 630 g / L, 640 g / L, 650 g / L, or any specific concentration within a range between any of these two numerical values.

[0036] In certain embodiments, the lysine decarboxylase in step (2) is a purified lysine decarboxylase. In certain embodiments, the lysine decarboxylase in step (2) is from a cell expressing lysine decarboxylase. In certain embodiments, the cell comprises a wet cell, a cell lysate, or an immobilized cell. In certain embodiments, the cell is from a recombinant engineered bacterium. In certain embodiments, the lysine decarboxylase is from an E. coli recombinant engineered bacterium expressing lysine decarboxylase. In certain embodiments, the lysine decarboxylase is from a wet cell of an E. coli recombinant engineered bacterium expressing lysine decarboxylase. In certain embodiments, the lysine decarboxylase is from a cell lysate of an E. coli recombinant engineered bacterium expressing lysine decarboxylase. In certain embodiments, the lysine decarboxylase is from an immobilized cell of an E. coli recombinant engineered bacterium expressing lysine decarboxylase.

[0037] In certain embodiments, the lysine X hydrochloride reacts with the lysine decarboxylase at a temperature ranging from 20 °C to 40 °C (for example, 20 °C, 25 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, or any specific temperature within a range between any of these two numerical values) to generate pentamethylene diamine X hydrochloride.

[0038] In certain embodiments, the reaction time of the lysine X hydrochloride with the lysine decarboxylase ranges from 5 hours to 15 hours (for example, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, or any specific time within a range between any of these two numerical values).

[0039] In certain embodiments, the catalytic reaction of lysine X hydrochloride with lysine decarboxylase is considered complete when the lysine content is < 0.5% (w / v), for example, 0.4%, 0.3%, 0.2%, 0.1%, or even lower. One skilled in the art can determine the lysine content using conventional means in the art, for example, HPLC method.

[0040] In some embodiments, after the catalytic reaction of lysine X hydrochloride with lysine decarboxylase is completed, further removing the residual in the reaction solution is included. In some embodiments, the residual includes large particulate impurities, such as cells, bacterial fragments, aggregates, flocs, and the like, and also includes small molecular impurities, such as nucleic acids and nucleic acid fragments in the bacterial culture medium, proteins, culture medium components, and the like. Those skilled in the art can remove the residual of the catalyst in the mixture according to their actual needs using conventional separation means, such as one or more of filtration, centrifugation, microfiltration, ultrafiltration, and the like.

[0041] In some embodiments, the filtration is achieved by using filter paper or filter cloth. The filter paper or filter cloth used in the present application can be commercially available filter paper or filter cloth, such as those produced by GE Healthcare Life Sciences, Sipernat, Asahi Kasei, and the like. In some embodiments, the pore size of the filter paper or filter cloth is 10-150 μm, such as 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, or any value within any range between any two of the above values. Those skilled in the art can select a suitable pore size of the filter paper or filter cloth to remove impurities according to the size of the impurities.

[0042] In some embodiments, the microfiltration is achieved by passing the reaction solution through a microfiltration membrane. The microfiltration membrane used in the present application can be commercially available microfiltration membrane, such as the microfiltration hollow fiber membrane series produced by GE Healthcare Life Sciences, Sipernat, Asahi Kasei, and the like. In some embodiments, the pore size of the microfiltration membrane is 0.1 μm-0.6 μm, such as 0.1 μm, 0.15 μm, 0.2 μm, 0.22 μm, 0.25 μm, 0.3 μm, 0.35 μm, 0.4 μm, 0.45 μm, 0.5 μm, 0.55 μm, 0.6 μm, or any value within any range between any two of the above values. Those skilled in the art can select a suitable pore size of the microfiltration membrane to remove impurities according to the size of the impurities.

[0043] In some embodiments, the ultrafiltration is achieved by passing the reaction solution through an ultrafiltration membrane. The ultrafiltration membrane used in the present application can be a commercially available ultrafiltration membrane, such as the ultrafiltration hollow fiber membrane series produced by GE Healthcare Life Sciences, Sipernat, Asahi Kasei, and the like. In some embodiments, the ultrafiltration membrane is a hollow fiber ultrafiltration membrane with a pore size of 5 kD to 500 kD, such as a hollow fiber ultrafiltration membrane with a pore size of 5 kD, 6 kD, 7 kD, 8 kD, 9 kD, 10 kD, 20 kD, 30 kD, 40 kD, 50 kD, 60 kD, 70 kD, 80 kD, 90 kD, 100 kD, 150 kD, 200 kD, 250 kD, 300 kD, 350 kD, 400 kD, 450 kD, 500 kD, or any value within any two of the above-mentioned numerical ranges. Those skilled in the art can select an appropriate pore size of the ultrafiltration membrane to remove impurities according to the size of the impurities.

[0044] In some embodiments, the prepared pentamethylene diamine X hydrochloride is further concentrated. In some embodiments, the concentration is achieved by reducing the pressure, for example, the filtered, micro-filtered or ultra-filtered reaction solution is pumped into a concentration device for concentration under reduced pressure to 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10 or any value within any two of the above-mentioned numerical ranges of the original volume. In some embodiments, the prepared pentamethylene diamine X hydrochloride is further concentrated to a content of 98.5% or more, for example, 98.6% or more, 98.7% or more, 98.8% or more, 98.9% or more, 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.

[0045] In some embodiments, the prepared pentamethylene diamine X hydrochloride is further crystallized. In some embodiments, the crystallization is achieved by reducing the temperature, adding an organic solvent (such as methanol, ethanol, isopropanol, etc.), for example, 1-fold, 2-fold, 3-fold, 4-fold, etc. volume of organic solvent is added dropwise to the concentrated reaction solution, and crystallization is carried out under low temperature conditions (such as 10°C, 5°C or lower). In some embodiments, the crystallization is carried out by vacuum drying. For example, the prepared pentamethylene diamine X hydrochloride is dried in a vacuum oven at 50-70°C (such as 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, or any specific temperature within any two of the above-mentioned numerical ranges) to obtain pentamethylene diamine X hydrochloride.

[0046] In certain embodiments, a solution of lysine X hydrochloride is prepared at a concentration of 400 g / L to 650 g / L (e.g., 400 g / L, 450 g / L, 500 g / L, 510 g / L, 520 g / L, 530 g / L, 540 g / L, 550 g / L, 560 g / L, 570 g / L, 580 g / L, 590 g / L, 600 g / L, 610 g / L, 620 g / L, 630 g / L, 640 g / L, 650 g / L, or any specific concentration within a range between any of these two values), and then wet cells of E. coli engineered to contain lysine decarboxylase are added to the prepared solution of lysine X hydrochloride for enzymatic reaction for 8 to 12 hours (e.g., 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or any specific time within a range between any of these two values) at a temperature of 35 to 40 °C (e.g., 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, or any specific temperature within a range between any of these two values), and the reaction is terminated when the lysine content is < 0.5% (w / v) as determined by HPLC. The residue in the reaction solution is then removed and dried in a vacuum oven at 50 to 70 °C to obtain the crude pentamethylene diamine X hydrochloride.

