阅读说明：本技术 制备基于赖氨酸的二异氰酸酯的方法 (Process for preparing lysine-based diisocyanates ) 是由 E·斯皮鲁 H·洛斯奇 S·克雷舍 A·迪斯维尔德 A·泰辛 J-J·尼茨 于 2021-06-25 设计创作，主要内容包括：本发明涉及制备基于赖氨酸的二异氰酸酯的方法,具体涉及制备式(A)的二异氰酸酯的方法,式(A)中R选自烷基、芳基和它们的组合,该方法包括以所指出顺序的以下方法步骤：1)采用使用赖氨酸和脲的方法提供式(B)的中间体,式(B)中R和每个R’独立地选自烷基、芳基和它们的组合；和2)将式(B)的中间体热裂解,从而获得式(A)的二异氰酸酯；并且还涉及由该方法直接制备的二异氰酸酯。(The present invention relates to a process for the preparation of a lysine-based diisocyanate, in particular to a process for the preparation of a diisocyanate of formula (a) wherein R is selected from the group consisting of alkyl, aryl and combinations thereof, comprising the following process steps in the indicated order: 1) employing a process employing lysine and urea to provide an intermediate of formula (B) wherein R and each R' are independently selected from alkyl, aryl, and combinations thereof; and 2) thermally cracking the intermediate of formula (B) to obtain the diisocyanate of formula (A); and also to diisocyanates directly prepared by this process.)

1. A process for preparing diisocyanates of the formula (A),

wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof,

the method comprises the following method steps in the indicated order:

1) the process using lysine and urea provides an intermediate of formula (B),

wherein R and each R' are independently selected from alkyl, aryl, and combinations thereof; and

2) thermally cracking the intermediate of formula (B),

thus obtaining the diisocyanate of formula (A).

2. Method according to claim 1, characterized in that the method comprises the following method steps before method step 1):

a.1) providing lysine;

a.2) reacting the lysine with urea to form a urea adduct of formula (C),

and

a.3) reacting the urea adduct of formula (C) with an alcohol to form an intermediate of formula (B).

3. Method according to claim 1, characterized in that the method comprises the following method steps before method step 1):

b.1) providing lysine;

b.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

b.3) reacting the lysine salt of the formula (Z) with urea to form a urea salt of the formula (Y),

wherein X is a counterion;

b.4) reacting the urea salt of the formula (Y) with an alcohol to form the carbamate of the formula (X),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof, and

x is a counterion;

b.5) reacting the carbamate of formula (X) with an acid to form the carboxylic acid of formula (W),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof; and

b.6) reacting the carboxylic acid of formula (W) with an alcohol to form an intermediate of formula (B).

4. Method according to claim 1, characterized in that the method comprises the following method steps before method step 1):

c.1) providing lysine;

c.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

c.3) reacting the lysine salt of formula (Z) with urea to form a urea salt of formula (Y),

wherein X is a counterion;

c.4) reacting the urea salt of formula (Y) with an alcohol to form an intermediate of formula (B).

5. Process according to any one of the preceding claims, characterized in that R is selected from C1-C8 alkyl groups, more preferably from methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups.

6. Method according to any one of the preceding claims, characterized in that the thermal cleavage is mediated by an intermediary, preferably by a metal-based catalyst, more preferably by a tin (II) salt.

7. Method according to any of the preceding claims, characterized in that the method comprises after and/or during method step 2) one further method step 3):

3) the diisocyanate of formula (A) is purified, preferably by fractional distillation.

8. Process according to any one of the preceding claims 2 to 7, characterized in that the molar ratio of urea is in the range from 1:1 to 5:1, based on the primary amine groups of the lysine or lysine salt of formula (Z).

9. The process according to any of the preceding claims 2 to 8, characterized in that the pressure during the reaction with the alcohol in process steps a.3), b.4), b.6), c.4) is in the range ≥ 1 bar, preferably in the range from 1 to 35 bar, more preferably in the range from 1 to 25 bar, at least for part of the time.

