WO2008064887A1

WO2008064887A1 - A bislactamamide derivative as intermediate in the production of di i socyanate

Info

Publication number: WO2008064887A1
Application number: PCT/EP2007/010356
Authority: WO
Inventors: Aylvin Jorge Angelo Athanasius Dias; Bartholomeus Johannes Margretha Plum; Jacobus Antonius Loontjens
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2006-11-29
Filing date: 2007-11-29
Publication date: 2008-06-05
Anticipated expiration: 2009-05-29
Also published as: WO2008064887A8

Abstract

The invention relates to a method for preparing an intermediate compound for a diisocyanate, comprising reacting a diamine represented by the formula H2N-(CH2)0-Y-(CH2)p-NH2 wherein Y is selected from CH(OX) or CH(COOX), o and p each are an integer of 0-4, with the proviso that the sum of o and p is 4 or less, preferably 2, 3 or 4, X is a protective group, with a carbonylbislactam, preferably carbonylbiscaprolactam, thereby forming a compound with the formula (I) wherein each L is a lactam from the carbonylbislactam.

Description

DIISOCYANATE FROM NATURAL DIAMINE

This invention relates to a compound from which a diisocyanate can be made and to a method for preparing the compound. The present invention further relates to a method for preparing a diisocyanate, to a method for preparing a polymer from the diisocyanate, and to a method for preparing a shaped article comprising such polymer, in particular an implantable article.

Diisocyanates are compounds which can be polymerised with polyols, such as diols, to form polyurethanes. Polyurethanes may be used in various applications, e.g. in coatings, thermal insulation articles, adhesives, wheels, furniture, car components or construction sealants.

Polyurethanes may also be used in medical applications, e.g. as described in WO 2004/074342. These applications include medical coatings and bulk plastic medical devices such as catheters, leads for pacemaker, tubing, hospital bedding, surgical drapes, wound dressings, as well as in a variety of injection moulded devices and short-term implants. Polyurethanes are widely used because of their wide range of physical properties and biological properties. These are toughness and flexibility to biocompatibility, and hemocompatibility.

The use of polyurethane in a medical application requires the polymer to have a low as possible toxicity.

A common way of preparing a diisocyanate involves the phosgenation of a diamine in a suitable solvent. However, phosgene is poisonous and presents certain handling risks. This is particularly in cases wherein a small volume of a specialised medical grade polurethane is prepared. Accordingly, the manufacturing process is potentially hazardous.

Moreover, especially remnants of phosgene may be found in the product, which makes phosgenation an undesired route to obtain the diisocyanate, in particular in case the diisocyanate is intended to be used in the manufacture of a medical article, such as an implantable article. Also, this method is sensitive to side reactions, such as cyclisation.

It is also possible to prepare a diisocyanate from a diazide. However, such a process is dangerous, since azides can lead to explosion. Thus, special precautions must be taken to maintain safety, which add to the complexity of the process and make the diisocyanate production from azide on an industrial scale impractical. The present inventors have further found that undesired cyclisation reactions may occur in a process such as described above, in particular in case the diamine is a short chain compound for instance a natural diamine, such as lysine or ornithine. Furthermore cyclisation reactions may occur in a process as disclosed in WO-A-03070784 in which compounds comprising unprotected functional groups are reacted with carbonylbiscaprolactam. These cyclisation reactions which occur between the functional group and the lactam leads to undesired side products.

DE 196 27 552 describes the preparation of an organic polyisocyanate by reacting polyamine and a carbamide acid ester or urea, to provide a monomeric polyurethane and thermally cleave the polyurethane to obtain the polyisocyanate and an alcohol. Usually the reaction is carried out in the presence of a catalyst and at a temperature of up to 250 ⁰C to carry out the cleaving within an economically advantageous time-span. Moreover, handling isocyanates at high temperature results often in polymeric side products. It is contemplated that in particular in the reaction with urea a volatile toxic intermediate may be formed, such as H-N=C=O.