[0047] In certain embodiments, a solution of lysine X hydrochloride is prepared at a concentration of 500 g / L, and then wet cells of E. coli engineered to contain lysine decarboxylase are added to the prepared solution of lysine X hydrochloride for enzymatic reaction for 10 hours at a temperature of 37 °C, and the reaction is terminated when the lysine content is < 0.5% (w / v) as determined by HPLC. The residue in the reaction solution is then removed and dried in a vacuum oven at 50 to 70 °C to obtain the crude pentamethylene diamine X hydrochloride.

[0048] In certain embodiments, a solution of lysine monohydrochloride is prepared at a concentration of 500 g / L, and then wet cells of E. coli engineered to contain lysine decarboxylase are added to the prepared solution of lysine monohydrochloride for enzymatic reaction for 10 hours at a temperature of 37 °C, and the reaction is terminated when the lysine content is < 0.5% (w / v) as determined by HPLC. The residue in the reaction solution is then removed and dried in a vacuum oven at 50 to 100 °C to obtain the crude pentamethylene diamine monohydrochloride.

[0049] The mixture comprising pentamethylene diamine X hydrochloride can be in any suitable state. In certain embodiments, the mixture comprising pentamethylene diamine X hydrochloride is in a solid state. In certain embodiments, the mixture comprising pentamethylene diamine X hydrochloride is in a powder form.

[0050] Method for preparing pentamethylene isocyanate

[0051] In another aspect, the present application also provides a method for preparing pentamethylene diisocyanate, comprising the following steps:

[0052] (a) mixing pentamethylene diamine X hydrochloride (wherein X ranges from 0.8 to 1.2) with a solvent to form a first mixture;

[0053] (b) bubbling phosgene into the first mixture obtained in step (a), adjusting the heating temperature to 80°C to 150°C, and incubating for 1 to 6 hours until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is generated, to form a second solution;

[0054] (c) adjusting the temperature of the second solution obtained in step (b) to 150°C to 180°C, and incubating for 6 to 24 hours until the reaction is completed when the second solution is clear and free of solid matter, and stopping the bubbling of phosgene.

[0055] In certain embodiments, the method for preparing pentamethylene diisocyanate provided by the present application further comprises step (d): collecting the pentamethylene diisocyanate prepared in step (c). In certain embodiments, the pentamethylene diisocyanate prepared by the method described in the present application is 1,5-pentamethylene diisocyanate.

[0056] The following describes steps (a), (b) and (c) of the method for preparing pentamethylene diisocyanate described in the present application, and optionally step (d), in detail.

[0057] Step (a)

[0058] In the method for preparing pentamethylene diisocyanate provided by the present application, step (a) comprises mixing pentamethylene diamine X hydrochloride (wherein X ranges from 0.8 to 1.2) with a solvent to form a first mixture. In certain embodiments, the pentamethylene diamine X hydrochloride in step (a) is prepared by the method for preparing pentamethylene diamine X hydrochloride described in the present application. All the content described in the section “Method for preparing pentamethylene diamine X hydrochloride” also applies to the description of the method for preparing pentamethylene diisocyanate in this section, and thus will not be repeated here.

[0059] In certain embodiments, pentamethylene diamine X hydrochloride (wherein X ranges from 0.8 to 1.2) is mixed with a solvent to form a first mixture, wherein the solvent is selected from the group consisting of dichloromethane, chlorobenzene, o-dichlorobenzene, benzene, toluene, xylene, hexane, tetrahydrofuran, chloronaphthalene, and any combination thereof. In the present application, the preferred solvent for pentamethylene diamine X hydrochloride is o-dichlorobenzene or chlorobenzene.

[0060] In certain embodiments, the mass ratio of the pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) to the solvent in step (a) is 1 :2 to 1 : 10 (e.g., 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, or any specific ratio between any two of the recited specific ratio ranges). In certain embodiments, the mass ratio of the pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) to the solvent in step (a) is 1 :3. In certain embodiments, the pentamethylene diamine X hydrochloride salt in step (a) is pentamethylene diamine monohydrochloride, the solvent is ortho-dichlorobenzene, and the mass ratio of pentamethylene diamine monohydrochloride to ortho-dichlorobenzene is 1 :2 to 1 : 10 (e.g., 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, or any specific ratio between any two of the recited specific ratio ranges).

[0061] In certain embodiments, the pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and the solvent in step (a) are mixed at a temperature ranging from 20 °C to 50 °C (e.g., 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, or any specific temperature within the range between any two of the recited values).

[0062] In certain embodiments, step (a) comprises mixing pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and a solvent (e.g., dichloromethane, chlorobenzene, ortho-dichlorobenzene, benzene, toluene, xylene, hexane, tetrahydrofuran, chloronaphthalene, and any combination thereof) to form a first mixture. In certain embodiments, step (a) comprises mixing pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and ortho-dichlorobenzene to form a first mixture. In certain embodiments, step (a) comprises mixing pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and ortho-dichlorobenzene to form a first mixture, wherein the mass ratio of the pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) to ortho-dichlorobenzene is 1 :2 to 1 : 10 (e.g., 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, or any specific ratio between any two of the recited specific ratio ranges). In certain embodiments, step (a) comprises mixing pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and ortho-dichlorobenzene to form a first mixture, wherein the mass ratio of the pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) to ortho-dichlorobenzene is 1 :3. In certain embodiments, step (a) comprises mixing 60 g to 90 g of pentamethylene diamine X hydrochloride salt (wherein X ranges from 0.8 to 1.2) and 200 g of ortho-dichlorobenzene to form a first mixture.

[0063] In certain embodiments, step (a) comprises mixing pentamethylene diamine monohydrochloride with o-dichlorobenzene to form a first mixture. In certain embodiments, step (a) comprises mixing pentamethylene diamine monohydrochloride with o-dichlorobenzene to form a first mixture, wherein the mass ratio of pentamethylene diamine monohydrochloride to o-dichlorobenzene is 1 :2 to 1 :10 (e.g., 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, or any specific ratio between any two of the foregoing). In certain embodiments, step (a) comprises mixing pentamethylene diamine monohydrochloride with o-dichlorobenzene to form a first mixture, wherein the mass ratio of pentamethylene diamine monohydrochloride to o-dichlorobenzene is 1 :3. In certain embodiments, step (a) comprises mixing 68 g of pentamethylene diamine monohydrochloride with 200 g of o-dichlorobenzene to form a first mixture.