10. The process according to claim 9, characterized in that the pressure during the reaction with the alcohol in process steps a.3), b.4), b.6), c.4) is within the specified range for 1 to 20 hours, more preferably 3 to 10 hours, in particular 4 to 6 hours.

11. The process according to any of the preceding claims 2 to 10, characterized in that the reaction with the alcohol in process steps a.3), b.4), b.6), c.4) is carried out at least at a temperature of 150 to 300 ℃, preferably at a temperature of 180 to 230 ℃, more preferably at a temperature of 190 to 220 ℃.

12. The process according to claim 11, characterized in that the reaction with the alcohol in process steps a.3), b.4), b.6), c.4) is continued for 1 to 20 hours, preferably 3 to 10 hours, in particular 4 to 6 hours, within the specified temperature range.

13. Process according to any one of the preceding claims 2 to 12, characterized in that the molar ratio of the alcohols is in the range of 2:1 to 100:1, based on the urea adduct of formula (C), the carboxylic acid of formula (W) or the urea salt of formula (Y).

14. The process according to any of the preceding claims 2 to 13, characterized in that the reactions in process steps a.2), b.3) and c.3) are carried out in a polar solvent, more particularly in water.

15. Diisocyanate of the formula (A) prepared by a process according to one of claims 1 to 14,

wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof.

Technical Field

The present invention relates to a process for preparing diisocyanates, and to diisocyanates prepared therefrom.

Background

Lysine-based diisocyanates (also referred to in the art as "lysine diisocyanates") are known compounds and are used primarily for medical applications. For these compounds, various preparation methods are disclosed in the prior art.

EP 3527593 a1 teaches a process for their preparation using phosgene. The significant toxicity of such compounds necessitates laborious and expensive safety precautions during storage and preparation. In addition to health and environmental aspects, such laborious and expensive safety precautions are also undesirable, as they ultimately make the process less economical. Common substitutes for phosgene, such as triphosgene, also have similar toxicity. The above considerations thus apply also to these compounds and to the methods of using these compounds.

EP 3626705 a1 discloses processes which can be used for preparing lysine diisocyanates, in particular by thermal decomposition of carbamates. However, the corresponding carbamates initially need to be prepared expensively. For example, the lysine carbamates used in the examples must be laboriously prepared from the compounds diphenyl carbonate, triethylamine and lysine β -aminoethyl ester trihydrochloride, which are in some cases not readily available.

Other processes of the prior art additionally have the disadvantage that the diisocyanates have an undesirable color. In order to remove these colors, laborious purification procedures are necessary, which makes these methods no longer cost-effective.

Disclosure of Invention

Object of the Invention

The processes known from the prior art have the disadvantage, inter alia, that the compounds used are highly toxic and ecologically harmful. However this does not match the requirements of a more sustainable economic development.

Accordingly, there is a need to overcome the disadvantages of the prior art and to provide an improved process for the preparation of diisocyanates of formula (a). Such improvements are aimed in particular at improving process control, improving environmental compatibility and reducing health risks of the process. The method should ideally also be simplified, in particular with regard to the safety requirements necessary for its implementation. Finally, it is also desirable to improve the economics of the process, for example by using simpler equipment, or by avoiding laborious purification processes.

Summary of The Invention

The object of the present invention is achieved by the process according to the invention for preparing diisocyanates of the formula (A),

wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof,

the method comprises the following method steps in the indicated order:

1) providing intermediates of formula (B) using a process employing lysine and urea

Wherein R and each R' are independently selected from alkyl, aryl, and combinations thereof; and

2) thermally cracking the intermediate of formula (B),

thus obtaining the diisocyanate of formula (A).

Detailed Description

The percentage data in the specification and claims are weight percentages (abbreviated as wt.%), unless explicitly stated otherwise. The yield is given as a percentage of the theoretical yield. The different embodiments described below can be combined with one another as long as this is technically possible and no contrary remarks are explicitly indicated. The terms "conversion" and "reaction" are used synonymously, as is usual in the prior art.

For the purposes of the present invention, the term "alkyl" includes branched and unbranched alkyl groups comprising cyclic and/or acyclic structural units wherein the cyclic structural units necessarily contain at least three carbon atoms. In the specification and in the claims, C1-CX alkyl refers to an alkyl group containing from 1 to X carbon atoms (X is a natural number). C1-C8 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, heptyl, and octyl.