It is an object of the present invention to provide a novel compound from which a diisocyanate can be prepared.

It is in particular an object to provide a method for preparing a diisocyanate from the novel compound that overcomes one or more of the above identified drawbacks of said prior art methods.

It is more in particular an object of the present invention to provide a method for preparing a diisocyanate whereby undesired side products can be avoided.

It is further an object to provide a method for preparing such compound from which a diisocyanate can be made, in particular a diisocyanate with a low level of impurities that may impose a health risk, more in particular a diisocyanate of sufficient quality for use in the preparation of a medical article, such as an implantable article, in particular an artificial meniscus.

One or more other objects which may be solved by the present invention will follow from the description, below, and/or claims.

It has now been found that one or more objects underlying the invention are met by providing a specific intermediate compound from which a diisocyanate can be made.

Accordingly, the invention relates to a compound represented by formula I H H O

-N (CH₂)₀ Y (CH₂)p N C L

[I]

wherein

Y is selected from CH(OX) or CH(COOX); o and p each are an integer of 0-4, with the proviso that the sum of o and p is 4 or less, preferably 2, 3 or 4; X is a protective group; and each L is a lactam, which may be the same or different.

Further, the invention relates to a method for preparing the intermediate compound for a diisocyanate, comprising reacting a diamine represented by the formula H₂N-(CH₂)_O-Y-(CH₂)_P -NH₂, wherein Y, o and p are as identified above, with a carbonylbislactam, preferably carbonylbiscaprolactam, thereby forming a compound with formula I, wherein L is a lactam from the carbonylbiscaprolactam.

The invention provides a compound and a method to prepare such a compound which is suitable for safely preparing a diisocyanate, without requiring the use of a highly toxic reagent such as phosgene or HNCO or a highly explosive reagent such as an azide.

The invention further provides a compound and a method to prepare such a compound which is suitable for preparing a diisocyanate, without the formation of undesired side products.

Further, it has been found that a diisocyanate can be formed from a compound represented by formula I, whilst cyclisation reactions are avoided or at least reduced, compared to a known method, in particular a method wherein the diisocyanate is prepared from by phosgenation of the diamine. Thus, it is possible to obtain the diisocyanate in a high yield, if desired.

In particular, the compound of formula I may be used in the preparation of a polymer, especially a polymer of medical grade. Preferred application areas include polymers for implantable articles, such as bone substitutes; cartilage substitutes; vascular substitutes, for instance grafts; housing for implantable devices, for instance pacemakers; and tubing, catheters and drains; medical coatings; leads for pacemaker; hospital bedding; surgical drapes, wound dressings; injection moulded devices; porous implantable articles, tissue engineering and short-term implants.

A preferred example of a cartilage substitute is an artificial meniscus. Accordingly, the invention further relates to a compound represented by formula I in the manufacture of an implantable article for treating a malfunctioning body part, in particular a malfunctioning joint, more in particular a malfunctioning knee.

The compound of formula I may in principle be made from any diamine, having two primary amines, meeting the above definition for -(CH₂)₀-Y- (CH₂)_P-. Moiety Y, providing a carboxylic acid or a hydroxyl functional group which is preferably protected, in view of the synthesis of the compound with formula I and/or in view of its further use such as in the preparation of a diisocyanate (see Formula II, below). Suitable protective groups include protective hydrocarbons, such as phenyl and alkyls, in particular C1-C4 alkyls, such as methyl, ethyl, propyl, n-butyl, t- butyl; oxazines; oxazolines; imidazole, t-butyloxycarbonyl groups and protective organo-silicon compounds, such as Si(OR)₃ and SiR₃, wherein R is a hydrocarbon group, in particular a hydrocarbon selected from phenyl and alkyls, more in particular a C1-C4 alkyl, as mentioned above. The skilled person will know how to protect the functional group with any of these protective groups or another suitable protective group, based on the information disclosed herein and common general knowledge.