[0064] Step (b)

[0065] In the methods of making pentamethylene diisocyanate provided herein, step (b) comprises sparging the first mixture obtained in step (a) with phosgene, adjusting the heating temperature to 80 °C to 150 °C, and maintaining the heating for 1 to 6 hours until the pentamethylene diamine X hydrochloride (wherein X has a value ranging from 0.8 to 1.2) is completely reacted and no hydrogen chloride gas is produced, forming a second solution.

[0066] In the preparation of pentamethylene diisocyanate, it is often necessary to input a large excess of phosgene, because when the concentration of phosgene is insufficient, the pentamethylene diisocyanate formed reacts with the excess amine to form urea or other high-viscosity solid byproducts. Therefore, in order to prevent the formation of byproducts, phosgene is preferably provided in excess. For example, in certain embodiments, the amount of phosgene sparged in step (b) into the first mixture obtained in step (a) is a stoichiometric excess based on the amine groups of the pentamethylene diamine X hydrochloride. For example, the molar ratio of phosgene to amine groups of pentamethylene diamine X hydrochloride is typically 1.1 : 1 to 28: 1 (e.g., 1.1 : 1, 1.2: 1, 1.3: 1, 1.4: 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, 5.5: 1, 6: 1, 6.5: 1, 7: 1, 7.5: 1, 8: 1, 8.5: 1, 9: 1, 9.5: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1, 28: 1, and ranges between any of the foregoing values).

[0067] In certain embodiments, the ratio of the phosgene to the pentanediamine X hydrochloride in the first mixture (by moles) in step (b) is from 2: 1 to 25: 1 (e.g., 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, or any number in between any two of the foregoing ratios). Preferably, the ratio of the phosgene to the pentanediamine X hydrochloride in the first mixture (by moles) in step (b) is from 3: 1 to 20: 1. In certain embodiments, the ratio of the phosgene to the pentanediamine X hydrochloride in the first mixture (by moles) in step (a) is about 14: 1 (e.g., 13.5: 1, 13.6: 1, 13.7: 1, 13.8: 1, 13.9: 1, 14: 1, 14.1: 1, 14.2: 1, 14.3: 1, 14.5: 1, etc.). In certain embodiments, the ratio of the phosgene to the pentanediamine X hydrochloride in the first mixture (by moles) in step (a) is about 11: 1 (e.g., 10.5: 1, 10.6: 1, 10.7: 1, 10.8: 1, 10.9: 1, 11: 1, 11.1: 1, 11.2: 1, 11.3: 1, 11.4: 1, 11.5: 1, etc.).

[0068] The amount of phosgene delivered can be controlled by adjusting flow meters, valves, etc. In certain embodiments, the flow rate of the phosgene introduced in step (b) is from 0.1 to 5 L / min (e.g., 0.1 L / min, 0.2 L / min, 0.3 L / min, 0.4 L / min, 0.5 L / min, 0.6 L / min, 0.7 L / min, 0.8 L / min, 0.9 L / min, 1 L / min, 1.1 L / min, 1.2 L / min, 1.3 L / min, 1.4 L / min, 1.5 L / min, 1.6 L / min, 1.7 L / min, 1.8 L / min, 1.9 L / min, 2 L / min, 2.5 L / min, 3 L / min, 3.5 L / min, 4 L / min, 4.5 L / min, 5 L / min, or any specific number in between any two of the foregoing ranges). In certain embodiments, the flow rate of the phosgene introduced in step (b) is 0.5 L / min.

[0069] The phosgene in step (b) can be fresh phosgene or recycled phosgene. The term "fresh phosgene" refers to a phosgene-containing stream that has not been recycled from the phosgenation process and has not passed through any reaction stage involving phosgene reaction after the synthesis of phosgene from chlorine and carbon monoxide. The term "recycled phosgene" refers to a phosgene-containing stream produced from the tail gas collected during the reaction process for preparing piperazine from phosgene. As described above, in the process for preparing piperazine in liquid phase, it is often necessary to use excess phosgene, and therefore the reaction tail gas contains a large amount of phosgene. Recycling the phosgene in the tail gas can achieve the purpose of reducing production cost. In certain embodiments, the phosgene in step (b) is in liquid form.

[0070] In certain embodiments, in step (b), the first mixture and phosgene are reacted at any temperature between 80 °C and 150 °C, such as 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, 150 °C, or any temperature between any two of the above values. In certain embodiments, in step (b), the first mixture and phosgene are reacted at any temperature between 110 °C and 140 °C. In certain embodiments, the reaction can be carried out at any constant temperature between 100 °C and 150 °C, or at varying temperatures between 100 °C and 150 °C. In certain embodiments, the reaction is carried out at 100 °C. In certain embodiments, the reaction can be carried out at any constant temperature between 110 °C and 140 °C, or at varying temperatures between 110 °C and 140 °C.

[0071] In certain embodiments, the phosgene is stored in a gas tank before entering the first mixture, and the pressure of the gas tank is maintained at 0.05-0.1 MPa (e.g., 0.06 MPa, 0.07 MPa, 0.08 MPa, 0.09 MPa, 0.1 MPa, etc.).

[0072] In certain embodiments, the phosgene is pressurized prior to the reaction with the first mixture, for example, to a pressure of between 0.1 MPa and 0.7 MPa (e.g., 0.15 MPa, 0.16 MPa, 0.17 MPa, 0.18 MPa, 0.19 MPa, 0.2 MPa, 0.21 MPa, 0.22 MPa, 0.23 MPa, 0.24 MPa, 0.25 MPa, 0.26 MPa, 0.27 MPa, 0.28 MPa, 0.29 MPa, 0.3 MPa, 0.31 MPa, 0.32 MPa, 0.33 MPa, 0.34 MPa, 0.35 MPa, 0.4 MPa, 0.45 MPa, 0.5 MPa, 0.55 MPa, 0.6 MPa, 0.65 MPa, 0.7 MPa, or any range of values between any two of these values).

