Biodegradable polymers and process for producing thereof

BACKGROUND OF THE INVENTION The present invention relates to biodegradable polymers, more particularly to non-crosslinked, low water soluble or water insoluble polymers, which comprise a polymer backbone other than a polypeptide which forms water soluble polymers by biodegradation.

Biodegradable polymers have long been used in the medical field to provide, inter alia, biodegradable implants and sustained release systems. At present, these materials are of growing interest in eliminating pollution caused by long-life packaging materials, household articles, detergents and the like.

There is also a need for polymers which, after complete or partial chemical or biological degradation, yield reliable non-toxic and readily eliminable products.

Biodegradation generally involves the enzymatic hydrolysis of specific chemical bonds in the polymer. These chemical bonds are particularly attached to ester, urethane or amide groups and are otherwise stable in the absence of enzymes. These hydrolytic processes may be influenced by the presence of acids or bases in addition to or independently of the action of the enzymes. Thus, aliphatic polyesters, such as polycaprolactone, polyethylene adipate and polyglycolic acid, while polyethylene terephthalate, which is widely used for tissues and fibers, are potentially resistant to biodegradation.

Absorbable polymers are important in the medical field for sutures and wound closure, as well as absorbable incorporated materials used in the treatment of purulent osteoporosis and other bone disorders, tissue raw materials and gauzes, anastomosis, drug delivery systems and diagnostic materials. Poly lactic acid, polyglycolic acid, poly (L-dilactide-co-glycolide), polydioxanone, polyglycolide-co-trimethylene carbonate, poly (ethylene carbonate), poly (iminocarbonates), polyhydroxybutyrate have been proposed in these fields. poly (amino acids), poly (ester amides), poly (ortho esters) and poly (anhydrides) (TH Barrows: Clinical Materials 1, 233-257 (1986)), and the use of natural products such as polysaccharides. US-A 4 180 646 discloses new poly (orthoesters) for use in a very wide range of products.

WO 92/04392 discloses a wide range of polymers containing optionally substituted methylene diester units of formula (I)

- [CO-OC (R^XR²) -0-C0] - (I)

- in which formula

R1 and R5² represents a hydrogen atom or a monovalent organic group attached to a carbon atom, or r; and R²together they form a divalent organic group attached to a carbon atom.

Such units are particularly rapidly degradable

<img file="HUT69070A_D0001.tif" />

however, they are stable in the absence of enzymes. These units may bind not only to organic groups attached to carbon atoms, as in the simple carboxylate esters, but also to -O atoms, such as in carbonate esters.

The aforementioned units of formula (I) are usually present in the polymer backbone either as repeating units or as linking groups between polymer portions or as crosslinking groups between polymer chains. In connection with the latter, water-soluble, long-chain natural or synthetic, non-biodegradable or only slowly degradable material, including protein, such as gelatin or albumin, polysaccharide or oligosaccharide or lower polyacrylamide, containing water-insoluble but biologically degradable units , with crosslinks created through cross-linking groups. This reduces the cost of production of the product compared to polymers containing the units of formula I in the polymer backbone, since the relative content of the units of relatively expensive formula I can be reduced.

Although such cross-linked polymers are widely used within the meaning of the aforementioned WO 92/04392, their structure inevitably restricts the processability of the polymers to a certain extent, since cross-linkers are generally insoluble in all organic,

- 5 in both aqueous solvents and have no thermoplastic properties. Accordingly, they cannot be processed by conventional methods such as solvent casting or melt processing.

The present invention is based on the discovery that it is possible to produce biodegradable lipophilic side chains containing substantially cross-linked (i.e. linear) methylene diester units of formula (I) by combining substantially water insoluble reduced water solubility) and thermoplastic properties, while being soluble in many organic solvents and biodegradable, and water-soluble (and thus readily dispersible and / or removable) products of biodegradation, in particular water-soluble polymers formed by cleavage of lipophilic side chains by biodegradation.

Biodegradable esterified polypeptides of the general formula EP-A-0 130 935 (A)

- (NH-CH-CO)_χ(CH₂)_y-COO-CR^theR^b-OOC-R^c (THE)

- in which formula

R^the and R^b is alkyl or hydrogen, and R^c is an optionally substituted aliphatic or aromatic group, or

R^b is hydrogen or alkyl, and

R^the and R^c together they form a divalent radical, such as dimethylene, vinylene, or phenylene, · ····················································

Y is 1 or 2, and x is selected such that the polymer has a molecular weight of at least 5,000 and their other copolymers of poly (amino acids) as delayed release carriers for pharmaceutical agents that can be mixed with or coated with these polymers. The first step in the biodegradation of such polymers is the cleavage of the methylene diester groups present as side chains to form polymers containing the units of formula (B)

- (NH-CH-CO) I (CH₂) y-COOH (B)

Such polymers are reported to be further degraded by peptidases to the constituent amino acid (s) that are taken up by the host to which the polymer / drug combination has been administered. This mode of degradation is different from the polymers of the present invention, wherein the polymers formed by biodegradation of the methylene diester side chains carrying the lipophilic substituent are selected as water soluble, so that no further degradation is required to disperse and / or remove them.

A potential disadvantage of the polymers disclosed in EP-A-0 130 935 is that a large number of hydrogen bonds in the polypeptides cause relatively high melting points, so that their melt can only be processed at the expense of forced decomposition. In addition, when used in vivo, the peptides discussed are allergic.

- Can trigger 7 * reactions.

Accordingly, the present invention provides biodegradable, non-crosslinked, low water soluble or water insoluble polymers comprising a polymer backbone other than a polypeptide, wherein at least a portion of the side chains have the methylene diester units of formula (I).

- (CO-O-CÍRÍR²) -O-COJ- (I)

- in which formula

RI and R² each independently represents a hydrogen atom or a monovalent organic group attached to a carbon atom, or R 1 and R 1² together form a divalent organic group attached to a carbon atom and contain substituents to form a lipophilic, biodegradable, water-soluble polymer bonded to the polymer backbone.

As discussed above, the ester groups of the methylene diester units of formula I may be carboxylate or carbonate groups. The polymers of the invention may therefore be illustrated as polymers containing the units of formula II

- [A] (L) 1 (0)_m-CO-OC (RLR²) -0-C0 (O)_n-R³ (II)

- in which formula

A is a repeat unit of a polymer backbone other than a polypeptide,

L is a linking group,

1, m and n are independently 0 or 1,

R¹ and R² is as defined above, and

R³ is a lipophilic organic group.

The biodegradation of methylene diester groups in polymers containing the units of formula (II) is generally the result of -OC- (R²) -0- by cleavage of the bond to the adjacent carbonyl group by enzymatic hydrolysis, and is typically R1-CO-R² aldehyde or ketone. The nature of the other degradation products varies depending on whether m and n are 0 or 1. When n is 0, a water-soluble polymer containing a carboxyl group and units of formula (III) is formed,

[AJI (L) i-COOH (III) wherein A and L are as defined above and 1 is as defined above. When n is 1, the hypothetically formed carbonic acid group will generally remove carbon dioxide to form a water-soluble polymer containing hydroxy and units of formula IV

- [A] I (L) x-OH (IV) wherein A and L are as well as 1 having the meanings given above, while depending on whether n is 0 or 1, R³-COOH and R³Reaction products of the formula -OH are also formed.

Factors affecting the water solubility of polymer degradation products containing units of formula III or IV include the material nature of the repeating unit A and any comonomer units present, the length of the linking groups L and the gross chain length of the polymer, which is generally such that the biodegradable polymer preferably has a molecular weight of no greater than 2,000,000. Lower molecular weight polymers may be advantageous, inter alia, for applications where a higher degree of biodegradability is expected. Therefore, polymer systems designed for in vivo use, such as drug delivery systems or parenterally administered diagnostic auxiliaries, preferably have a molecular weight of not more than 40,000.

The repeating units A and the comonomer units in the polymers of the present invention are preferably relatively short-chain and thus contain up to 10, typically 1 to 6, carbon atoms optionally interrupted by one or more heteroatoms selected from oxygen, nitrogen and sulfur, and / or substituted by one or more substituents containing such heteroatoms, such as oxo, hydroxy and / or amino. If the repeating units A and / or any comonomer units contain hydrophilic groups, the size of these units need not be limited, and the possible units may therefore include polyoxyethylenes (such as polyoxyethylene esters of methacrylic acid).

The linker groups L are preferably short-chain, including, inter alia, C 1 -C 3 alkylene groups.