Preferred examples of suitable diamines are in particular lysine provided with a protective group or ornithine provided with a protective group. In particular in case the compound is to be used in the manufacture of an implantable article, the diamine is preferably a natural diamine chosen from lysine and ornithine. Lysine has been found particularly suitable to prepare a diisocyanate for the preparation of a polyurethane from which an implant, especially an artificial meniscus, may be manufactured. A natural diamine is in particular preferred in case the implant is biodegradable, because as the implant degrades, the diamine may be released into the body. The term "natural" is in particular used herein as being naturally present in a human body.

The diamine may in principle be reacted with any carbonylbislactam. Usually, the lactam ring comprises 4-16 carbon atoms, including the carbon from the carbonyl. Preferably the lactam ring comprises 6 carbon atoms, including the carbon from the carbonyl group. Methods to prepare carbonylbislactam are known in the art. Good results have been achieved with carbonylbiscaprolactam, a compound inter alia obtained from DSM, Geleen, the Netherlands.

The reaction of the diamine and the carbonylbislactam can take place in a melt of the reaction components or in a suitable solvent. Suitable solvents include aromatic solvents, e.g. toluene, xylene; esters, in particular formiate esters and acetate esters, more in particular ethylacetate; halogenated alkanes, e.g. chloroform; aliphatic alcohols, e.g. methanol, ethanol, a propanol; and mixtures thereof.

Good results have in particular been achieved in toluene and in an ester, in particular ethyl acetate. An ester, such as ethyl acetate, has surprisingly been found to be a highly inert solvent, as it has been reported that amines and esters may react with each other. Advantages of esters, such as ethyl acetate, include low toxicity and the ease of removal from the product.

The molar ratio diamine:carbonylbislactam usually is at least about stoichiometric, i.e. at least about 2:1.

The reaction temperature may be chosen within wide limits. Usually the temperature is less than 150 ⁰C, to avoid undesirable levels of side reactions. Preferably, the reaction temperature is 125 ⁰C or less, in particular 100 ⁰C or less.

The temperature is usually higher than 25 °C, preferably at least 50 ⁰C, in particular at least 60 ^CC, more in particular at least 80 ⁰C to reduce reaction time.

The reaction time may suitably be chosen, depending upon the reaction temperature, desired yield and one or more optionally present aids, such as a catalyst. A suitable catalyst may for instance be chosen from the group consisting of acids and bases, including Lewis acids and Lewis bases.

Examples of acids, including Lewis acids, that are suitable as a catalyst are LiX₁Sb₂O₃, GeO₂ en As₂O₃ ,BX₃₁MgX₂, BiX₃, SnX₄, SbX₅₁FeX₃, GeX₄, GaX₃₁HgX₂, ZnX₂₁AIX₃JiX₄₁MnX₂, ZrX₄, R₄NX₁ R₄PX₁ HX₁ wherein X is selected from the group consisting of I, Br₁CI, F₁OR, acetylacetonate and compounds with the formula

in which formula R and R' are independently selected from the group consisting of alkyl, aryl, alkoxy and aryloxy. Brόnstedt acids, such as H₂SO₄, HNO₃, HI, HCI, HBr, HF, H₃PO₄,

H₃PO₃, RH₂PO₂, RH₂PO₃, R [(CO)OH]_n , n being an integer in the range of 1-6, are also suitable. In these Brόnstedt acids, R represents an alkyl or aryl, in particular C1- C20 alkyl or aryl.

Examples of bases which are suitable as a catalyst are: alkali metal hydrides, earth alkali metal hydrides, hydroxides, C1 -20 alkoxides and phenolates, NR_nH₄._nOH (R=C1-C20 alkyl or aryl), triamines, such as triethylamine, tributylamine and trioctylamine, and cyclic amines, such as diazabicyclo [2,2, 2] octane (DABCO), dimethylaminopyridine (DMAP), guanidine and morpholine.