[0073] In certain embodiments, phosgene is bubbled into the first mixture obtained in step (a) and the heating temperature is adjusted to between 80 °C and 150 °C (e.g., 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, 150 °C, or any range of values between any two of these values) and the heating is maintained until the reaction of the pentamethylene diamine X hydrochloride is complete and no hydrogen chloride gas is produced, forming a second solution. In certain embodiments, phosgene is bubbled into the first mixture obtained in step (a) and the heating temperature is adjusted to between 80 °C and 150 °C (e.g., 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, 150 °C, or any range of values between any two of these values) and the heating is maintained for between 1 and 6 hours (e.g., 1, 2, 3, 4, 5, 6 hours, or any range of values between any two of these values) until the reaction of the pentamethylene diamine X hydrochloride is complete and no hydrogen chloride gas is produced, forming a second solution.

[0074] In some embodiments, step (b) is replaced by bubbling phosgene into the first mixture obtained in step (a) and then adding the pentanediamine X hydrochloride (where X is in the range of 0.8 to 1.2) by flow addition to form a second solution. In some embodiments, step (b) is replaced by bubbling phosgene into the first mixture obtained in step (a) and then adding the pentanediamine X hydrochloride (where X is in the range of 0.8 to 1.2) by flow addition to form a second solution. In some embodiments, the flow addition is performed for a duration of 1 to 3 hours (e.g., 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or any value in between any two of the aforementioned values). In some embodiments, the flow addition is performed for a duration of 2 hours.

[0075] Without being bound by any theory, it is believed that the additional flow addition of pentanediamine X hydrochloride is particularly beneficial. For example, in this case, the amount of pentanediamine X hydrochloride in the first mixture of step (a) can be small, thereby reducing the amount of solvent used, saving cost and reducing environmental pollution. Moreover, the flow addition of pentanediamine X hydrochloride can avoid the situation that the reaction is initiated too violently due to the excess of amine at the beginning of the reaction, which can cause the overflow of the reaction mixture, and can also reduce the proportion of by-products and stabilize the amount of phosgene used per unit time. The pentanediamine X hydrochloride can be added by flow addition in various ways, for example, by a screw feeder. The pentanediamine X hydrochloride added by flow addition can be in solid form or in liquid form dissolved in a solvent (e.g., o-dichlorobenzene, etc.). In some embodiments, the pentanediamine X hydrochloride is dissolved in a solvent to form a high-concentration dispersion solvent, and then added by flow addition in liquid form. In some embodiments, it is preferred to add the pentanediamine X hydrochloride at a constant rate, because this can better control the reaction rate of pentanediamine X hydrochloride with phosgene, thereby improving the yield and reducing the generation of by-products.

[0076] In some embodiments, step (b) is the first stage of the reaction for preparing pentanediyiisocyanate by the phosgene liquid phase method, i.e., the reaction of pentanediamine X hydrochloride with phosgene to produce aminoacyl chloride and hydrogen chloride gas. In some embodiments, the second solution obtained in step (b) contains aminoacyl chloride. In some embodiments, the second solution obtained in step (b) is a mixed solution of aminoacyl chloride and the solvent (e.g., o-dichlorobenzene).

[0077] Step (c)

[0078] In the method for preparing pentanediyiisocyanate provided in the present application, step (c) comprises adjusting the temperature of the second solution obtained in step (b) to 150°C to 180°C and maintaining the heating for 6 to 24 hours until there is no solid in the reaction mixture, and then stopping the bubbling of phosgene.

[0079] In certain embodiments, step (c) comprises adjusting the temperature of the second solution obtained in step (b) to a temperature in the range of 150 °C, 155 °C, 160 °C, 161 °C, 162 °C, 163 °C, 164 °C, 165 °C, 166 °C, 167 °C, 168 °C, 169 °C, 170 °C, 171 °C, 172 °C, 173 °C, 174 °C, 175 °C, 176 °C, 177 °C, 178 °C, 179 °C, 180 °C, or any value in the range between any two of these values. In certain embodiments, step (c) involves the second stage reaction of the liquid phase process for the preparation of pentamethylene diisocyanate, i.e., the aminoacyl chloride produced in step (b) is further reacted with phosgene to produce pentamethylene diisocyanate and hydrogen chloride gas.

[0080] In certain embodiments, step (c) comprises adjusting the temperature of the second solution obtained in step (b) to a temperature in the range of 160 °C to 180 °C, and maintaining the temperature for 6 to 24 hours, e.g., 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or any value in the range between any two of these values.

[0081] In certain embodiments, after the cessation of the introduction of phosgene in step (c), the temperature is reduced to room temperature. In certain embodiments, the room temperature in step (c) is in the range of -10 °C to 40 °C, e.g., -10 °C, -5 °C, 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, or any value in the range between any two of these values.

[0082] In certain embodiments, an inert gas is introduced while the temperature is being reduced in step (c). In certain embodiments, the inert gas is selected from the group consisting of nitrogen, carbon dioxide, carbon monoxide, helium, argon, and any combination thereof.

[0083] Step (d)

[0084] Optionally, the method for the preparation of pentamethylene diisocyanate provided herein further comprises step (d) of collecting the pentamethylene diisocyanate produced in step (c).

[0085] The pentamethylene diisocyanate produced in step (c) can be collected using conventional methods known in the art, e.g., by removing the solvent under negative pressure, and then collecting the pentamethylene diisocyanate by vacuum distillation under negative pressure.

[0086] In certain embodiments, the present application provides a method for the preparation of pentamethylene diisocyanate, wherein the method comprises:

[0087] (i). adding a hydrochloric acid solution to a lysine solution to form lysine X hydrochloride (wherein X ranges from 0.8 to 1.2), and then reacting the lysine X hydrochloride with a lysine decarboxylase to form a mixture comprising pentamethylene diamine X hydrochloride;

[0088] (ii). concentrating the mixture comprising pentamethylene diamine X hydrochloride obtained in step (i) to obtain pentamethylene diamine X hydrochloride;

[0089] (iii). mixing the pentamethylene diamine X hydrochloride obtained in step (ii) with a solvent to form a first mixture;

[0090] (iv). passing phosgene into the first mixture obtained in step (iii), adjusting the heating temperature to 80°C to 150°C (for example, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, or any value within a range between any two of the foregoing values), and maintaining the heating for 1 to 6 hours (for example, 1, 2, 3, 4, 5, 6 hours, or any value within a range between any two of the foregoing values) until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is produced, to form a second solution;

[0091] (v). adjusting the temperature of the second solution obtained in step (iv) to 150°C or higher, for example, 150°C to 180°C (for example, 160°C, 161°C, 162°C, 163°C, 164°C, 165°C, 166°C, 167°C, 168°C, 169°C, 170°C, 171°C, 172°C, 173°C, 174°C, 175°C, 176°C, 177°C, 178°C, 179°C, 180°C, or any value within a range between any two of the foregoing values), and maintaining the heating for 6 to 24 hours (for example, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or any value within a range between any two of the foregoing values) until the reaction is complete and no solid is present, stopping the passage of phosgene, and reducing the temperature to room temperature; and

[0092] (vi). collecting the pentamethylene isocyanate prepared in step (v).