<img file="HUT69070A_D0002.tif" />

which may be methylene, ethylene or propylene, optionally terminated in oxy, carbonyl, oxycarbonyl, imino or iminocarbonyl, and / or optionally interrupted by oxy, carbonyl, where appropriate; , oxycarbonyl, imino or iminocarbonyl. In the presence of polar groups such as oxygen atoms or imino groups, the linking groups may be longer and may contain up to 10 carbon atoms without excessively reducing water solubility. Suitable polymer degradation products include polyvinyl alcohol, polyhydroxyalkyl acrylates, l-2-hydroxyethyl acrylate, polyacrylic acid, polymethacrylic acid, and methacrylates such as popolysaccharides, polyesters, polyethers such as polyoxyethylenes, polyoxypropylenes, polyacrylamides and polymethacrylamides such as poly (N-hydroxyalkyl) acrylamides and methacrylamides, including poly-N

- (2-hydroxypropyl) methacrylamide, polyamides, polyurethanes and epoxy polymers.

Polymer degradation products of the biodegradable polymers of the present invention, because of their water solubility, generally do not need to be biodegradable themselves, including polyolefin-like materials. The invention therefore includes polymers containing units of formula II wherein A is a repeating unit of the polyolefin type, such as ethylene or propylene. Note that this type of polymer can be produced in a relatively simple and economical manner.

Unlike the more complex polypeptide synthesis methods required for the preparation of the polymers described in EP-A-0 130 935, free radical polymerization methods are provided.

In the biodegradable polymers of the present invention, at least a portion of the repeating units must be linked by side chain units of formula (IIa), (L) i-iJm-CO³ (Ha) wherein L, r1, R² and R³ and 1, m and n are as defined for the symbols in the formula (II) of the polymer chain. It will be appreciated that the exact value of the substitution may be varied, inter alia, by the copolymerization and partial esterification procedures detailed below, in order to modify the solubility parameters of the biodegradable polymer and polymer degradation products.

In the side chains of formula Ha, R¹ and R²(other than hydrogen) and R³ may be a hydrocarbon or heterocyclic group attached to a carbon atom, such as a C 1 -C 20 group including an aliphatic group such as an alkyl or alkenyl group (preferably up to C 10), a cycloalkyl group (preferably up to C 10), an aryl aliphatic group. preferably up to 20 carbon atoms) arylalkyl, (preferably up to 20 carbon atoms) aryl, or up to 20 carbon atoms and one or more oxygen, sulfur and nitro.

- a heterocyclic group containing 12 heteroatoms selected from Rogen. Such hydrocarbon or heterocyclic groups may carry one or more functional groups such as halogen or -NR⁴R⁵, -CONR⁴R⁵, -0R⁶, -SR⁶and -COOR⁷ a group of the general formula wherein R⁴and R⁵ each independently represents a hydrogen atom, an acyl group, or R 1 and R 4² may be a defined hydrocarbon group; R⁶ represents a hydrogen atom or an acyl-bonded or one of R 4 and R 6² a group defined as meaning; and R⁷ is hydrogen or one of R6 or R6² the group specified for your report. If R³ and R² denotes a divalent radical, including, but not limited to, alkylidene, alkenylidene, alkylene or alkenylene (preferably up to 10 carbon atoms) which may be mono- or polysubstituted by the functional groups defined above. The R³ may be interrupted and / or terminated by a heteroatom such as oxygen, nitrogen or sulfur.

Among others, R³, R² or R³ aliphatic groups as used herein may be linear or branched, saturated or unsaturated. These groups include, inter alia, alkyl and alkenyl groups such as methyl, ethyl, propyl, isopropyl, butyl, decyl or allyl. Aryl aliphatic groups include (monocarbocyclic aryl) alkyl groups, for example benzyl. Aryl groups include mono- or bicyclic aryl groups, such as phenyl, tolyl or naphthyl. Heterocyclic Groups ···

They include 5- or 6-membered heterocyclic groups preferably containing one heteroatom, such as furyl, thienyl or pyridyl. Halogen substituents may be chlorine, bromine or iodine.

RI, R² and R³ Both their material nature and their size influence the extent to which polymers containing the units of formula II become lipophilic and thus water-insoluble, as well as the rate at which the side chain is cleaved by biodegradation. Therefore, large and / or bulky groups reduce the rate of biodegradation by spherical inhibition and increase the lipophilic nature of the polymer. In a useful class of side chains, R 1 and R 1² is hydrogen or (C1-C4) -alkyl, such as methyl, R³ and lower alkyl, preferably having from 1 to 20 carbon atoms. Such side chains combine a substantial degree of lipophilicity and biodegradability.

It should be noted that both the backbones and side chains of the polymers of the invention are selected so that their degradation products are biologically acceptable, in particular, non-toxic. In the case of polymers for pharmaceutical applications, the degradation products must also be physiologically acceptable, therefore R¹, R² , R³, A and each linking group L have the meaning that R1-CO-R² compounds of formula (III) or (IV); and R³-C00H or R³The products of the formula -0H are physiologically acceptable, easily dispersible and removable, preferably all of them are water soluble. Carbon dioxide liberated by cleavage of a carbonate group present is generally physiologically acceptable, and may be functionally desirable for certain uses of the polymers of the present invention.

The invention further provides a process for the preparation of the above biodegradable polymers comprising:

A) introducing a lipophilic methylene diester side chain into a preformed water soluble polymer by reacting with a suitable reagent, or

B) polymerizing a functional monomer bearing a lipophilic methylene diester side chain.

Process variant A may be carried out by reacting a polymer containing alcoholic hydroxyl groups (such as polyvinyl alcohol, polyhydroxyalkyl acrylate or polysaccharide) with a compound of formula V

X-CO-O-CÍRiR²) -0-C0 (0)_n-R³ (V) wherein R 1, R 2 are² and R³ and n is as defined above and X is a leaving group such as halogen, i.e., fluorine, chlorine, bromine or iodine. Reagents of formula (V) may be prepared, inter alia, by methods known in the art (Folkmann and Lund, Synthesis 1990, 1159). Reactions which result in polymers containing units of the formula (II) in which m is 1 may conveniently be carried out in solution, such as in a solvent including:

In tetrahydrofuran in the presence of a weak nucleophilic base such as pyridine. Catalytic amounts of tertiary amines such as 4-dimethylaminopyridine may also be used. The number of hydroxyl groups to be reacted to form the desired lyophilized methylene diester groups can be controlled by influencing the final hydrophilic lipophilic balance of the lyophilized polymer by appropriate factors such as reagent volume, reaction time and temperature. The product may be purified by conventional techniques such as solvent extraction and / or dissolution / precipitation.

Process variant A may also be carried out by reacting a carboxyl-containing polymer (such as polyacrylic acid or polymethacrylic acid) with a compound of formula VI

X-CR¹R²-O-CO- (0)_n-R³ (VI) wherein R 1, R 2 are², R³ and X and n are as defined above. Such reactions are carried out in which the polymers containing the units of formula II wherein m is 0 are preferably carried out in a solution such as a solvent, including Ν, Ν-dimethylformamide, in the presence of a strong base such as an alkali metal alkoxide, in the presence of butoxide. A catalytic amount of a crown ether such as 18-crown-6 may also be used. Again, the balance of the hydrophilic lipophilic nature of the polymeric product can be controlled by appropriate selection of reaction parameters to determine the number of carboxyl groups to be reacted.

The products may be purified by conventional methods.

Reagents of formula (VI) may be prepared, inter alia, from R 1 -CO-R² an aldehyde or ketone of the formula: with an acid halide or R³-(SHE)_nBy reaction with a halogenated carbonic acid ester of the formula -CO-X in the presence of a catalyst such as zinc chloride or pyridine.

Process A may also be carried out by reacting a polymer bearing functional groups, such as epoxy groups, with a reagent containing the desired lipophilic methylene diester groups and a reactive end group reactive with such functional groups. End-group reactive with epoxy groups include amino, hydroxy and carboxy. The latter groups may also be present in the starting polymer, in which case the end-epoxy group is contained in the reagent.

In general, it is preferred that the polymer starting material used in Process A) has a molecular weight of up to about 20,000.

Process variant B) can be carried out using any monomer that can be polymerized or copolymerized to form a cross-linked polymer and has one or more substituents which are not involved in the polymerization and which can be converted to the desired lipophilic methylene diester prior to polymerization. Free radical, condensation and ionic polymerization techniques can be used.