For the purposes of the present invention, the term "aryl" includes cyclic aromatic molecular fragments (or groups), such as phenyl or naphthyl, in which one or more of the carbon atoms forming the ring may be replaced by N, O and/or S, for example in pyridyl. Preferably, none of the carbon atoms forming the ring is substituted with N, O and/or S.

For the purposes of the present invention, combinations of alkyl and aryl are molecular fragments comprising at least one alkyl group and at least one aryl group, such as benzyl and tolyl.

Optionally, the alkyl and aryl groups are functionalized. Here, the hydrogen atoms in the radicals are formally replaced by functional groups, preferably by hydroxyl groups (-OH) and/or amino groups (-NH)₂) And (4) substituting the groups.

If more than one group is required to be selected for a compound mentioned in the claims or in the description, the selection of said groups is independent of each other, irrespective of whether the selection is from one or more lists. Thus, if set forth in the list, they may be the same or different.

If the word "a" (e.g. "a diisocyanate" or "an alcohol") is used in the claims or in the specification, this is generally to be understood as meaning "at least one" (e.g. "at least one diisocyanate" or "at least one alcohol"), i.e. one or more than one. Such wording is not used in order to improve readability.

The process according to the invention is suitable for preparing diisocyanates of the formula (A)

Wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof,

r is preferably selected from C1-C8 alkyl, more preferably from methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl, in particular from methyl, ethyl and n-butyl.

For the purposes of the present invention, very particularly preferred diisocyanates of the formula (A) are the following racemic mixtures or the following corresponding L-enantiomers:

methyl ester (CAS number 4460-02-0, in the form of a racemic mixture; CAS number 45158-78-9, L-form), ethyl ester (CAS number 4254-76-6, in the form of a racemic mixture; CAS number 45172-15-4, L-form) and butyl ester (CAS number 24305-78-0, in the form of a racemic mixture; CAS number 1291098-99-1, L-form). These very particularly preferred diisocyanates are of particular economic importance.

The method according to the invention comprises at least method steps 1) and 2). The process according to the invention optionally comprises further process steps, which can be carried out before, during, between and/or after process steps 1) and 2).

The process using lysine and urea in process step 1) provides an intermediate of formula (B),

wherein R and each R' are independently selected from the group consisting of alkyl, aryl, and combinations thereof.

Here, a process using lysine and urea is understood to mean a process in which lysine, urea, at least one alcohol and optionally at least one base and/or at least one acid are reacted with one another.

Here, it is preferred either i) to react lysine and urea and to react the urea adduct formed further with alcohol to intermediate (B), or ii) to initially add lysine, to react this lysine with a base to form a carboxylic acid salt and to react said carboxylic acid salt with urea to form a urea salt which is either ii) a) reacted directly with alcohol to form intermediate (B), or ii) B) reacted with alcohol after intermediate reaction with acid back to carboxylic acid to form intermediate (B).

R and R' are preferably selected from C1-C8 alkyl groups, more preferably from methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups, in particular from methyl, ethyl and n-butyl groups.

It is also possible to initially charge in a suitable reaction vessel and thus provide the intermediate of formula (B). Processes for the preparation of intermediates of formula (B) are known in the art.

In process step 2), the intermediate of formula (B) is subjected to thermal cleavage. The diisocyanate of the formula (A) is thus obtained. The thermal cleavage is preferably mediated by a mediator, more preferably by a metal-based catalyst, even more preferably by a tin (II) salt. Particular preference is given to using tin (II) halides, such as tin (II) chloride or tin (II) bromide. For the purposes of the present invention, an intermediary is either a compound capable of effecting the thermal cleavage or a compound which desirably accelerates the thermal cleavage. For the purposes of the present invention, the catalyst is either a compound capable of achieving the thermal cracking or a compound which ideally accelerates the thermal cracking, and it can be used in substoichiometric amounts based on the reactants, in the case of the present invention the intermediate of formula (B).