In particular in the absence of a catalyst, the reaction time will usually be at least about 1 hour, more in particular at least 2 hours. In particular in case the diamine, comprises a protected functional group {i.e. Y is present) a reaction time of at least 6 hours, at least 24 hours, or at least 36 hours may be preferred, for improved conversion.

Usually a reaction time of 24 hours or less, in particular of 12 hours or less, more in particular of 2 hours or less. A longer reaction time may be desired for improved conversion, for instance the reaction may be continued for up to 24 hours, for instance up to 36 hours or even for 60 hours or more.

The compound with formula I obtained from the above described reaction may be purified, e.g. by recrystallisation.

From the compound represented by formula I, the corresponding diisocyanate can be made. This diisocyanate may be represented by formula Il

O=C=N (CH₂)₀ Y (CH₂)_p N^C=O _[M] wherein Y, o and p have the same meaning as identified above.

The diisocyanate is suitably made by heating the compound represented by Formula I to a suitable temperature.

Although generally not necessary, the formation of the diisocyanate may be carried out in the presence of a catalyst. Suitable catalysts include those described in K. Frisch, Advances in Urethane Science and Technology, vol 1 (1971), p 1-30. Specific examples include dialkyl tin oxides, such as dibutyl tin oxide, and tetraalkyltitanate, such as tetrabutyl titanate. This may in particular be advantageous in case the protective group X has been removed.

A desired temperature depends to some extent on the lactam. Usually a temperature above 150 ⁰C is used, preferably a temperature of 160 ⁰C or more. It is envisaged that a lower temperature may be sufficient, in particular in case the reaction is carried out in the presence of a suitable catalyst, such as a tin catalyst. In an effort to avoid undesired side reactions such as polymerization of the formed diisocyanate, the temperature is usually 225 ⁰C or less. Preferably, the temperature is 215 ⁰C or less, in particular 200 ⁰C or less, more in particular 180 ⁰C or less.

Depending upon the temperature, the reaction time may be chosen within suitable limits, e.g. in the range of about 1 min. to about 3 hours.

The diisocyanate may be purified, e.g. by distillation. At least the removal of the lactam (originating from the carbonylbislactam) preferably takes place above 150 ⁰C, in particular up to 225 ⁰C more in particular up to 200 ⁰C. Alternatively, the product to be purified is rapidly cooled to about 25 ⁰C or less, after which the diisocyanate is isolated.

In particular, purification may comprise extraction with water or an aqueous solution - which may comprise an agent to increase the solubility of caprolactam in water, in particular CaCI₂ - whereby caprolactam is removed from the crude product. Subsequently, unreacted blocked isocyanate may be separated from the diisocyanate by distillation.

The protective group may be removed from the diisocyanate, if desired. In particular, it may be removed before or after polymerizing the diisocyanate. Preferably it is removed after the polymerisation. After it has been deprotected, the functional group may be used to couple an active agent to the compound. The protective group may be removed by a chemical route.

The active agent may in principle being any agent having a specific functionality. In particular the active agent may be selected from pharmaceuticals, stabilisers, antithrombotic moieties and moieties increasing hydrophilicity or moieties increasing hydrophobicity.

The active agent may for instance be selected from cell signalling moieties, moieties capable of improving cell adhesion to the compound/polymer/article, moieties capable of controlling cell growth (such as stimulation or suppression of proliferation), antithrombotic moieties, moieties capable of improving wound healing, moieties capable of influencing the nervous system, moieties having selective affinity for specific tissue or cell types and antimicrobial moieties. The moiety may exert an activity when bound to the remainder of the compound/polymer/article and/or upon release therefrom. Examples of active agents that may be coupled include perfluoralkanes (increasing hydrophobicity); polyalkylene oxides, such as polyethylene oxide and polypropylene oxide (increasing hydrophilicity and/or for reduced fouling); polyoxazolines; amino acids; peptides, including cyclic peptides, oligopeptides, polypeptides, glycopeptides and proteins, including glycoproteins; nucleotides, including mononucleotides, oligonucleotides and polynucleotides; and carbohydrates.