For free radical polymerization, carboxyl-containing monomers such as acrylic acid or methacrylic acid may be reacted with a compound of formula VI or hydroxyl-containing monomers such as 2-hydroxyethyl acrylate or N- (2-hydroxypropyl) methacrylamide. With a compound of formula (V). Alternatively, the monomers containing a hydroxyl group may be reacted with a compound of formula VII

X-CO-OC (R³R²) -X (VII)

wherein R³, R² and X is as defined above, then R is obtained³With a suitable salt of the carboxylic acid of the formula -COOH.

Free radical polymerization can also be carried out using vinyl carbonate esters of formula VIII

CH₂= CH-0-C0-0-C (R^xR²) -0-C0 (0)_n-R³ (VIII) wherein R 1, R 2 are² and R³ and n is as defined above. Such monomers, including those wherein n is 0, may be prepared as the vinyl chloro carbonate ester R¹R²By reaction with an aldehyde or ketone of formula C = O in the presence of a catalytic amount of pyridine or Lewis acid to give an optionally substituted chloromethyl vinyl carbonate of formula IX

CH₂= CH-O-CO-OC (RIR²) -Cl (IX)

wherein R³ and R² and R³The reaction with the corresponding salt of the carboxylic acid of the formula -COOH preferably proceeds in the presence of a catalytic amount of a suitable crown ether. It is noted that compounds of Formula VIII are formally considered to be vinyl alcohol which are derivatives of a compound of Formula VII. The resulting polymeric degradation of the resulting polymers results in polyvinyl alcohol.

Conventional bulk polymerization processes in solution, emulsion and suspension may be employed. The molecular weight of the polymer final product, preferably up to 2,000,000, can be controlled by the use of chain transfer agents, such as mercaptans, which break the growth of the polymer chain through an abstracted proton and initiate new polymer chain growth. The molecular weight of the polymer can thus be controlled by the type and concentration of the chain transfer agent.

Suitable vinyl monomers, such as carbonyl monomers adjacent to the vinyl group, including acrylic or methacrylic esters prepared as described above, can also be used in ionic (both anionic and cationic) polymerization processes. These processes are particularly suitable for the production of polymers of a particular molecular weight, in particular of relatively low molecular weight.

Condensation polymerization can be carried out using a wide variety of monomers having appropriate functional groups, examples of which are illustrated in formulas (X) and (XI).

<img file="HUT69070A_D0003.tif" />

<img file="HUT69070A_D0004.tif" />

(X)

Y

I (CH₂)_the

CH (O)_m-CO-OC (RLR²) -O-CO- (0)_n-R³ (CH₂)_b (XI)

CH (0)_m-CO-OC (RIR²) -O-CO- (0)_n-R³ (CH₂)_c

Y in which R¹, R² and R³ and m and n are as defined above, Y is a reactive group such as carboxy, hydroxy or epoxy, including 2,3-epoxypropyloxy, and a, b and c are 0 or a small integer. , such as 1, 2 or 3. In the two side chains of formula (XI), R1, R5² and R³ and m and n may be the same or different. Such monomers may be used in conventional condensation reactions with suitable reagents such as dicarboxylic acids, dialkols, diamines, di (acid chloride), diisocyanates and bisepoxy compounds to prepare polymers such as polyesters, polyamides, polyurethanes and epoxy polymers. The molecular weight of the polymer product is determined by the appropriate reaction time, temperature and • · · ·

And the like, and / or monofunctional barrier agents.

The polymers of the invention may also be prepared, where appropriate, by emulsion polymerization processes. This may be particularly useful if it is desirable to produce polymers in the form of monodisperse particles. EP-A-0 003 905, EP-A-0 091 453, EP-A-0 010 986 and EP-A-0 106 873 describe emulsion polymerization processes for producing particles, in particular monodisperse particles.

The polymers of the present invention are used, inter alia, in surgical implants such as sutures, soft tissue prostheses, tampons, foils (such as artificial skin) or wound dressings (such as hydrogel sheets), flexible sheets and containers made therefrom, pharmaceutical agents or agricultural agents. for the production of biodegradable delayed-release formulations for chemicals, as well as for kindergarten auxiliaries, Thus, in the manufacture of water retaining protective covers and plant containers. Such applications and the molded polymers used therein are also within the scope of the invention. The molded polymers used as prostheses preferably contain at least a surface - heparin.

In the sense discussed above, the linear nature of the polymers of the invention enhances their processability. Thus, due to their thermoplastic nature, they can be melt processed by conventional techniques such as injection molding, extrusion and film blasting. Solutions of polymers in suitable organic solvents may be used, inter alia, to coat tablets, to form films and to draw fibers.

If the polymer of the present invention is to be used as a biodegradable sustained release agent, the active ingredient may be within the biodegradable shell, such as capsules or microspheres, or be physically embedded in the polymerization so that the polymer is uniformly distributed and biodegradable. will be released. Alternatively, the active ingredient may partially or completely replace R 1, R 1²or R³ and thus is released by enzymatic cleavage. Typical active ingredients included in delayed-release formulations include steroids, contraceptives, antibacterial agents, narcotic antagonists and antitumor agents.

The polymers of the present invention can be used as plasticizers for other polymers at sufficiently short chain lengths. Because the polymers of the present invention are biodegradable, degradation of the plasticizer will either break the integrity of the material or open it to attack by enzymes.

The biodegradable polymer particles of the present invention are also useful for diagnostic purposes. Thus, an X-ray contrast agent, which is usually an aromatic compound which is polysubstituted with iodine, may partially or completely replace the R³ or —C (RI²) - a group of the general formula such that it is liberated by biological degradation and safely removed from the body. Such particles can be used to visualize the liver and spleen as they accumulate in the reticuloendothelial systems of these organs. X-ray contrast media may also simply be physically held in the polymers by being incorporated during polymerization.

The polymer particles of the present invention may also contain paramagnetic, superparamagnetic or ferromagnetic materials used in diagnostic procedures for magnetic resonance imaging (MRI). Therefore, in order to produce ferromagnetic or superparamagnetic particles, polymers can physically incorporate iron or magnetic iron oxide submicron particles into the polymers. Paramagnetic MRI contrast agents contain essentially paramagnetic metal ions, such as gadolinium ions, which bind to chelating agents that substantially eliminate ion release (and hence their toxic nature). Such chelating agents, together with the complexed metal ions, may be physically anchored in the polymers by being present during polymerization or by the presence of R 1, R² and R³ groups are suitable chelating groups. In general, many of these chelating agents are polyamino-polycarboxylic acids, such as diethylenetriaminepentaacetic acid (Lauffer, RB: Chem. Rev. 87: 901-927 (1987).

The polymer particles of the invention also contain ultrasonic contrast agents such as high density materials such as barium sulfate or iodinated compounds such as the above-mentioned X-ray contrast agents. «· · ·

- 23 can provide ultrasound contrast media. The polymers of the present invention may also be used to produce gas-porous polymer microparticles and gas-coated polymer-coated microspheres which are equally suitable as ultrasonic contrast media.

1 is a graph showing the consumption of 1M NaOH in 20 mL of 0.9% NaCl over time.

The invention is further illustrated by the following non-limiting examples. The general operations and aspects of the examples are summarized below.

Methacrylic acid was distilled under high vacuum to remove the stabilizer. The 2,2'-azobisobutyronitrile thermal initiator was purified by recrystallization from methanol.

All reactions were carried out under a nitrogen atmosphere.

Operational Parameters of Gel Filtration (SEC): Pump: Knauer HPLC Type 64 Pump Detector: Knauer Differential Refractometer Columns: Polymer Laboratories PL Type Gel-Linked Row Columns: 10⁴ A, 500 A and 100 A, particle size: 5 pm, column height: 30, 50 and 60 cm solvent: THF calibration: (Polymer Laboratories) polystyrene adjusters ·· · «

- 24 Flow Rate Material: Toluene Software: Polymer Laboratories GPC / SEC Version 5.10

<td>Mw:</td><td>weighted average molecular weight</td>

<td>Mn:</td><td>average molecular weight</td>

<td>Mw / Mn:</td><td>polydispersity</td>

<td>Mt:</td><td>molecular weight at maximum detector signal</td>

<td>abbreviations</td><td>The list:</td>

<td>Tg</td><td>Glass transition temperature</td>

<td>TBA-OH</td><td>tetrabutylammonium hydroxide</td>

<td>TBA</td><td>tetrabutylammonium</td>

<td>AIBN</td><td>2,2'-azobisisobutyronitrile</td>

<td>salt₂ci₂</td><td>sulfuryl chloride</td>

<td>EtSCl</td><td>ethane sulfenyl chloride</td>

<td>DBU</td><td>l, 8-diazabicyclo [5.4.0] undec-7- ene (l, 5-5)</td>

<td>THF</td><td>tetrahydrofuran</td>

<td>DMF</td><td>N, N-dimethylformamide</td>

First example

Preparation of butyl methacryloxy oxymethyl carbonate

2.84 (22.0 mmol) of chloromethyl chloro carbonate ester and

To a solution of pyridine (1.78 mL, 22.0 mmol) in methylene chloride (24 mL) was added n-butanol (1.84 g, 20.0 mmol) at 0 ° C. After 30 minutes at 0 [deg.] C. and 21 hours at 25 [deg.] C., the reaction mixture is washed with 10-10 ml of a 1M aqueous hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate and water. (Anhydrous

After drying over MgSO 4), the solvent was removed under reduced pressure to give crude product ···

There were obtained 2.66 g of the intermediate n-butyl chloromethyl carbonate (yield: 80%).