The thermal cleavage is optionally carried out in a solvent. Such optional solvents are selected from aprotic solvents. The optional solvent is preferably anhydrous. This means that the concentration of water in the solvent is not more than 1% by weight, preferably not more than 0.1% by weight, more preferably not more than 0.01% by weight. The optional solvent is preferably high boiling, i.e. has a boiling point of preferably at least 200 ℃, more preferably at least 250 ℃. A preferred example is Marlotherm SH. The optional solvent and other volatile components are removed, for example by distillation, before the thermal cracking is started.

The temperature during the thermal cracking is preferably in the range from 160 to 240 ℃, more preferably in the range from 170 to 230 ℃, in particular in the range from 180 to 220 ℃. The diisocyanate formed is preferably distilled off continuously from the reaction vessel during the reaction.

The duration of the thermal cracking reaction depends on various parameters and can be selected as appropriate by the person skilled in the art.

In a first preferred embodiment, the intermediate of formula (B) (hereinafter referred to as "variant 1") is obtained by the following process steps:

a.1) providing lysine;

a.2) reacting the lysine with urea to form a urea adduct of formula (C),

and

a.3) reacting the urea adduct of formula (C) with an alcohol to form an intermediate of formula (B).

In a second preferred embodiment, the intermediate of formula (B) (hereinafter referred to as "variant 2") is obtained by the following process steps:

b.1) providing lysine;

b.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

b.3) reacting the lysine salt of the formula (Z) with urea to form a urea salt of the formula (Y),

wherein X is a counterion;

b.4) reacting the urea salt of the formula (Y) with an alcohol to form the carbamate of the formula (X),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof, and

x is a counterion;

b.5) reacting the carbamate of formula (X) with an acid to form the carboxylic acid of formula (W),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof; and

b.6) reacting the carboxylic acid of formula (W) with an alcohol to form an intermediate of formula (B).

In a third preferred embodiment, the intermediate of formula (B) (hereinafter referred to as "variant 3") is obtained by the following process steps:

c.1) providing lysine;

c.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

c.3) reacting the lysine salt of formula (Z) with urea to form a urea salt of formula (Y),

wherein X is a counterion;

c.4) reacting the urea salt of formula (Y) with an alcohol to form an intermediate of formula (B), optionally with prior protonation of the carboxylate.

Variant 1 advantageously comprises very few reaction steps and is therefore cost-effective, also in view of the yields that can be achieved in the individual process steps.

Variant 2 allows a large number of different possible options for the targeted introduction of the group R. For example, it is also possible to allow the incorporation of higher molecular weight groups into the diisocyanates, which otherwise may lead to problems in the thermal cleavage of the intermediates of the formula (B), since otherwise all the groups R and R' in the intermediates of the formula (B) are generally identical. Variant 3 achieves lower byproduct formation, however the salt byproduct formed must be removed. Preferably, either variant 1 or variant 2 is used. More preferably, variation 1 is used.

Variations 1, 2 and 3 are used to provide intermediates of formula (B). These variants can therefore be carried out in addition to or before process step 1).

Lysine is provided in process steps a.1), b.1) and c.1). To this end, it is, for example, initially charged to a suitable reaction vessel or added to a suitable reaction mixture. For this purpose, lysine is used in the form of L-lysine, R-lysine or as a mixture thereof (for example, in the form of racemate).

In process steps a.2), b.3) and c.3), lysine is reacted with urea to form a urea adduct of the formula (C) or a lysine salt of the formula (Z) is reacted with urea to form a urea salt of the formula (Y).

(in process steps a.2), b.3) and c.3) the molar ratio of urea is preferably in the range of 1:1 to 5:1 based on the primary amine groups of the lysine or lysine salt of the formula (Z). This means that the calculated amount of urea used is 1 to 5 molecules per primary amine group of the lysine or per primary amine group of the lysine salt. The best yield of the desired reaction product is thus obtained. More preferably, the molar ratio is in the range of 1.25:1 to 3:1, and even more preferably in the range of 1.4 to 2.5.

The reactions in process steps a.2), b.3) and c.3) are preferably carried out in a polar solvent, more particularly in water, taking into account their solubility properties and advantageous ecological characteristics.