For instance, an amino acid may be linked for stimulating wound healing (arginine, glutamine) or to modulate the functioning of the nervous system (asparagine). In a preferred embodiment, the bioactive moiety is a peptide, more preferably an oligopeptide. Peptides or epitopes with specific functions are known in the art and may be chosen based upon a known function. For instance, the peptide may be selected from growth factors and other bioactive peptides.

The diisocyanate obtained in accordance with the invention may be used to prepare a polymer, for instance a polyurethane, a polyamide, a polythio- urethanes or a polyurea. Suitable polymerisation techniques are known in the art.

In particular, the diisocyanate may be polymerised together with one or more polyols. The polyol may be a monomeric or a polymeric polyol.

Suitable monomeric polyols include glycerol and C1-C6 diols, such as 1 ,2-ethane diol, 1 ,2-propane diol, 1 ,3-propane diol, 1 ,4-butane diol, neopentyldiol, cyclohexyldiol and butene diol.

Suitable polymeric polyols include polyalkylene oxides, polymers comprising one or more polyalkylene oxide segments and at least one other segment, polyester polyols, and polymers comprising one or more polyester polyol segments and at least one other segment.

Preferred polymeric polyols include polyethylene oxide, polypropylene oxide, polytetramethylene oxide, polyester diols, polycarbonate diols, α,ω- hydroxypolybutadiene, polyurethane diols, and copolymers thereof.

It is also possible to polymerise the diisocyanate with a polyamine, in particular a diamine, to form a polyurea. Preferred polyamines include polyoxyalkyleneamines, in particular amine terminated polyakylene glycols, such as of an polyalkylene glycol mentioned above. Commercially available are inter alia amine- terminated polypropylene oxides and amine-terminated polyethylene oxides, e.g. under the trademark Jeffamine®. Compositions comprising monomeric or polymeric diols and monomeric or polymeric diamines can be used as well.

The polymerization with a compound having one or more unsaturated carbon-carbon bonds may in particular be advantageous in case the polymer is to be cross-linked. The polymer, such as a polyurethane, prepared according to the invention may in particular be a segmented polymer. The segments chosen allow a wide variety of properties which may be tailored. For instance the polyurethane may comprise one or more soft segments that provide flexibility and one or more hard segments that provide strength. A segmented polyurethane may in particular be prepared by a method for preparing a polyurethane wherein a macrodiol, a diisocyanate and a chain extender, the chain extender comprising a (cyclo) aliphatic diol, are used, comprising: a) reacting either the macrodiol or the chain extender with an excess of diisocyanate, resulting in a macrodiisocyanate or a reaction product of the diisocyanate and the chain extender, b) removing the remaining unreacted diisocyanate, c) reacting, the macrodiisocyanate with the chain extender or the macrodiol with the reaction product, wherein a) and c) are carried out in the substantial absence of a catalyst. In more detail, such method is described in WO 2004/074342 of which the contents are incorporated herein by reference. It is also possible to prepare a polymer directly from the compound represented by formula I. Polymerisation can be done in essentially the same manner as when using a diisocyanate, in particular by reacting the compound of formula I with polyols, such as diols, or polyamines, such as diamines. During the polymerisation caprolactam is usually released as a side product, which may be removed from the polymer. In particular, in case a porous article is made, such as a porous implant, for instance a meniscus implant, the caprolactam can easily be washed out. In fact, as porous articles are often made by blending the polymer (or the starting materials that are to be polymerised) with a matrix material for forming the pores (such as a sugar or a salt), which matrix material is washed out after the article is formed, removal of caprolactam may be accomplished without needing an extra reaction step. Thus, the preparation of an article, such as a porous implant, by directly polymerising the compound of formula I may be advantageous in that a reaction step (deblocking the blocked isocyanate moieties) may be omitted.

The polymerisation may take place in a mould, such that a shape article is formed, as the polymer is formed or first the polymer may be made from which - if desired - the shaped article may be formed. Suitable techniques are known in the art.