1 H-NMR (60 MHz, CDCl 3)?₃) δ: 0.86 (CH₃CH₂, m), 1.40 (CH₂CH₂,

Here), 4.15 (CH₂-0, t), 5.63 (CH₂~ C1, s).

Intermediate n-butyl chloromethyl carbonate (2.5 g, 15.0 mmol) was dissolved in dimethylformamide (80 mL) and then potassium methacrylate (1.77 g, 15.0 mmol) was added in a catalytic amount (0.2 g). (7.5 mmol) in combination with 18-crown-6. After 3 days at 25 ° C, the solvent was removed under reduced pressure, chloroform (30 ml) and water (20 ml) were added and the product was extracted into the chloroform phase (MgSO4).₄After drying over 100 ° C, the solvent was removed under reduced pressure. Flash chromatography gave 1.96 g (61%) of butyl methacryloxyoxymethyl carbonate.

1 H-NMR (300 MHz, CHCl 3) δ: 0.99 (CH₃CH₂, t), 1.47 (CH₂CH₂,

m), 1.72 (CH₂CH₂, m), 2.01 (CH₃, s), 4.25 (CH₂-Five) ,

5.74 (HC =, m), 5.89 (OCH₂O, s), 6.27 (HC =, m).

¹³C-NMR (75 MHz, CDCl 3) δ: 13.47 (CH₃), 17.97, 18.71, 30.36 (CH₃ and CH₂X2), 68.46 (CH₂O), 82.07 (O-CH₂-O), 127.46 (CH₂=), 135.05 (C =), 153.89 (C = O), 165.50 (C = O).

Second example

a) Preparation of a polymer from butyl methacryloxy oxymethyl carbonate

350 mg of butyl methacryloyl oxymethyl carbonate monomer was dissolved in ml THF. 1 mg of AIBN was added as the free radical initiator. The solution is heated to 50 ° C for 5 minutes

- Polymerized for 26 hours. The product was isolated by precipitation in water. SEC: Mw = 165,000, Mn = 70,000, Mw / Mn = 2.3.

b) Preparation of a polymer from butyl methacryloyl oxymethyl carbonate

A solution of 1.0 g of butyl methacryloxyoxymethyl carbonate in DMF was heated to 60 ° C and 0.005 g (0.03 mol) of AIBN was added. After 24 hours, the reaction mixture was cooled and the polymer solution was added dropwise to excess methanol with stirring. The polymer was filtered, washed with methanol and water and dried under reduced pressure.

IR (KBr): 1763 (C = O) cm @ -1^-1.

1 H-NMR (300 MHz, CDCl 3)₃Δ: 0.90 (t, 3H, CH)₃), 1.00 (m, 2H,

CH₂), 1.39 (m, 2H, CH)₂), 1.70 (m, 2H, CH)₂), 1.90 (m, 3H, CH)₃), 4.20 (t, 2H, CH₂O), 5.68 (s, 2H, OCH)₂SHE). ¹³C-NMR (75 MHz, CDCl₃) &lt;5: 13.54 (CH₃CH₂), 18.73 (CH₂),

30.39 (CH₂), 46.26 (C-CH₃), 69.72 (CH₂O), 83.67 (-OCH₂O-), 153.86 (C = O), 175.80 (C = O).

Differential calorimetry (DSC) showed an initial decomposition temperature of 239.9 ° C (no Tg observed). Thermomechanical analysis showed a glass transition temperature of 24.7 ° C.

SEC: Mw = 60,000, Mn = 29,000, Mw / Mn = 2.1.

Third example

Preparation of Copolymer from Butyl Methacryloxy Oxymethyl Carbonate and Acrylic Acid Amide

250 mg of butyl methacryloxyoxymethyl carbonate and 250 mg of acrylic acid amide monomers were dissolved in 5 ml of THF. To the oil was added 1 mg of AIBN as the free radical initiator. The solution was polymerized at 60 ° C for 2 hours. The product was isolated by precipitation in cold water.

4th example

General procedure for the preparation of chloromethyl carbonates

Chloromethyl-chloro-carbonic ester and the indicated alcohol

200 To a solution of 1 ml of methylene chloride in pyridine was added at 0 ° C. After 20 minutes at 0 ° C and 21 hours at 25 ° C, the reaction mixture was washed with 1 N hydrochloric acid (10-10 ml), saturated aqueous sodium bicarbonate and water. The solvent (anhydrous MgSO 4)₄ After drying under reduced pressure to give crude chloromethyl carbonate. Specific data for Examples 4a-4d are shown in Table 1.

1 «Table

<td>Example</td><td>chloromethyl-chloro-</td><td>alcohol, ROH</td><td>pyridine</td>

<td>number</td><td>-szénsav ester</td><td>R, (g, mmol)</td><td>g, mmol</td>

<td></td><td>g, mmol</td><td></td><td></td>

<td>4. a</td><td> 25,01, 194</td><td>CH₃ (5,64, 176)</td><td> 15,52, 194</td>

<td>4b</td><td> 15,81, 124</td><td>CH₃CH₂ (5,20, 113)</td><td> 9,91, 124</td>

<td>4. c</td><td> 20,01, 155</td><td>CH₃(CH₂)9, (22,25,</td><td> 12,54, 157</td>

<td></td><td></td><td> 139)</td><td></td>

<td>4d</td><td> 20,02, 155</td><td>PhCH₂ (15,23, 141)</td><td> 12,54, 157</td>

(a) Methyl chloromethyl carbonate

The compound was obtained from chloromethyl-chloro-carbonic acid ester and methanol.

¹1 H-NMR (60 MHz, CDCl 3)?₃6: 3.98 (s, 3H, OCH)₃), 5.85 (s, 2H,

CH₂C1).

b) Ethyl chloromethyl carbonate

The compound was obtained from chloromethyl chlorocarbon ester and ethanol.

1 H-NMR (60 MHz, CDCl 3) δ: 1.25 (t, 3H, CH)₃), 4.25 (q, 2H,

CH₂), 5.70 (s, 2H, OCH)₂C1).

c) Decyl chloromethyl carbonate

The compound was obtained from chloromethyl-chloro-carbonic acid ester and decyl alcohol.

¹1 H-NMR (60 MHz, CDCl 3) δ: 0.90-1.50 (m, 19H, CH)₃ and CH₂),

4.20 (m, 2H, CH)₂O), 5.75 (s, 2H, OCH)₂C1).

d) Benzyl chloromethyl carbonate

The compound was obtained from chloromethyl-chloro-carbonic ester and benzyl alcohol.

1 H-NMR (60 MHz, CDCl 3) δ: 5.20 (s, 2H, PhCH₂O), 5.70 (s,

2Η, C1CH₂O), 7.32 (s, 5H, Ph).

5th example

General procedure for the preparation of methacryloxyoxymethyl carbonates

To a solution of methacrylic acid in DMF (200 mL) was added potassium tert-butoxide. To the resulting suspension was added chloromethyl carbonate prepared in Example 4, followed by 18-crown-6, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (30 ml), washed with saturated aqueous sodium bicarbonate solution (10 ml) and water (20 ml). The organic phase was dried (over anhydrous MgSO4) and the solvent removed under reduced pressure. The data for Examples 5.a-5.d is shown in Table 2.