The reactions in process steps a.2), b.3) and c.3) are preferably carried out at temperatures of from 50 to 120 ℃, more preferably from 80 to 110 ℃.

Typically, the reaction is carried out until complete conversion of at least one reactant, which is usually lysine or a lysine salt of formula (Z). The skilled person can test this by standard analytical methods, for example by gas chromatography. The end point of ammonia formation (which can be detected, for example, by wet pH paper in the off-gas) can also be used as a means of determining the completion of the reaction. The duration of the reaction depends on various parameters, such as temperature. The reaction time is usually in the range of 10 minutes to 1200 minutes, preferably 60 to 600 minutes, more preferably 120 to 420 minutes.

In process steps a.3), b.6) and c.4), the intermediate of formula (B) is formed from a urea adduct of formula (C), from a carboxylic acid of formula (W) or from a urea salt of formula (Y) with an alcohol.

For the purposes of the present invention, the alcohols are organic compounds having at least one, preferably (only) one, hydroxyl group. It comprises an alkyl group, an aryl group, or a combination thereof having at least one hydroxyl group bonded thereto. The alcohol is preferably selected from the group consisting of C1-C8 alcohols, more preferably from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol and tert-butanol.

In order to achieve a rapid and as quantitative as possible reaction of the urea adduct of the formula (C), the carboxylic acid of the formula (W) or the urea salt of the formula (Y), the one alcohol is used in stoichiometric excess based on the components mentioned. More preferably, the molar ratio of the one alcohol is in the range of 2:1 to 100:1 based on the urea adduct of formula (C), the carboxylic acid of formula (W) or the urea salt of formula (Y). Even more preferably, the molar ratio is in the range of 5:1 to 50:1, desirably in the range of 10:1 to 25: 1. When more than one alcohol is used, the sum of all molar amounts of the alcohols (Stoffmenge) is within the specified range.

The pressure during the reaction with the alcohol in process steps a.3), b.6), c.4) is preferably in the range ≥ 1 bar, preferably in the range from 1 to 35 bar, more preferably in the range from 1 to 25 bar, at least during part of the time.

The pressure during the reaction with the alcohol in process steps a.3), b.6), c.4) is preferably in the range mentioned for 1 to 20 hours, more preferably 3 to 10 hours, in particular 4 to 6 hours.

The reaction with the alcohol in process steps a.3), b.6), c.4) is preferably carried out at a temperature in the range from 150 to 300 ℃, preferably at a temperature of from 180 to 230 ℃, more preferably at a temperature of from 190 to 220 ℃. In principle, in the process according to the invention, excessively high temperatures can lead in unfavorable cases to a reduction in the yield as a result of decarboxylation or similar decomposition reactions. If the temperature is too low, an undesirably long reaction time may be required in order to achieve good yields.

Typically, the reactions in process steps a.3), b.6), c.4) are carried out until the conversion of the urea adduct of the formula (C), the carboxylic acid of the formula (W) or the urea salt of the formula (Y) is as complete as possible. For this purpose, the reaction with the alcohol in process steps a.3), b.6), c.4) is preferably carried out at the temperature range mentioned for a period of from 1 to 20 hours, preferably from 3 to 10 hours, in particular from 4 to 6 hours. Reaction times outside the reaction times mentioned may also be advantageous, depending on the relevant reaction kinetics.

An esterification catalyst can optionally be used in process steps a.3), b.6), c.4). Suitable esterification catalysts are known to those skilled in the art. For example, acids such as sulfuric, methanesulfonic or phosphoric acid, and metal organic compounds such as the common tin or titanium salts can be used.

In process step b.2) or c.2), lysine is reacted with a base to form a lysine salt of the formula (Z). The base (in process steps b.2) and c.2)) is not subject to further restrictions. Any base suitable for removing the protons of the lysine and for forming the lysine salt of formula (Z) may be used. A large number of bases suitable for this are known to the person skilled in the art. Particularly suitable bases are metal hydroxides (in particular alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide), amines and ammonia.