[0093] In certain embodiments, the lysine decarboxylase in step (i) is a purified lysine decarboxylase or is from a lysine decarboxylase-expressing bacterium.

[0094] In certain embodiments, the present application provides a method for preparing pentalameric isocyanate, wherein the method comprises:

[0095] (i). adding a hydrochloric acid solution to a lysine solution to form lysine monohydrochloride, and then reacting the lysine monohydrochloride with a lysine decarboxylase to form a mixture comprising pentalameric diamine monohydrochloride;

[0096] (ii). concentrating the mixture comprising pentalameric diamine monohydrochloride obtained in step (i) to obtain pentalameric diamine monohydrochloride;

[0097] (iii). mixing the pentalameric diamine monohydrochloride obtained in step (ii) with a solvent to form a first mixture;

[0098] (iv). passing phosgene into the first mixture obtained in step (iii), adjusting the heating temperature to 80-150°C (e.g., 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, or any number within a range between any two of the above values), and incubating for 1-6 hours (e.g., 1, 2, 3, 4, 5, 6 hours, or any number within a range between any two of the above values) until the pentalameric diamine monohydrochloride is completely reacted and no hydrogen chloride gas is produced, to form a second solution;

[0099] (v). adjusting the temperature of the second solution obtained in step (iv) to above 150°C, e.g., 150-180°C (e.g., 160°C, 161°C, 162°C, 163°C, 164°C, 165°C, 166°C, 167°C, 168°C, 169°C, 170°C, 171°C, 172°C, 173°C, 174°C, 175°C, 176°C, 177°C, 178°C, 179°C, 180°C, or any number within a range between any two of the above values), and incubating for 6-24 hours (e.g., 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or any number within a range between any two of the above values) until the reaction is complete and no solid is present, stopping the passage of phosgene, and reducing the temperature to room temperature; and

[0100] (vi). collecting the pentalameric isocyanate prepared in step (v).

[0101] In certain embodiments, the lysine decarboxylase in step (i) is a purified lysine decarboxylase or is from a lysine decarboxylase-expressing bacterium.

[0102] The method for preparing pentamethylene diisocyanate provided by the application has at least the following advantages:

[0103] (1) The biosynthesis of pentamethylene diamine monohydrochloride can obtain a single salt due to controllable reaction, and the raw material is low in price and easy to obtain, thereby reducing the overall cost, and the biosynthetic re-concentrated salt has good particle size and exists in a suspended form in a solvent without agglomeration;

[0104] (2) The pentamethylene diamine monohydrochloride is insoluble in a solvent, thereby avoiding reaction between each other, but can be uniformly dispersed in the solvent;

[0105] (3) The pentamethylene diamine monohydrochloride can quickly react with phosgene to generate a monoaminocarbamoyl chloride hydrochloride due to a naked amino group, and the intermediate is more stable and is more easily reacted in subsequent high-temperature photochemical reaction, thereby shortening the overall reaction time, reducing the impurity amount and hydrolysis chlorine, and improving the yield;

[0106] (4) In the method for preparing pentamethylene diisocyanate provided by the application, the reaction process is relatively smooth, the selectivity of the target product prepared is high, and less by-products are generated.

[0107] The above is a summary of the application, which may be simplified, generalized and omitted in details, and therefore those skilled in the art should recognize that this part is only illustrative and is not intended to limit the scope of the application in any way. Neither is this summary part intended to determine the key features or essential features of the claimed subject matter, nor is it intended to serve as an auxiliary means to determine the scope of the claimed subject matter.

[0108] Examples

[0109] In order to more fully understand the application, the following examples are shown. It should be understood that these examples are only for illustrative purposes and are not to be interpreted in any way as being limiting.

[0110] Example 1A: Preparation of pentamethylene diamine monohydrochloride (PDA·1HCl)

[0111] The E. coli engineering bacteria containing lysine decarboxylase were cultured in a 15L fermentation tank, and after 30 hours of culture, a high-speed centrifuge was used for centrifugation at a speed of 8000 rpm for 10 min to obtain wet E. coli engineering bacteria, which were collected for standby.

[0112] A solution of 500 g / L lysine monohydrochloride (also referred to as "lysine monohydrochloride") was prepared by first adding 400 g of lysine (99% purity) to 423 ml of water, stirring to dissolve, and then adding 277.1 g of 36% hydrochloric acid solution to the solution. Then 6 g of the wet bacterial cells of E. coli containing lysine decarboxylase prepared in the above step were added to the solution, and 0.05 g of pyridoxal phosphate was added. The reaction was started and the reaction temperature was maintained at 37°C. The reaction pH was not controlled during the reaction, and the reaction was terminated when the lysine content was less than 0.5% (w / v) as determined by HPLC after 10 hours of reaction.

[0113] The reaction solution was centrifuged at high speed to remove large particulate impurities such as bacterial cells, bacterial debris, and the like, and was concentrated under reduced pressure using a rotary evaporator to 410 g. The concentrate was transferred to a vacuum oven and dried at 90°C to obtain a paste-like solid product weighing 377.8 g. Analysis showed that the PDA-HCl content was 98.9%, and the yield was 98.1%. The PDA-HCl was not subjected to further distillation and purification steps, and was used directly in the preparation of PDI.

[0114] Example IB: Preparation of pentamethylene diisocyanate (PDI)

[0115] 68 g of PDA-HCl prepared in Example 1A and 200 g of o-dichlorobenzene were weighed into a flask, and the exhaust gas was absorbed. The stirring was started and phosgene was introduced at a flow rate of 0.5 L / min. The heating temperature was adjusted to bring the internal temperature to 100°C, and the solution was heated at this temperature for 2 hours. When the PDA-HCl particles in the solution disappeared and hydrogen chloride gas was no longer generated, the first stage of the reaction was terminated.

[0116] In the second stage of the reaction, the internal temperature was adjusted to 160-180°C, and the solution was heated at this temperature for 8 hours. When the solution became clear and no particles were present, the reaction was terminated, the phosgene introduction was stopped, and nitrogen was introduced while the temperature was decreasing. When the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. PDI was prepared in a yield of 74.1 g, with a purity of 99.9% and a hydrolytic chlorine content of 20 ppm.