Second spreadsheet

Example compound potassium methacryl-18-crown-6-DMF

<td>number</td><td> (9/</td><td colspan="2">mmol)</td><td colspan="2">see (g, mmol)</td><td> (9/</td><td>mmol)</td><td>(Ml)</td>

<td>5a</td><td>4a,</td><td> (9,67,</td><td> 78)</td><td> 8,71,</td><td> 78</td><td> 1,01</td><td> , 38</td><td> 350</td>

<td>5b</td><td>4b,</td><td> (8,04,</td><td> 60)</td><td> 6,73,</td><td> 60</td><td> 0,6,</td><td> 23</td><td> 300</td>

<td>5c</td><td>4c,</td><td> (30,61,</td><td> 122)</td><td> 13,67,</td><td> 122</td><td> 2,5,</td><td> 94</td><td> 600</td>

<td>5d</td><td>4d,</td><td> (22,01,</td><td> 110)</td><td> 13,63,</td><td> 110</td><td> 1,5,</td><td> 57</td><td> 550</td>

(a) Preparation of methyl methacryloyl oxymethyl carbonate

The title compound was obtained from methyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 1772 (C = O, str.), 1737 (C = O, str.), 1635 (C = C, str.), Cm^-1.

³1 H-NMR (300 MHz, CDCl 3)?₃) S: 1.91 (s, 3H, CH)₃C =), 3.79 (s, 3H, CH)₃0), 5.64 (m, 1H, CH)₂ =), 5.80 (s, 2H, -OCH)₂0-), 6.16 (m, 1H, CH)₂=)· ¹³C-NMR (75 MHz, CDCl₃S, 17.95 (CH₃C =), 55.13 (CH₃0), 82.18 (-OCH₂O-), 127.52 (CH₂=), 135.02 (C =), 154.44 (C = 0), 165.46 (C = 0).

b) Preparation of ethyl methacryloxy-oxymethyl carbonate

The title compound was obtained from ethyl chloromethyl carbonate and potassium methacrylate.

• · ·

- 30 IR (KBr): 1772 (C = O, str.), 1736 (C = O, str.), 1635 (C = C, str.), Cm -1.

1 H-NMR (300 MHz, CDCl 3)₃) Δ: 1.27 (t, 3H, CH₃), 1.92 (s, 3H, CH)₃C =), 4.23 (q, 2H, CH)₂), 5.66 (m, 1H, CH)₂=), 5.80 (s, 2H, -OCH)₂O-), 6.20 (m, 1H, CH)₂=).

¹³C-NMR (75 MHz, CDCl₃) 8: 15.70 (CH₃CH₂), 19.60 (CH₃C)

65.72 (CH₂O), 83.05 (-OCH₂O-), 127.76 (CH₂=), 135.40 (C =), 153.82 (C = O), 165.42 (C = O).

c) Preparation of decyl methacryloyl oxymethyl carbonate

The title compound was obtained from decyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 1772 (C = 0, str.), 1763 (C = O, str.), 1635 (C = C, str.), Cm -1.

1 H-NMR (300 MHz, CDCl 3)₃Δ: 0.90 (t, 3H, CH)₃), 1.28 (m, 14H,

CH₂), 1.72 (m, 2H, CH)₂), 1.99 (s, 3H, CH)₃C =), 4.21

<td>(t, 2H, CH₂O), 5.70 (m, 1H, CH)₂), 5,86</td><td>(s, 3H, -OCH₂SHE-),</td>

6.24 (m, 1H, CH₂=).

<td>¹³C-NMR (75 MHz, CDCl 3) δ: 13.78 (CH₃), 17,76</td><td>(CH₃C)</td>

<td>22.76-31.55 (CH₂), 68.60 (CH₂O), 81.90</td><td>(OCH₂SHE-),</td>

127.28 (CH₂=), 134.86 (C =), 153.73 (C = 0), 165.33 (C = O).

d) Preparation of benzyl methacryloxy oxymethyl carbonate

The title compound was obtained from benzyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 3077 (Ph), 1772 (C = O, str.), 1763 (C = O, str.), 1635 (C = C, str.), Cm^-l.

1 H-NMR (300 MHz, CDCl 3)₃Δ: 1.96 (s, 3H, CH)₃C =), 5.22 (s, 2H,

CH₂O), 5.70 (m, 1H, CH)₂ =), 5.87 (s, 3H, -OCH)₂O-), 6.22 (m, 1H, CH)₂=), 7.39 (s, 5H, Ph).

• · • · · ¹³C-NMR (75 MHz, CDCl₃) &lt;5: 17.96 (CH₃C =), 69.91 (CH₂SHE) ,

82.03 (-OCH₂O-), 127.41 (CH₂=), 128.32 (Ph), 134.78 (C =), 153.58 (C = O), 165.28 (C = O).

6th example

General procedure for the polymerization of methacryloxyoxymethyl carbonates

A solution of 1.0 g of methacryloxyoxymethyl carbonate prepared in Example 5 in 8.0 g of DMF was heated to 60 ° C and AIBN (0.005 g, 0.03 mmol) was added. After 24 hours, the reaction mixture was cooled and the polymer solution was added dropwise to an excess of methanol (not solvent) while stirring. The polymer was filtered, washed with methanol and water and dried under reduced pressure.

a) Preparation of a polymer from methyl methacryloxyoxymethyl carbonate

IR (KBr): 1763 (C = 0, str.) Cm^-1.

1 H NMR (300 MHz, CDCl 3)?₃δ: 1.00 (m, 2H, CH)₂), 1.90 (m, 3H),

3.85 (s, 3H, CH3 O), 5.70 (s, 2H, OCH)₂SHE).

13_C-NMR (75 MHz, CDCl 3) δ: 46.35 (C-CH 3), 56.55 (CH₃SHE),

83.59 (—OCH₂0-), 154.41 (CHO), 175.50 (C = O).

According to DSC, Tg = 59.8 ° C, with an initial decomposition temperature of 242.2 ° C. Thermomechanical analysis showed a glass transition temperature of 59.9 ° C.

SEC: Mw = 100,000, Mn = 59,000, Mw / Mn = 1.7.

b) Preparation of a polymer from ethyl methacryloyloxymethyl carbonate

-1.

IR (KBr): 1763 (C = 0, str.) Cm ^X1 H-NMR (300 MHz, CDCl 3)?₃S: 1.00 (m, 2H, CH)₂), 1.32 (t, 3H,

CH₃), 1.90 (m, 3H, CH)₃), 4.25 (m, 2H, CH)₂O), 5.70 (s, 2H, OCH)₂SHE).

¹³C-NMR (75 MHz, CDCl 3) δ 15.77 (CH₃CH₂), 46.35 (C-CH 3), 65.90 (CH₂O), 83.50 (-OCH₂O-), 153.69 (C = O), 175.80 (C = O).

According to DSC, Tg = 35.9 ° C, with an initial decomposition temperature of 260.9 ° C. Thermomechanical analysis showed a glass transition temperature of 31.2 ° C.

SEC: Mw = 34,000, Mn = 20,000, Mw / Mn = 1.7.

c) Preparation of a polymer from decyl methacryloxyoxymethyl carbonate

IR (KBr): 1763 (C = O, str.) Cm^-1.

1 H NMR (300 MHz, CDCl 3)?₃6: 0.90 (t, 3H, CH)₃), 0.90 (m, 3H, CH)₂), 1.30 (m, 14H, CH)₂), 1.70 (m, 2H, CH)₂), 1.90 (m, 2H), 4.19 (t, 2H, CH)₂O), 5.66 (s, 2H, OCH)₂SHE).

¹³C-NMR (75 MHz, CDCl 3) δ: 13.78 (CH₃), 22.34-31.57 (CH₂), 46.26 (C-CH 3), 68.70 (CH₂O), 83.67 (-OCH₂O-), 153.55 (C = O), 175.80 (C = O).

According to DSC, Tg was not observed, with an initial decomposition temperature of 2392.9 ° C. Thermomechanical analysis showed a glass transition temperature of -3.3 ° C.

SEC: Mw = 160,000, Mn = 90,000, Mw / Mn = 1.7.

d) Preparation of a polymer from benzyl methacryloyloxymethyl carbonate

IR (KBr): 3077 (Ph), 1763 (C = O, str.) Cm^-1.

1 H-NMR (300 MHz, CDCl 3) δ: 0.95 (m, 3H, CH)₃), 1.90 (m, 2H),

5.25 (s, 2H, CH)₂O), 5.75 (s, 2H, OCH)₂Q), 6.70 (s,

5Η, Ph).

¹³C-NMR (75 MHz, CDCl₃) Δ S: 46.26 (-C-CH 3), 68.03 (-OCH₂Ph),

82.02 (-OCH₂O-), 129.45 (Ph), 153.67 (C = O), 175.80 (C = O).

According to DSC, Tg = 31.6 ° C, with an initial decomposition temperature of 197.1 ° C. Thermomechanical analysis showed a glass transition temperature of 32.8 ° C.