X (in formula (Z)) is a counterion. X is formed from the base used. X is preferably selected from the group consisting of alkali metal ions, in particular lithium, sodium or potassium ions, and ammonium ions. If X has multiple positive charges, it is therefore bound to more than one lysine anion, for example in Mg (Lys)₂In (1).

Typically, the molar ratio of base used in process steps b.2) and c.2) is at least 1:1 based on the lysine. The amount of base required depends inter alia on its base strength. It is preferably used in a molar ratio of 1.1:1, more preferably in a molar ratio of 1.05:1, based on lysine.

Optionally, the reaction of lysine with a base in process steps b.2) and c.2) to form the lysine salt of the formula (Z) is carried out in a polar solvent. Suitable solvents are selected from water, Tetrahydrofuran (THF), dioxane and N, N-Dimethylformamide (DMF) and mixtures thereof. Water is particularly preferred for the reasons already mentioned above.

The reaction of lysine with a base to form the lysine salt of the formula (Z) in process step b.2) or c.2) is preferably carried out at a temperature in the range from 0 to 50 ℃, preferably at a temperature of from 20 to 30 ℃, more preferably at a temperature of from 20 to 25 ℃.

Typically, the reaction of lysine with a base (in process steps b.2) and c.2) to form the lysine salt of the formula (Z) is carried out until the conversion of the lysine is as complete as possible. Typical reaction times are in the range of from 1 second to 3 hours, preferably in the range of from 0.1 to 1 hour. The reaction generally takes place without delay (acid-base reaction). The reaction time is limited only by the exotherm that occurs.

In process step b.4), the urea salt of the formula (Y) is reacted with an alcohol to form the carbamate of the formula (X).

The same information applies for process steps a.3), b.6), c.4) with respect to details and options relating to the alcohol, the molar ratio of alcohol to urea salt of formula (Y), the reaction conditions (pressure, temperature, reaction time and optionally the use of an esterification catalyst).

In an embodiment of the invention, the alcohols used in process step b.4) and in process step b.6) are different. The alcohol used in process step b.4) is preferably selected from methanol, ethanol and butanol, and the alcohol used in process step b.6) is preferably selected from methanol, ethanol and butanol. This embodiment can also be used to introduce ester groups into the diisocyanate which are not otherwise available, for example esters which are formed starting from the alcohol when the alcohol is bonded to the carbamate group, which may interfere with the thermal cleavage of the corresponding intermediate of formula (B).

In process step b.5), the carbamate of the formula (X) is reacted to form the carboxylic acid of the formula (W). The acid (in process step b.5) is not subject to further restrictions. Any acid suitable for forming the carboxylic acid of formula (W) from the carbamate of formula (X) may be used according to the present invention. A large number of acids suitable for this are known to the person skilled in the art. The acid is preferably selected from inorganic acids (preferably sulphuric acid, hydrochloric acid, phosphoric acid) and organic acids (e.g. methanesulphonic acid and citric acid). Hydrochloric acid is particularly preferred.

Typically, the molar ratio of the acids used (in process step b.5) is at least 1:1, based on the carbamate of the formula (X). The amount of acid required depends inter alia on its acid strength. It is preferably used in a molar ratio of 1.2:1, more preferably in a molar ratio of 1.05:1, based on the carbamate of formula (X).

Optionally, the reaction of the carbamate of the formula (X) with an acid to form the carboxylic acid of the formula (W) in process step b.5) is carried out in a polar solvent. Suitable solvents are selected from water, Tetrahydrofuran (THF), dioxane and N, N-Dimethylformamide (DMF) and mixtures thereof. Water is particularly preferred for the reasons already mentioned above.

The reaction of the carbamate of the formula (X) with the acid to form the carboxylic acid of the formula (W) in process step b.5) is preferably carried out at a temperature in the range from 0 to 50 ℃, preferably at a temperature of from 20 to 30 ℃, more preferably at a temperature of from 20 to 25 ℃. Any exothermic heat that may occur may be absorbed by cooling.

Typically, the process of reacting the carbamate of the formula (X) with an acid to form the carboxylic acid of the formula (W) (in process step b.5) is carried out until the conversion of the carbamate of the formula (X) is as complete as possible. Typical reaction times are in the range of from 1 second to 1 hour, preferably in the range of from 0.1 to 0.5 hour.