[0117] Example 2A: Preparation of pentamethylene diamine X hydrochloride (PDA-0.5HCl)

[0118] The E. coli containing lysine decarboxylase was cultured in a 15 L fermenter, and after 30 hours of culture, the wet bacterial cells were obtained by centrifugation at 8000 rpm for 10 min using a high-speed centrifuge.

[0119] A solution of 450 g / L lysine monohydrochloride was prepared as follows: 400 g of lysine (99% purity) was added to 561.4 ml of water, and after stirring and dissolving, 138.6 g of 36% hydrochloric acid solution was bubbled into the solution. Then 6 g of the wet bacterial cells of E. coli containing lysine decarboxylase prepared above, and 0.05 g of pyridoxal phosphate were added, and the reaction was started at a temperature of 37°C. The pH of the reaction was not controlled during the reaction, and the reaction was terminated after 10 hours when the HPLC measurement showed that the content of lysine was less than 0.5% (w / v).

[0120] The reaction solution was centrifuged at high speed to remove large-particle impurities such as bacterial cells, bacterial fragments, etc., and was concentrated under reduced pressure in a rotary evaporator to 440 g, and was then transferred to a vacuum oven for drying at 90°C to obtain a paste-like solid product weighing 249.8 g. Analysis showed that the content of PDA-0.5HCl was 98.9%, and the yield was 75%. The PDA-0.5HCl was not subjected to further distillation and purification, and was directly used for the preparation of PDI.

[0121] Example 2B: Preparation of pentamethylene diisocyanate (PDI)

[0122] 60 g of PDA-0.5HCl prepared in Example 2A and 200 g of o-dichlorobenzene were weighed into a flask, and a tail gas absorber was connected. The stirring was started, and phosgene was bubbled in at a flow rate of 0.5 L / min. The heating temperature was adjusted to bring the internal temperature to 100°C, and the heating was maintained for 2 hours. When the PDA-0.5HCl particles in the solution disappeared and hydrogen chloride gas was no longer generated, the first stage of the reaction was terminated.

[0123] In the second stage of the reaction, the internal temperature was adjusted to 160-180°C, and the heating was maintained for 8 hours. When the solution became clear and no particles were present, the reaction was terminated, the phosgene bubbling was stopped, and nitrogen was bubbled in while the temperature was lowered. When the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. PDI was prepared in an amount of 57.6 g, with a purity of 99.7% and a yield of 75%, and the hydrolytic chlorine content was 131 ppm.

[0124] Example 3A: Preparation of pentamethylene diamine X hydrochloride (PDA-0.8HCl)

[0125] The E. coli containing lysine decarboxylase was cultured in a 15 L fermenter, and after 30 hours of culture, it was centrifuged at a speed of 8000 rpm for 10 min using a high-speed centrifuge to obtain wet E. coli, which was collected for use.

[0126] A solution of 480 g / L lysine monohydrochloride was prepared as follows: 400 g of lysine (99% purity) was added to 478 ml of water, and after stirring and dissolving, 221.7 g of 36% hydrochloric acid solution was bubbled into the solution. Then 6 g of the wet bacterial cells of E. coli containing lysine decarboxylase prepared above, and 0.05 g of pyridoxal phosphate were added, and the reaction was started at a temperature of 37°C. The pH of the reaction was not controlled during the reaction, and the reaction was terminated after 10 hours when the HPLC measurement showed that the content of lysine was less than 0.5% (w / v).

[0127] The reaction solution was centrifuged at high speed to remove large-particle impurities such as bacterial cells, bacterial fragments, etc., and was concentrated under reduced pressure in a rotary evaporator to 390 g, and was then transferred to a vacuum oven for drying at 90°C to obtain a paste-like solid product weighing 316.1 g. Analysis showed that the content of PDA-0.8HCl was 98.9%, and the yield was 87%. The PDA-0.8HCl was not subjected to further distillation and purification, and was directly used for the preparation of PDI.

[0128] Example 3B: Preparation of pentamethylene diisocyanate (PDI)

[0129] Example 3B: Preparation of pentamethylene diisocyanate (PDI)

[0130] In the second reaction stage, the internal temperature was adjusted to 160-180°C, and the solution was heated for 8 hours until it became clear and no particles were present, at which point the reaction was terminated, and the flow of phosgene was stopped. Nitrogen was introduced while the temperature was decreasing, and when the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. PDI was prepared in an amount of 67.9 g, with a purity of 99.9%, a yield of 89%, and a hydrolytic chlorine content of 100 ppm.

[0131] Example 4A: Preparation of pentamethylene diamine X hydrochloride (PDA-1.2HCl)

[0132] The E. coli containing lysine decarboxylase was cultured in a 15 L fermenter, and after 30 hours of culture, it was centrifuged at a speed of 8000 rpm for 10 minutes to obtain wet E. coli, which was collected for use.

[0133] A solution of lysine monohydrochloride with a concentration of 520 g / L was prepared as follows: 400 g of lysine (99% purity) was first added to 367.5 ml of water, and after stirring and dissolving, 332.5 g of 36% hydrochloric acid solution was bubbled into the solution. Then 6 g of the wet bacterial body of E. coli containing lysine decarboxylase prepared above, 0.05 g of pyridoxal phosphate were added, and the reaction was started. The reaction temperature was 37°C. The reaction pH was not controlled during the reaction, and the reaction was terminated when the lysine content was <0.5% (w / v) as determined by HPLC after 10 h of reaction.

[0134] The reaction solution was centrifuged at high speed to remove large-particle impurities such as bacterial bodies, bacterial fragments, etc., and concentrated to 430 g under reduced pressure using a rotary evaporator. The concentrated solution was then transferred to a vacuum oven and dried at 90°C to obtain a paste-like solid product weighing 398.1 g. Analysis showed that the PDA-1.2HC1 content was 98.5%, and the yield was 98.2%. The PDA-1.2HC1 was not subjected to further distillation and purification steps and was directly used to prepare PDI.

[0135] Example 4B: Preparation of pentamethylene diisocyanate (PDI)

[0136] The PDA-1.2HC1 prepared in Example 4A was weighed at 72 g, and 200 g of o-dichlorobenzene was added to a flask, and the exhaust gas was absorbed. The stirring was started while bubbling in phosgene at a flow rate of 0.5 L / min. The heating temperature was adjusted to reach an internal temperature of 100°C, and the solution was heated for 2 h. When the PDA-1.2HC1 particles in the solution disappeared and hydrogen chloride gas was no longer generated, the first stage of the reaction was completed.