The polymer, in particular the polyurethane, can be processed using extrusion, injection moulding, film blowing, solution dipping, and/or two-part liquid moulding.

If desired, a porous material may be formed, for instance in an implant to allow in-growth of cells or even vasculature. A porous material may for instance be formed by

- dissolving the polymer in a solvent, - adding particulate material to the polymer solution or to the solvent prior to dissolving the polymer, under conditions wherein the particulate material remains substantially undissolved,

- solidifying the polymer from the polymer solution containing the particulate matter, e.g, by precipitation or drying, resulting in a solid polymer comprising the particulate matter, and thereafter

- removing the particulate matter.

Removal may for instance be accomplished by contacting the solid polymer with a liquid that is a solvent for the particulate matter but not for the polymer. Particularly suitable is a method for making a porous scaffold from the polymer comprising: a) providing a homogeneous solution of the polymer in a solvent wherein the polymer-solvent combination is chosen in such a way that for the chosen combination liquid-liquid phase separation occurs, upon cooling down, at a temperature (TNq) that is higher than the crystallization temperature of either the polymer (Tc₁ p) or the solvent (Tc, s), b) adding a particulate material that is insoluble in the solvent, c) cooling down the mixture obtained in b) at a rate that allows liquid-liquid phase separation to result in the desired micropore morphology for the porous scaffold, to a temperature below the crystallization temperature of either the polymer (Tc, p) or the solvent (Tcfs) d) washing the mixture obtained in c) with a non-solvent, wherein the polymer is insoluble, but wherein the particulate material can be dissolved, at a temperature below the melting temperature of the polymer in solution (Tm, p), or at a temperature below the melting temperature of the solvent (Tm, s) for a time sufficient to allow dissolution of the particles of the particulate material. Such method is described in more detail in WO 2004/07342. It is for instance highly suitable for providing a meniscus implant. The polymer prepared according to the invention, such as a polyurethane may be used to provide a coating, which can be hydrophilic or hydrophobic. It can be used to provide an antimicrobial, non-thrombogenic, drug releasing, and/or lubricious coating. One or more biological functions may be provided in combination with specific physical properties such as toughness, strength and/or abrasion resistance.

The polymer may be advantageously used in a drug-eluting stent coating. Patients having bare-metal stents have a high rate of restenosis, or blockage. Specific drugs that can lower the restenosis rate may be incorporated into the polyurethane matrix and gradually released once the stent is in place. Drug-release rates are controlled by the ratio of the hard-segment to soft-segment content of the polymer and the specific chemistry. Another useful property for coating of a polymer, in particular a polyurethane, prepared according to the invention is its ability to stretch conformally with to the metal stent when the stent is deployed and expanded such that the coating must no delaminate, tear or break.

The invention will now be illustrated by the following examples without being limited thereto.

EXAMPLES

Materials

CBC (ALLINCO^®) (99%), Caprolactam, isophthaloylbiscaprolactam

(IBC) en 1 ,6-hexaandiisocyanaat blocked with caprolactam were obtained via DSM.

All other chemicals were purchased via Aldrich, Acros, Merck and used as such

Instrumentation

NMR Advance 300 MHz spectrometer (Bruker) and FTIR spectrometer were used to characterize the chemical structure and purity. TLC was carried out on Merck precoated silica gel 60 F-254 plates. Compounds were visualized by UV quenching and dipping in a 5% (m/m) K₂CO₃/0,75 %(m/m) KMnO₄/0,0625

%(m/m) NaOH solution in water. Example 1 Synthesis of L-lysine methylester (^hydrochloride.

78.59 g (0.4306 mol) L-lysine monohydrochloride were suspended in 500 ml methanol, whilst being cooled at 5⁰C.