In process step c.4), the urea salt of the formula (Y) is reacted with an alcohol to form the intermediate of the formula (B). For this purpose, optionally, intermediates can be used, which are not subject to further restrictions. The mediator typically has acidic or water absorbing properties. Any intermediate suitable for mediating the process of reacting the urea salt of formula (Y) with an alcohol to form the intermediate of formula (B) may be used. A large number of options suitable for this are known to the person skilled in the art. Useful examples include acidic molecular sieves, strong mineral acids (preferably sulfuric acid, hydrochloric acid, phosphoric acid) and strong organic acids (e.g., methanesulfonic acid). Particularly advantageous for this purpose are those selected from the group consisting of sulfuric acid, methanesulfonic acid, hydrochloric acid and mixtures thereof.

Typically, the mediator is used in catalytic amounts (in process step c.4) based on the urea salt of formula (Y). The amount of mediator required depends inter alia on its performance. It is preferably used in an amount of 0.001 to 1% by weight, based on the urea salt of formula (Y).

Optionally, the reaction of the urea salt of formula (Y) with an alcohol to form the intermediate of formula (B) (in process step c.4) is carried out in a polar solvent. Suitable solvents are selected from water, Tetrahydrofuran (THF), dioxane and N, N-Dimethylformamide (DMF) and mixtures thereof.

The reaction of the urea salt of the formula (Y) with an alcohol to form the intermediate of the formula (B) in process step c.4) is preferably carried out at a temperature in the range from 150 to 300 ℃, preferably at a temperature of from 180 to 230 ℃, more preferably at a temperature of from 190 to 220 ℃.

Typically, the reaction of the urea salt of the formula (Y) with an alcohol to form the intermediate of the formula (B) in process step c.4) is carried out until the conversion of the urea salt of the formula (Y) is as complete as possible. Typical reaction durations are in the range from 1 to 20 hours, preferably from 3 to 10 hours, in particular from 4 to 6 hours.

The method preferably comprises a further method step (3) after and/or during method step 2):

3) the diisocyanate of formula (A) is purified, preferably by fractional distillation.

Particularly preferably, the diisocyanate is purified by distillation, preferably by fractional distillation, at least during the thermal cracking. This means that the diisocyanate has already been removed from the reaction mixture during its formation. This sometimes improves the reaction yield, in particular the space-time yield. In order to achieve the best yields, it may sometimes be necessary to carry out further purification, even after the thermal cracking has ended.

The distillation is preferably carried out under reduced pressure. The preferred pressure for the distillation is in the range of from 0.01 to 200 mbar, preferably in the range of from 0.1 to 100 mbar, more preferably in the range of from 1 to 50 mbar. The possibly thermally unstable diisocyanates are thus purified more gently, improving the yield. Alternatively, the purification can also be carried out after the end of process step 2).

In a preferred embodiment, the process according to the invention for preparing the diisocyanates of the formula (a) comprises the following process steps in the order indicated:

wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof,

a.1) providing lysine;

a.2) reacting the lysine with urea to form a urea adduct of formula (C),

and

a.3) reacting the urea adduct of formula (C) with an alcohol to form an intermediate of formula (B);

or

b.1) providing lysine;

b.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

b.3) reacting the lysine salt of the formula (Z) with urea to form a urea salt of the formula (Y),

wherein X is a counterion;

b.4) reacting the urea salt of the formula (Y) with an alcohol to form the carbamate of the formula (X),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof, and

x is a counterion;

b.5) reacting the carbamate of formula (X) with an acid to form the carboxylic acid of formula (W),

wherein each R' is independently selected from alkyl, aryl, and combinations thereof; and

b.6) reacting a carboxylic acid of formula (W) with an alcohol to form an intermediate of formula (B);

or

c.1) providing lysine;

c.2) reacting the lysine with a base to form a lysine salt of the formula (Z),

wherein X is a counterion;

c.3) reacting the lysine salt of formula (Z) with urea to form a urea salt of formula (Y),

wherein X is a counterion;

c.4) reacting the urea salt of formula (Y) with an alcohol to form an intermediate of formula (B);

thereby providing an intermediate of formula (B),

and

wherein R and each R' are independently selected from alkyl, aryl, and combinations thereof;

2) thermally cracking the intermediate of formula (B),

and optionally

3) Purification of the diisocyanate of formula (A), preferably by fractional distillation,

thus obtaining the diisocyanate of formula (A).