[0137] In the second reaction stage, the internal temperature was adjusted to 160-180°C, and the solution was heated for 15 h. When the solution was clear and no particles were present, the reaction was terminated, the phosgene bubbling was stopped, and nitrogen was bubbled in while cooling. When the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. PDI was prepared at 64.6 g, with a purity of 99.9%, a yield of 85%, and a hydrolytic chlorine content of 76 ppm.

[0138] Example 5A: Preparation of pentamethylene diamine X hydrochloride (PDA-1.5HC1)

[0139] The E. coli containing lysine decarboxylase was cultured in a 15 L fermenter, and after 30 hours of culture, it was centrifuged at a speed of 8000 rpm for 10 min using a high-speed centrifuge to obtain wet E. coli, which was collected for use.

[0140] A solution of 550 g / L lysine monohydrochloride was prepared as follows: 400 g of lysine (99% purity) was added to 284.3 ml of water, and after stirring and dissolving, 415.7 g of 36% hydrochloric acid solution was bubbled into the solution. Then 6 g of the wet bacterial cells of E. coli containing lysine decarboxylase prepared above, and 0.05 g of pyridoxal phosphate were added, and the reaction was started at a temperature of 37°C. The pH of the reaction was not controlled during the reaction, and the reaction was terminated after 10 hours when the HPLC measurement showed that the content of lysine was less than 0.5% (w / v).

[0141] The reaction solution was centrifuged at high speed to remove large-particle impurities such as bacterial cells, bacterial fragments, etc., and was concentrated under reduced pressure in a rotary evaporator to 440 g, and was transferred to a vacuum oven for drying at 90°C to obtain a yellowish solid product weighing 425.7 g. Analysis showed that the content of PDA-1.5HC1 was 98.6%, and the yield was 97.8%. The PDA-1.5HC1 was not subjected to further distillation and purification, and was directly used for the preparation of PDI.

[0142] Example 5B: Preparation of pentamethylene diisocyanate (PDI)

[0143] Example 5B: Preparation of pentamethylene diisocyanate (PDI)

[0144] In the second reaction stage, the internal temperature was adjusted to 160-180°C, and the solution was heated for 26 hours until it became clear and no particles were present, at which point the reaction was terminated, and the passage of phosgene was stopped. Nitrogen was passed in while the temperature was lowered, and when the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. PDI was prepared in an amount of 61.1 g, with a purity of 99.8%, a yield of 91%, and a hydrolytic chlorine content of 83 ppm.

[0145] Example 6A: Preparation of pentamethylene diamine X hydrochloride (PDA-2HC1)

[0146] The E. coli containing lysine decarboxylase was cultured in a 15 L fermenter, and after 30 hours of culture, it was centrifuged at a speed of 8000 rpm for 10 minutes to obtain wet E. coli, which was collected for use.

[0147] A solution of 600 g / L lysine monohydrochloride was prepared as follows: 400 g of lysine (99% purity) was added to 146 ml of water, and after stirring and dissolving, 554.2 g of 36% hydrochloric acid solution was bubbled into the solution. Then 6 g of the wet bacterial body of E. coli containing lysine decarboxylase prepared above, 0.05 g of pyridoxal phosphate were added, and the reaction was started. The reaction temperature was 37°C. The reaction pH was not controlled during the reaction, and the reaction was terminated when the lysine content was <0.5% (w / v) as determined by HPLC after 10 h of reaction.

[0148] The reaction solution was centrifuged at high speed to remove large particulate impurities such as bacterial bodies, bacterial fragments, etc., and concentrated to 500 g under reduced pressure using a rotary evaporator, and then transferred to a vacuum oven for drying at 90°C to obtain 480.6 g of a light yellow solid product. Analysis showed that the PDA-2HC1 content was 98.2%, and the yield was 98.5%. The PDA-2HC1 was not subjected to further distillation and purification steps, and was directly used to prepare PDI.

[0149] Example 6B: Preparation of pentamethylene diisocyanate (PDI)

[0150] 86 g of PDA-2HC1 prepared in Example 6A and 200 g of o-dichlorobenzene were weighed into a flask, and connected to a tail gas absorber. While stirring, phosgene was bubbled in at a flow rate of 0.5 L / min. The heating temperature was adjusted to reach an internal temperature of 100°C, and the solution was heated for 2 h. When the PDA-2HC1 particles in the solution disappeared and hydrogen chloride gas was no longer generated, the first stage reaction was terminated.

[0151] In the second reaction stage, the internal temperature was adjusted to 160-180°C, and the solution was heated for 37 h. When the solution was clear and no particles were present, the reaction was terminated, the phosgene flow was stopped, and nitrogen was bubbled in while cooling. When the temperature returned to room temperature, the sample was analyzed. The PDI reaction solution was dephosgenated and subjected to distillation. 67.4 g of PDI was prepared with a purity of 99.9% and a yield of 89%, and the hydrolytic chlorine content was 75 ppm.

[0152] Comparative Example

[0153] Comparative Example 1: Preparation of pentamethylene diamine hydrochloride (PDA-1HC1) by bubbling HCl gas into pure PDA to prepare pentamethylene diisocyanate

[0154] PDA (content 99.9%) and 200g o-dichlorobenzene were weighed into a multi-neck flask and stirred, after mixing, hydrogen chloride gas was introduced into the mixture at a flow rate of 100ml / min through a gas dosing meter, the temperature was controlled at 20-30°C, after 110min of hydrogen chloride introduction, the hydrogen chloride introduction was stopped. During the hydrogen chloride introduction, syrup solid appeared on the bottle wall and stirring paddle, and large clumps of solid appeared on the stirring paddle and in the reaction solution. Phosgene was introduced at a flow rate of 0.5L / min. The heating temperature was adjusted to reach an internal temperature of 150°C, and the solution was heated for 40h until it was clear. The phosgene introduction was stopped, and nitrogen was introduced while cooling, and the sample was analyzed when the temperature returned to room temperature. The PDI reaction solution was dephosgenated and subjected to distillation. PDI 62.8g was prepared, with a purity of 99.3%, a yield of 83%, and a hydrolytic chlorine content of 78ppm.

[0155] Comparative Example 2: Preparation of pentamethylene diisocyanate from pure PDA

[0156] PDA (content 99.9%) and 200g o-dichlorobenzene were weighed into a multi-neck flask and connected to a tail gas absorber, and phosgene was introduced at a flow rate of 0.5L / min while stirring, and the internal temperature was controlled at 10-20°C. The low-temperature phosgenation was carried out for 8h. The heating temperature was adjusted to reach an internal temperature of 180°C, and the solution was heated for 15h until it was clear, the phosgene introduction was stopped, and nitrogen was introduced while cooling, and the sample was analyzed when the temperature returned to room temperature. The PDI reaction solution was dephosgenated and subjected to distillation. PDI 61.9g was prepared, with a purity of 99.8%, a yield of 82%, and a hydrolytic chlorine content of 177ppm.