SEC: Mw = 92,000, Mn = 44,000, Mw / Mn = 2.1.

7th example

Free radical polymerization of benzylmethacryloxyoxymethyl carbonate in solution to produce kia molecular weight polymer

A solution of 0.5 g (2.0 mmol) of benzyl methacryloxymethyl carbonate in 7.5 g of DMF prepared in Example 5d was heated to 60 ° C and 0.0015 g (0, Allyl mercaptan (02 mmol) and AIBN (0.0025 g, 0.015 mmol) were added. After 24 hours, the reaction mixture was cooled and the polymer solution was added dropwise to the excess methanol (not solvent) while stirring. The polymer was filtered, washed with methanol and water and dried under reduced pressure.

SEC: MW = 22,000, Mn = 14,000, Mw / Mn = 1.6.

8th example

Free radical polymerization of ethyl methacryloxyoxymethyl carbonate and methacrylic acid in solution

The feed monomer mixture of ethyl methacryloxyoxymethyl carbonate and methacrylic acid prepared in Example 5b (8.0 g) in DMF was heated to 60 ° C and 0.005 g (0.03 mol) of AIBN was added. After 24 hours, the polymer solution was added dropwise to chloroform (not solvent) with stirring, filtered, washed with chloroform and then dried under reduced pressure.

Third spreadsheet

Example Methacrylic acid number (g, mmol) ethyl methacryloyl methacrylic acid: 5.b

oxoxymethylcarbomol ratio sodium (g, mmol)

<td>8. a</td><td> 0,73,</td><td> 8,48</td><td> 0,25,</td><td> 1,33</td><td> 86:14</td>

<td>8 .b</td><td> 0,73,</td><td> 8,48</td><td> 0,17,</td><td> 0,90</td><td> 90:10</td>

<td>8. c</td><td> 0,73,</td><td> 8,48</td><td> 0,14,</td><td> 0,74</td><td> 92:8</td>

<td>8d</td><td> 0,92,</td><td> 10,7</td><td> 0,08,</td><td> 0,43</td><td> 96:4</td>

1 H NMR (200 MHz, CDCl 3)?₃6: 1.10 (s, 6H, 2sCH)₃), 1.27 (t, 3H, CH₃CH₂), 1.90 (s, 4H, 2xCH)₂), 3.52 (broad, 1H, OH), 4.2 (m, 2H, CH)₃CH₂), 5.72 (s, -OCH.)₂SHE-).

4th spreadsheet

The solubility of the copolymers in hot and cold water

Example number

Solubility (cold water)

Solubility (in hot water) .a

8b

8th c --8.d complete * slight complete * Complete solubilization only after a relatively long dissolution time

9th example

Preparation of ethyl 1-chloroethyl carbonate

To a solution of 23.16 g (0.162 mol) of l-chloroethyl chloro-carbonic ester and 7.45 g (0.162 mol) of ethanol in 200 ml of methylene chloride was added 12.82 g (0.162 mol) of pyridine at 0 ° C. . After 10 minutes at 0 ° C and then 21 hours at 25 ° C, the reaction mixture was washed with 100 ml of aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and water. The solvent (anhydrous MgSO 4)₄ After drying under reduced pressure to give 18.5 g (74%) of ethyl chloroethyl carbonate as a crude product.

1 H-NMR (60 MHz, CDCl 3)₃Δ: 1.30 (t, 3H, CH)₃), 1.85 (d, 3H,

CH₃CH), 4.25 (q, 2H, CH)₂), 6.45 (q, 1H, CH).

10th example

Preparation of ethyl 1-methacryloxy-oxyethyl carbonate

To a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml) was added potassium tert-butoxide (3.70 g, 0.033 mol). To the resulting slurry was added 5.08 g (0.033 mol) of ethyl 1-chloroethyl carbonate (prepared in Example 9). To the reaction mixture was then added 0.61 g (2.3 mmol) of 18-crown-6 and kept under stirring at room temperature for 3 days. The reaction mixture was then filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water. The organic phase (anhydrous MgSO 4)₄ above) and the solvent was removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Yield: 75%, corrected for recovered starting material)

1 H-NMR (60 MHz, CDCl 3)?₃1.30 (t, 3H, CH)₃), 1.60 (d, 3Η,

CH₃CH), 2.00 (s, 3Η, CH₃C =), 4.20 (q, 2Η, CH)₂), 5.70 (m, 1H, CH)₂=), 6.25 (q, 1H, -OCH (CH₃) 0-), 6.90 (m,

1H, CH₂=).

II. example

Free radical polymerization of ethyl 1-methacryloxy-oxyethyl carbonate

To a solution of 0.504 g (2.49 mmol) of ethyl 1-methacryloxyloxyethyl carbonate in Example 10 in 8 mL of dry THF at 50 ° C under a dry nitrogen atmosphere was added 0.033 g (0.02 mmol) of AIBN. We added. After 7 hours, the reaction mixture was cooled to 20 ° C, the polymer was precipitated in 50 mL of methanol, and the solution was filtered. The resulting polymer was dissolved in THF, re-precipitated in 70 mL of methanol and filtered to give 0.138 g of a white powder.

1 H-NMR (300 MHz, CDCl 3)₃) S: 0.90 (m, 3Η, CH)₃), 1.25 (s, 2H,

CH₃), 1.45 (s, 3Η, CH₃), 1.87 (m, 2Η, CH)₂), 4.15 (bs, 2H, CH₂O), 6.62 (bs, 1H, -CHCH)₃).

SEC: Mw = 26,500, Mn = 18,600, Mp = 22,000, Mw / Mn = 1.43.

12th example

Preparation of Polymer from Ethyl Methacryloxyoxymethyl Carbonate by Emulsion Polyerisation

A solution of sodium dodecyl sulfate (0.056 g, 0.19 mmol) in water (20.5 mL) was heated to 60 ° C under nitrogen, followed by ethyl methacryloxy (5.266 g, 28.00 mmol) prepared in Example 6b. -methyl carbonate was added. Polymerization was initiated using a redox system of 53.4 mg (0.24 mmol) of potassium disulfite and 4.38 mg of 0.02 mmol of potassium persulfate. After 16 hours at 60 ° C, potassium persulfate (4.38 mg, 0.02 mmol) was added, and the polymerization was continued at 60 ° C for 3 hours under nitrogen before the reaction mixture was stirred at 20 ° C. cooled.

13th example

Preparation of O-Acetoxymethyl-S-ethylcarbonothioate to 4.50 g (0.028 mol) of O-chloromethyl-S-ethylcarbonothioate in DMF / ml 2.74 g (0.028 mol) of potassium acetate in 100 ml of THF was added. To the reaction mixture was then added 0.22 g (0.84 mmol) of 18-crown-6 and kept under stirring at room temperature for 3 days. The reaction mixture was then filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (silica gel) to give 4.23 g (85%) of the title product.

¹1 H-NMR (60 MHz, CDCl 3)?₃Δ: 1.30 (t, 3H, CH)₃CH₂), 2.20 (s, 3H,

CH₃C = O), 2.95 (q, 2H, CH)₂CH₃), 5.80 (s, 2H, OCH)₂SHE).

14th example

Preparation of Acetoxymethyl Chloro-Carbonic Acid Ester

To 3.15 g (0.018 mol) of O-acetoxymethyl-S-ethylcarbonothioate prepared in Example 13 at -5 DEG C. with stirring over 15 minutes, 2.43 g (0.018 mol) of S0.₂cl₂and the resulting mixture was stirred at room temperature for 45 minutes. Evaporation of EtSCl at room temperature and 146.6 Pa gave a colorless liquid (2.44 g, 89%).

1 H-NMR (60 MHz, CDCl 3)?₃) S: 2.20 (s, 3H, CH)₃C = 0), 5.76 (s, 2H,

OCH₂SHE).

15th example

Preparation of Acetoxymethyl-2-methacryloyloxyethyl carbonate

A solution of 1.00 g (0.0066 mole) of acetoxymethyl chloro-carbonic acid ester and 0.86 g (0.0066 mole) of 2-hydroxyethyl methacrylate in 30 ml of methylene chloride at 0 ° C, Pyridine (52 g, 0.0066 mol) was added. After 10 minutes at 0 ° C and then 18 hours at 25 ° C, the reaction mixture was washed with 100 mL of 100 mL of hydrochloric acid, saturated aqueous sodium bicarbonate, and then water. The solvent (anhydrous MgSO 4)₄ after drying) was removed under reduced pressure. Flash chromatography on silica gel (hexane: ethyl acetate = 3: 2) gave the title product (1.05 g, 65%).