In a further aspect, the present invention also relates to diisocyanates of the formula (A) prepared directly by the process according to the invention,

wherein R is selected from the group consisting of alkyl, aryl, and combinations thereof.

The analogy applies, if applicable, to the diisocyanates directly obtained therefrom, for the details and embodiments set forth in the present description and in the claims relating to the process according to the invention. To avoid unnecessary repetition, detailed description thereof will not be repeated here.

INDUSTRIAL APPLICABILITY

The process according to the invention and the diisocyanates obtained therefrom can be used for a large number of application purposes. For example, the process according to the invention can be used to provide diisocyanates for use in polyurethanes. Such polyurethanes are in turn useful in many industries. Examples thereof include the preparation of biocompatible materials for medical applications or biodegradable products for use in e.g. the agricultural field, or environmentally compatible products which are usually prepared from renewable raw materials.

Detailed Description

The invention is illustrated in more detail by the following examples without restricting the subject matter.

Examples

Gas Chromatography (GC): GC was performed using a Trace 1300 instrument using a 15 meter Zebron ZB-1HT column. It was heated from 50 ℃ to 270 ℃ at a rate of 10 ℃/min. The amine number is determined in accordance with DIN 53176: 2002. The acid number is determined in accordance with DIN EN ISO 2114: 2002.

Reaction 1: reacting lysine to form a urea adduct of the formula (C) (process step a.2)

A10L pressure reactor was initially charged with 584.4g (4.0mol) of L-lysine (method step a.1)). To this was then added 600g of deionized water, followed by 720.7g (12.0 mol; 1.5 equivalents based on the primary amine groups of the lysine) of urea, and finally 600g of deionized water. The reaction mixture was heated to 105 ℃ with stirring and heated at reflux for 390 minutes. The reaction mixture was then cooled to room temperature and the water was distilled off under reduced pressure. The reaction mixture thus obtained is used in the subsequent reaction 2. Product purity was determined according to the excess urea¹³C-NMR is>90％。

Reaction 2: reacting the urea adduct of formula (C) to form an intermediate of formula (B) (process step a.3)

To the mixture in the pressure reactor from reaction 1 was added 2209.9g (48.0mol) of ethanol. The pressure reactor was heated to 205 ℃ with stirring by means of a W-4010 thermostat device (Lauda LTH 350). This was accompanied by a pressure rise, which was maintained at 25 bar overpressure for 5 hours, at which time pressure was released manually through a valve. After 5 hours, the reaction mixture was cooled to room temperature. The volatile fractions were then removed by distillation under reduced pressure. Purity of the product is according to¹³C-NMR was about 70%. Has an amine number of<1, acid value 14mg KOH/g.

Reaction 3: thermal cleavage of the intermediate of formula (B) (method step 2)

250.0g of the product obtained in reaction 2 (method step 1)) were mixed with 50mg of tin (II) chloride dissolved in 50mL of ethanol and the mixture was heated slowly with stirring in an apparatus consisting of a multi-necked flask equipped with a Liebig condenser, which initially resulted in distilling off residual amounts of ethanol at a bottom temperature of about 80 ℃. It was then concentrated until molten. Here, the bottom temperature was about 150 ℃. The pressure was then reduced to 0.5 mbar and the bottom temperature was slowly and continuously increased. Starting from a bottom temperature of about 190 ℃, a diisocyanate condensate (boiling point of about 110 ℃ at the indicated pressure) is formed. The bottom temperature was slowly raised up to 235 ℃ and a total of 60.3g of diisocyanate were collected (yield: 34% of theory). The removed ethanol was collected in a cold trap. The product was colorless, liquid, and about 95% pure by GC.