[0157] From the above example and comparative example data comparison, it can be seen that using pentamethylene diamine monohydrochloride as the raw material for phosgenation liquid phase method to prepare PDI can obtain PDI with higher yield and purity, and low hydrolytic chlorine content, which may be due to the following reasons:

[0158] • The reaction of PDA with acidic gas in the solvent is uncontrollable, so if PDA is directly salted with HCl, it is mainly in the form of di-salt, and little monosalt is obtained. The salted solid is mostly syrup-like viscous solid, and the salted solid contains free amine that is not salted, which will react with carbamoyl chloride to form urea during the reaction, thereby affecting the yield;

[0159] • PDA·2HCl is difficult to dissolve in the reaction solution due to the salt formation of the two amino groups with hydrogen chloride, so the reaction time is too long, and if the reaction time is to be shortened, a catalyst needs to be added, and the catalyst needs to be recovered and reactivated after the reaction, resulting in increased cost;

[0160] In the traditional process of synthesizing PDI from PDA, low-temperature photochemical reaction is generally needed due to the high activity of PDA, and the concentration is low, and if the time of low-temperature photochemical reaction is not controlled well, impurities are easily produced, and then the yield is affected;

[0161] In the biosynthesis of PDA monohydrochloride, monosalts can be obtained due to controllable reaction, and the raw materials are low in price and easy to obtain, so that the overall cost is reduced. The granularity of the concentrated salt particles is good, and the salt particles exist in the form of suspension in the solvent, and do not form agglomerates;

[0162] Since the PDA monohydrochloride is insoluble in the solvent, the mutual reaction is avoided, but the PDA monohydrochloride can be uniformly dispersed in the solvent;

[0163] Since the PDA monohydrochloride has a naked amino group, the PDA monohydrochloride can quickly react with phosgene to generate monaminocarbamoyl chloride hydrochloride, and the intermediate is more stable, and is more easily reacted in subsequent high-temperature photochemical reaction, so that the overall reaction time is shortened, the amount of impurities and hydrolyzed chlorine is reduced, and the yield is improved.

[0164] In summary, the inventor believes that the PDA monohydrochloride has greater advantages than other methods for synthesizing PDI.

Claims

1. A method for preparing pentamethylene diamine X hydrochloride, comprising the following steps: (1) adding a hydrochloric acid solution to a lysine solution to form a lysine X hydrochloride solution; (2) adding a lysine decarboxylase to convert the lysine X hydrochloride solution obtained in step (1) into a pentamethylene diamine X hydrochloride solution; (3) concentrating the pentamethylene diamine X hydrochloride obtained in step (2) ; wherein X is in the range of 0.8 to 1.

2. 2.The method of claim 1, wherein the concentration of the lysine X hydrochloride solution is in the range of 400 to 650 g / L, and the pentamethylene diamine X hydrochloride obtained after the concentration step has a content of 98.5% or more. 3.A method for preparing pentamethylene diisocyanate, comprising the following steps: (a) mixing pentamethylene diamine X hydrochloride (wherein X is in the range of 0.8 to 1.2) with a solvent to form a first mixture; (b) passing phosgene into the first mixture obtained in step (a), adjusting the heating temperature to 80 ℃ to 150 ℃, and maintaining heating for 1 to 6 hours until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is generated, to form a second solution; (c) adjusting the temperature of the second solution obtained in step (b) to 150 ℃ to 180 ℃, and maintaining heating for 6 to 24 hours until the reaction ends when there is no solid, and stopping the passage of phosgene. 4.The method of claim 3, wherein the solvent in step (a) is selected from the group consisting of dichloromethane, chlorobenzene, o-dichlorobenzene, benzene, toluene, xylene, hexane, tetrahydrofuran, chloronaphthalene, and any combination thereof. 5.The method of claim 3 or 4, wherein the pentamethylene diamine X hydrochloride in step (a) is prepared by the method of claim 1 or 2. 6.The method of any one of claims 3 to 5, wherein the mass ratio of the pentamethylene diamine X hydrochloride to the solvent in step (a) is 1:2 to 1:

10. 7.The method of any one of claims 3 to 6, wherein the flow rate of the phosgene passed in step (b) is 0.1 to 5 L / min; or the molar ratio of the phosgene passed in step (b) to the amino group of the pentamethylene diamine X hydrochloride in step (a) is 1.1:1 to 28:

1. 8.The method of any one of claims 3 to 7, wherein the second solution obtained in step (b) contains aminoacyl chloride. 9.The method of any one of claims 3 to 8, wherein after stopping the passage of phosgene in step (c), the temperature is reduced to room temperature. 10.The method of claim 9, wherein an inert gas is passed while reducing the temperature in step (c). 11.The method of claim 10, wherein the inert gas is selected from the group consisting of nitrogen, carbon dioxide, carbon monoxide, helium, argon, and any combination thereof. 12.The method of any one of claims 9 to 11, wherein the room temperature in step (c) is in the range of -10 ℃ to 40 ℃. 13.The method of any one of claims 3 to 12, wherein the method further comprises step (d) : ​ ​ ​ ​ ​ ​ ​ pentamethylene isocyanate prepared in step (c).

14. A method for preparing pentamethylene isocyanate, comprising the steps of: (i). adding a hydrochloric acid solution to a lysine solution to form lysine X hydrochloride (wherein X ranges from 0.8 to 1.2), and then reacting the lysine X hydrochloride with lysine decarboxylase to produce a mixture comprising pentamethylene diamine X hydrochloride; (ii). concentrating the mixture comprising pentamethylene diamine X hydrochloride obtained in step (i) to obtain pentamethylene diamine X hydrochloride; (iii). mixing the pentamethylene diamine X hydrochloride obtained in step (ii) with a solvent to form a first mixture; (iv). passing phosgene into the first mixture obtained in step (iii), adjusting the heating temperature to 80°C to 150°C, and incubating and heating for 1 to 6 hours until the pentamethylene diamine X hydrochloride is completely reacted and no hydrogen chloride gas is produced, to form a second solution; (v). adjusting the temperature of the second solution obtained in step (iv) to above 150°C (for example, 150°C to 180°C), and incubating and heating for 6 to 24 hours until the reaction ends when there is no solid, stopping the phosgene passage, and reducing the temperature to room temperature; and (vi). collecting pentamethylene isocyanate prepared in step (v).

15. The method according to any one of the preceding claims, wherein X is 1.