1 H-NMR (60 MHz, CDCl 3) δ: 1.95 (d, 3H, CH)₃C =), 2.10 (s, 3H,

CH₃C = O), 4.45 (s, 4H, CH)₂O), 5.55 (m, 1H, CH)₂=), 5.75 (s, 2H, -OCH)₂0-), 6.05 (m, 1H, CH)₂=).

16th example

Preparation of N- (2-chloromethoxycarbonyloxypropyl) methacrylamide

2.86 g (20 mmol) of N- (2-hydroxypropyl) methacrylamide²and a solution of pyridine (1.90 g, 24 mmol) in methylene chloride (100 mL) in methylene chloride (120 mL) were added methyl chloroformate (3.87 g, 30 mmol) at 0 ° C. After Mi39, the reaction mixture was kept at 0 ° C for 15 min and then at 25 ° C for 24 h, washed with water (5 x 25 mL). After drying (over anhydrous MgSO4), the solvent was removed under reduced pressure. Flash chromatography (silica gel, eluent: chloroform) gave the title product (3.30 g, 70%).

1 H-NMR (60 MHz, CDCl 3)?₃Δ: 1.42 (d, 3H, CH 3 -CH-O), 2.0 (m, 3H,

CH₃C =), 3.2-4.0 (m, 2H, NH-CH)₂-CH), 4.8-5.3 (m, 1H, CH 3 -CH-O), 5.6 (d, 2H, CH₂=), 5.7 (s, 2H, CH₂C1), 6.1-6.7 (bs, 1H, NH).

17th example

a) Preparation of N- (2-Acetoxymethoxycarbonyloxypropyl) methacrylamide

Freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid in TFA acetate (1.21 g, 4 mmol) in THF (30 mL) at room temperature with stirring, 0.943 g (4 mmol) in THF (10 mL) prepared in Example 16 ) Was added to N- (2-chloromethoxycarbonyloxypropyl) methacrylamide. After stirring for 5 days, the solvent was removed under reduced pressure and the residue was dissolved in chloroform (50 mL) and washed with water (5 x 10 mL). The organic phase (anhydrous MgSO 4)₄ ) and the solvent was removed under reduced pressure. Flash chromatography (silica gel, hexane / ethyl acetate = 3: 4) gave the title product (0.486 g, 47%).

1 H-NMR (60 MHz, CDCl 3)?₃Δ: 1.4 (d, 3H, CH 3 -CH-O), 2.0 (m, 3H,

<img file="HUT69070A_D0005.tif" />

CH₃C =), 2.2 (s, 3H, CH)₃C = O), 3.2-4.0 (m, 2H, NH-CH)₂-CH 4.8-5.3 (m, 1H, CH₃-CH-O), 5.6 (d, 2H, CH)₂=), 5.8 (s,

2H, OCH₂O), 6.1-6.7 (bs, 1H, NH).

b) Preparation of N- (2-Acetoxymethoxycarbonyloxypropyl) methacrylamide

0.430 g (3.0 mmol) of N- (2-hydroxypropyl) methacrylamide² and a solution of 0.285 g (3.6 mmol) of methylene chloride in 30 ml of methylene chloride at 0 ° C in a solution of 0.500 g (3.3 mmol) of acetoxymethyl-chloro-carbonic acid ester prepared in Example 14. We added. After 10 minutes at 0 ° C and 3 days at 25 ° C, the reaction mixture was washed with 100 ml of water. The solvent (anhydrous MgSO 4)₄ after drying) was removed under reduced pressure. Flash chromatography on silica gel (hexane / ethyl acetate = 3: 4) gave the title product (0.40 g, 51%).

The NMR data are in good agreement with that of Example a) above.

18th example

Free radical polymerization of N- (2-Acetoxymethoxycarbonyloxypropyl) methacrylamide

To a solution of N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide (0.519 g, 2 mmol) prepared in Example 17 in 8 mL of THF at 50 ° C and dry nitrogen, 0.0138 g (0.084 mmol). AIBN was added. After 3 days the solvent was removed under reduced pressure to give 0.439 g of a white powder.

·

41 H NMR (200 MHz, CDCl3) δ: 0.8-1.2 (m, 3H, CH₃), 1.2-1.4 (m,

3H, CH₂-CH (CH₃(O), 1.6-2.0 (m, 2H, CH)₂), 2.1 (s,

3H, CH₂CH (CH₃) -O), 5.8 (s, 2H, O-CH)₂~ 0), 6.2-7.0 (m, 1H, NH).

SEC: Mw = 5411, Mn = 2857, Mw / Mn = 1.894.

Tg = 52.91 ° ​​C.

19th example

Preparation of N-2- (1-chloroethoxycarbonyloxy) propyl methacrylamide

3.15 g (22 mmol) of N- (2-hydroxypropyl) methacrylamide²and a solution of pyridine (2.088 g, 26.4 mmol) in methylene chloride (100 mL) were added 1-chloroethyl chloro carbonate ester (4.718 g, 33 mmol) in methylene chloride (20 mL) at 0 ° C. After the reaction mixture was stirred at 0 ° C for 10 minutes, then

After 5.5 hours at 25 ° C, it was washed with water (5x40 mL). The solvent (anhydrous MgSO 4)₄ After drying under reduced pressure to give 4.84 g (88%) of the title compound.

1 H NMR (60 MHz, CDCl 3)?₃Δ: 1.37 (d, 3H, CH)₃-CH-O), 1.83 (d, 3H,

CH₃-CH-Cl), 1.97 (m, 3H, CH)₃C =), 3.3-3.6 (m, 2H,

NH-CH₂-CH), 4.7-5.3 (m, 1H, CH)₂-CH (CH₃) -O), 5.3 (m,

1H, CH₂=), 5.70 (m, 1H, CH)₂=), 6.0-6.6 (m, 2H, NH + + -C 1 -CH-CH)₃).

20th example

Preparation of Ν-Γ2- (1-Acetoxyethoxycarbonyloxy) propyl methacrylamide

Freeze-drying of aqueous solution of equimolar TBA-OH and acetic acid 6.93 g (23 mmol) TBA42

A solution of acetate in 100 mL of THF was added to N- [2- (1-chloroethoxycarbonyloxy) propyl] methacrylamide (4.736 g, 19 mmol) in THF (100 mL) at room temperature . After stirring for 4 days, the solvent was removed under reduced pressure, the residue was dissolved in chloroform (100 mL) and washed with water (5 x 20 mL). The organic layer was dried (over anhydrous MgSO 4) and the solvent removed under reduced pressure. Flash chromatography (silica gel, hexane: ethyl acetate = 3: 4) gave the title product (1.29 g, 25%).

¹1 H-NMR (60 MHz, CDCl 3)?₃Δ: 1.3 (d, 3H, CH)₂-CH (CH₃) -O), 1.5 (d, 3H, O-CH (CH₃(-0), 2.0 (m, 3H, CH)₃C =), 2.1 (s, 3H, CH)₃C = O), 3.3-3.6 (m, 2H, NH-CH)₂-CH), 4.7-5.3 (m, 1H,

CH₂-CH (CH₃(-O), 5.4 (m, 1H, CH)₂=), 5.7 (m, 1H, CH)₂=), 6.1-6.6 (br s, 1H, NH), 6.6-6.9 (m, 1H, O-CH (CH₃)SHE).

21st example

Ν-Γ2- (1-Acetoxyethoxycarbonyloxy) propyl! free radical polymerization of methacrylamide

To a solution of 1.23 g (4.5 mmol) of N- [2- (1-acetoxyethoxycarbonyloxy) propyl] methacrylamide prepared in Example 20 in 18 mL of dry THF was dried at 50 ° C. under nitrogen, 0.0031 g (0.189 mmol) of AIBN was added.

day after, the solvent was removed from the reaction mixture under reduced pressure. Flash chromatography (3: 4 v / v hexane / ethyl acetate / methanol) gave 0.96 g of a white powder.

♦ · · ·

- 43 1H NMR (200 MHz, CDCl3)?₃Δ: 0.8-1.2 (m, 3H, CH)₃), 1.2-1.4 (m,

3H, CH₂"CH (CH₃) -O), 1.5 (d, 3H, O-CH (CH₃(-0), 1.6-2.0 (m, 2H, CH)₂), 2.0-2.2 (s, 3H, CH)₃CO), 2.9-3.9 (m, 2H, NH-CH)₂), 4.7-5.0 (m, 1H, CH)₂CH (CH₃(-0), 6.2-7.0 (m, 2H, NH + O-CH (CH)₃)-SHE).