65.54 g (0.5507 mol) thionylchloride were added whilst maintaining the temperature below 2O⁰C. The mixture was refluxed for 18 hours at 63°C. The clear solution was cooled to 20 °C within 4 hours. The L-lysine methylester dihydrochloride crystals were isolated by filtration and washed with acetone. The filtrate was concentrated by evaporation and cooled in ice to form further crystals, which were washed with acetone and added to the crystals that had already formed upon cooling the refluxed mixture. The purity was 99%, the yield 96.7%.

¹H-NMR (DMSO-d6) δ = 1.26 to 1.66 (4 H, CH₂CH₂CH₂CH₂), 1.84 (2H, m, CH₂CH) 2.74 (4H, t, NH₃CICH₂), 3.75 (3H, s, OCH₃), 3.95 (1 H, t, CH), 8.23 (3H, s, CH₂NH₃CI), 8.77 (3H, s, CHNH₃CI).

Example 2 Synthesis of compound of formula I from L-lysine methylester

114.41 g CBC (0.454 mol) were dissolved in 200 ml chloroform at ambient temperature by stirring. To this solution 53,34 g (0,228 mol) L-lysine methylester dihydrochloride were added. The resultant mixture was heated to 40°C, after which 65 ml triethylamine (0.467 mol) were added. The resultant mixture was refluxed at 76°C for 60 hours. The reaction was monitored with TLC.

Next the mixture was cooled to ambient temperature within 1 hour, during which triethylamine hydrochloride crystals were formed. The crystals were removed by filtration. The clear filtrate was concentrated by evaporation to obtain a viscous turbid orange oily liquid. This liquid was dissolved in a mixture of ethyl acetate and hexane (3:2, v:v). The resultant solution was washed with 400 ml 0.5 N HCI / 5% (m/m) CaCI₂/ 5% (m/m) NaCI (aq), thereafter with 400 ml 5% (m/m) CaCI₂ (aq) and thereafter with 400 ml 1 N Na₂CO₃.

Next, the solvent was removed by evaporation to yield a light yellow, viscous oily substance. The purity was 97 %, the yield 97,5%.

¹H-NMR (CDCI₃) δ = 1.41 to 1.83 (18 H, CH₂CH₂CH₂ ring +

CHCH₂CH₂CH₂), 2.70 (4H, t, CH₂CO) 3.27 (4H, q, NHCH₂), 3.74, (3H, s, OCH₃), 3.98 (4H, t, NCH₂), 4.48, (1 H, m, CH), 9.25 (1 H, broad, CH₂NH), 9.70 (1 H, broad, CHNH). 115°C and 4 mbar to give the 1 ,4-butanediisocyanate (bp 75⁰C). Purity 99%, yield 54%. ¹H-NMR (CDCI₃) δ = 1.72 (4H, m, CH₂CH₂CH₂CH₂), 3.39 (4H, m, CH₂NCO).

Example 3 Synthesis of L-lvsinediisocvanate methylester

The product of Example 5 (19.8588 g= 0.04534 mol) was heated and subsequently distilled using a capillary (nitrogen flow) at 180 ⁰C. Due to the presence of small amounts of solvent in the melt the pressure was gently reduced from 500 mbar to 30 mbar. After removal, all the solvent the residue was distilled at 1 mbar (Bp= 1 15- 125°C). The distillate was dissolved in 200 ml of a 1 :1 (v/v) mixture of ethyl acetate and hexane and extracted two times with 100 ml 5% (m/m) CaCI₂ (aq) en once with 200 ml water. Thereafter, the organic layer was dried, using Na₂SO₄, and after filtration the solvent was evaporated. Next, the product was distilled at 1 10⁰C and 0.2-0.5 mbar to yield in L-lysinediisocyanate methylester. The purity was 98%, the yield 22%. 1H-NMR (CDCI₃) δ = 1.49 to 1.67 (6H, CHCH₂CH₂CH₂), 3.36 (2H, t,

CH₂NCO) 3.83, (3H, s, OCH₃), 4.05 (1 H, q, CH), 4.48, (1 H, m, CH).

Comparative experiment A

5,04 g (0.02 mol) CBC and 1.46 g (0.01 mol) L-Lysine were mixed in a glass flask under a nitrogen atmosphere and heated to 125 ⁰C for 1 h. During the heating the mixture remained turbid, indicating that no mixing took place. Moreover, the mixture turned brown, and no indication of a reaction was seen (thin layer chromatography).

Comparative experiment B

5.04 g (0.02 mol) CBC, 1.46 g (0.01 mol) L-Lysine and 25 ml pyridine were mixed in a glass flask under a nitrogen atmosphere. The mixture was heated to 80 ⁰C for 1 hour. After the pyridine was removed by distillation the reaction mixture was analyzed with ¹H-NMR. The spectrum of the reaction mixture showed still a substantial amount of the starting compounds and a complex number of other peaks.

Comparative experiment C

The same experiment as in comparative example 2 was done, but now at 125 ⁰C for 1 hour. After the pyridine was removed by distillation the reaction mixture was analyzed with ¹H-NMR. The spectrum of the reaction mixture showed still the starting compounds and in addition a complex number of other peaks, which has not been assigned.

Comparative experiment D

1.46 g (0.01 mol) L-Lysine and 0.56 g (0.01 mol) KOH and 0.5 g water were mixed in a glass flask under a nitrogen atmosphere to prepare the potassium salt of lysine. After removal of the water 5.04 g (0.02 mol) CBC was added and the mixture was heated to 90 ⁰C for 30 minutes. From the ¹H- and ¹³C-NMR spectra it appeared that all the CBC had disappeared. From the complex spectrum it could be seen that the mono functional blocked isocyanate of lysine and caprolactam were the main products. The amount of caprolactam was much more than the amount that could be expected if one amine group would react with one CBC molecule. Apparently, CBC was decomposed.

Claims

Compound represented by the formula I

H H O

-N- ^■(CH₂)α "(CH₂)P -N-

[I]

wherein Y is selected from CH(OX) or CH(COOX) ; o and p each are an integer of 0-4, with the proviso that the sum of o and p is

4 or less;

X is a protective group; and each L is a lactam, which may be the same or different.

Method for preparing a compound of formula I comprising reacting a diamine represented by the formula H₂N-(CH₂)_O-Y-(CH₂)_P-NH₂ wherein

Y is selected from CH(OX) or CH(COOX) ; o and p each are an integer of 0-4, with the proviso that the sum of o and p is

4 or less

X is a protective group; with a carbonylbislactam, thereby forming a compound with the formula

O H H O

L C N (CH₂)₀ Y (CH₂)_p N-

[I]

wherein each L is a lactam from the carbonylbislactam. 3. Method according to claim 2, wherein the diamine is selected from the group consisting of lysine or ornithine esterified with a protective group. 4. Method according to any one of claims 2-3 wherein the protective group is selected from phenyl, alkyls, oxazines, oxazolines, and protective organosilicon compounds. 5. Method for preparing a diisocyanate by heating the compound according to claim 1 and thereby forming a diisocyanate of formula Il O: :^|S^|- ^■(CH₂)₀ -(CH₂)_P -N:

[H]

6. Method for preparing a polymer, comprising a diisocyanate obtained according to claim 5 or a compound according to claim 1 and polymerising the diisocyanate or the compound optionally in the presence of another polymerisable compound.

7. Method according to claim 6 wherein the polymer is a polyurethane.

8. Method according to any one of the claims 6 or 7 wherein the polymerisation is carried out in a mould, thereby forming a shaped article. 9. Method according to claim 8 wherein an article is formed selected from the group consisting of catheters, medical coatings, leads for pacemaker, tubing, hospital bedding, surgical drapes, wound dressings or implantable articles.

10. Method according to claim 9 wherein the implantable article is selected from bone substitutes, vascular substitutes, cartilage substitutes or housings for implantable devices.

11. Use of a compound according to claim 1 in the manufacture of an implantable article for treating a malfunctioning body part.

12. Use of a compound according to claim 1 in tissue engineering.