SEC: MW = 1991, Mn = 1268, Mp = 2105Mw / Mn = 1.548.

Tg = 51.53 ° C.

22nd example

Preparation of methacryloyloxymethyl benzoate

To a solution of methacrylic acid (7.75 g, 0.090 mol) in DMF (300 ml) was added potassium tert-butoxide (10.0 g, 0.090 mol). To the resulting suspension, 15.0 g (0.088 mol) of chloromethyl benzoate³ We added. To the resulting mixture was added 18-crown-6 (1.8 g, 6.9 mmol), and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase (anhydrous MgSO 4)₄ above) and the solvent was removed under reduced pressure. Flash chromatography gave the title product (15.9 g, 82%).

1 H-NMR (60 MHz, CDCl 3) δ: 2.00 (S, 3H, CH₃C =), 5.65 (m, 1H, CH)₂=), 6.15 (s, 2H, -OCH)₂O), 6.35 (m, 1H, CH)₂=), 7.50 (m, 3H, Ph), 8.05 (m, 2H, Ph).

23rd example

Preparation of a polymer from methacryloxyoxymethyl benzoate

To a solution of 1.00 g (4.55 mmol) of methacryloxyoxymethylbenzoate prepared in Example 22 in 8 g of dry THF was added 0.005 g (0.03 mmol) of AIBN at 60 ° C under a dry nitrogen atmosphere. After 24 hours, the reaction mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was dissolved in CH 2 Cl 2 and precipitated in methanol. The methanol was separated from the polymer by filtration to give a white powder.

1 H-NMR (200 MHz, CDCl 3)₃6: 0.85 (m, 3H, CH)₃), 1.87 (m, 2H,

CH₂), 5.70 (m, 2H, -OCH)₂O-), 7.45 (m, 3H, Ph), 8.05 (m, 2H, Ph).

TSC = 60.98 ° C.

SEC: Mw = 30,281, Mn = 11,580, Mp = 32,286, Mw / Mn = 2,615.

24th example

Preparation of methyl chloroethyl carbonate

To a solution of 35.74 g (0.25 mole) of chloroethyl chloro carbonate ester and 8.00 g (0.25 mole) of methanol in 300 ml of methylene chloride was added 19.78 g (0.25 mole) of pyridine. At 0 ° C. After 10 minutes at 0 ° C and 2 days at 25 ° C, the reaction mixture was washed with 100 mL of 100 mL aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and water. After drying (over MgSO4), the solvent was removed under reduced pressure to give the crude methyl chloroethyl carbonate intermediate (25.5 g, 74%).

1 H-NMR (60 MHz, CDCl 3)?₃S, 1.85 (d, 3H, CH)₃CH), 3.80 (s, 3H,

CH₃O), 6.50 (q, 1H, CH).

·&lt;» ··

25th example

Preparation of methyl 1-methacryloxy-oxyethyl carbonate

To a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml) was added potassium tert-butoxide (3.70 g, 0.033 mol). To the resulting suspension was added methyl chloroethyl carbonate (4.55 g, 0.033 mol) prepared in Example 24 followed by 18-crown-6 (0.61 g, 2.3 mmol). The reaction mixture was stirred at room temperature for 3 days, then filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase (anhydrous MgSO 4)₄ above) and the solvent was removed under reduced pressure. Flash chromatography gave 4.46 g (72%) of the title product: 1 H NMR (60 MHz, CDCl₃) δ: 1.65 (d, 3H, CH 3 CH), 2.00 (s, 3H,

CH₃C =), 3.90 (s, 3H, CH3 O), 5.65 (m, 1H, CH)₂=), 6.25 (m, 1H, CH)₂=), 6.90 (q, 1H, CHCH 3).

26th example

Free radical polymerization of methyl 1-methacryloxy-oxyethyl carbonate

To a solution of 1.0 g (5.0 mmol) of methyl 1-methacryloxy-ethylcarbonate in 8 g of dry THF was added 0.005 g (0.03 mmol) of AIBN at 60 ° C under a nitrogen atmosphere. After 24 hours, the reaction mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was CH₂cl₂and precipitated again in methanol. Removal of methanol from the polymer by filtration gave a white powder.

1 H-NMR (200 MHz, CDCl 3)₃) Δ: 0.90 (m, 3H, CH)₃), 1.45 (s, 3H,

CH 3 CH), 1.87 (m, 2H, CH)₂), 3.80 (s, 3H, CH)₃O), 6.65 (bs, 1H, CHCH 3).

SEC: Mw = 16,033, Mn = 6641, Mp = 16,192, Mw / Mn = 2.41. TSC = 57.65 ° C.

27th example

Free Radical Homopolymerization of Benzyl Methacryloxy Oxymethyl Carbonate

In a two-necked round-bottomed flask with magnetic stirrer and condenser (50 ml), prepared 6,6 ml of deoxygenated water (6 x 10 ml).^-2 A solution of sodium dodecyl sulfate (mmol) was added. To this solution was added 0.015 g (6.7 x 10.0) in 1.0 ml deoxygenated water^-2 potassium disulfite (2.0 mmol) and benzyl methacryloxy-oxymethyl carbonate (2.0 g, 8.0 mmol) were added. The reaction mixture was heated to 60 ° C. For the heated reaction mixture, 1.25 x 10l³ g (4.6x10 ~³ potassium persulfate (mmol) was added and the reaction was allowed to proceed. After 5 hours the polymerization was stopped and the polymer emulsion was added dropwise to a large excess of methanol (not solvent). The polymer was then filtered and washed with methanol and water. This procedure was repeated 3 times to purify the polymer. The polymer was then collected and dried under vacuum to remove solvent impurities. A portion of the stable emulsion was not extracted as described above but isolated for light microscopic particle size determination. Produced by emulsion polymerization • · «

- 47 particle size, determined by light microscopy, was less than μπι.

28th example

Preparation of methacryloxy-oxymethyl acetate

To a solution of methacrylic acid (3.87 g, 0.045 mol) in DMF (150 mL) was added potassium tert-butoxide (5.0 g, 0.045 mol). Chloromethyl acetate (4.86 g, 0.045 mol) was added to the resulting suspension³then 18-crown-6 (0.9 g, 3.45 mmol) was added and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was then filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase (anhydrous MgSO 4)₄ ) and the solvent was removed under reduced pressure. Flash chromatography gave 5.19 g (75%) of the title product.

1 H-NMR (60 MHz, CDCl 3)₃) &lt;5: 2.00 (s, 3H, CH)₃C =), 2.18 (s, 3H,

CH₃C = O), 5.70 (m, 1H, CH)₂=), 5.85 (s, 2H, -OCH)₂SHE-),

6.25 (m, 1H, CH)₂=).

29th example

Preparation of butyl acryloyl oxymethyl carbonate

To a solution of acrylic acid (4.47 g, 0.045 mol) in DMF (220 ml) was added potassium tert-butoxide (5.84 g, 0.052 mol). To the resulting slurry was added 6.5 g (0.052 mol) of butyl chloromethyl carbonate in 150 ml of DMF followed by 0.6 g of 18-crown-6 and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was then filtered.

<img file="HUT69070A_D0006.tif" />

needles and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase (anhydrous MgSO 4)₄ ) and the solvent was removed under reduced pressure.

<td>Totten.</td><td>displacement</td><td>chromatography</td><td>process</td><td>by</td><td> 4,57</td><td>g</td>

<td colspan="2">title product</td><td>we got.</td><td></td><td></td><td></td><td></td>

<td>H-NMR</td><td>(60 MHz, CDCl₃]</td><td>1 &lt;5: 0.80 (t, 3H</td><td>, CH3CH2)</td><td> , 1,28</td><td>(M,</td><td>2 H,</td>

<td></td><td>CH₂), 1.60 (m,</td><td>2H, CH₂), 4,15</td><td>(t, CH₂SHE)</td><td> , 5,78</td><td>(S,</td><td>2 H,</td>

OCH₂O), 5.88 (dd, 1H, CH)₂=), 6.1 (dd, 1H, CH₂=), 6.45 (dd, 1H, CH)₂= CH-).

30th example

Preparation of a polymer from methacryloxyoxymethyl acetate

To 1.00 g (4.55 mmol) of methacryloxy-oxymethyl acetate (8 g) in dry THF prepared in Example 28 was added AIBN (0.005 g, 0.03 mmol) at 60 ° C under a dry nitrogen atmosphere. After 24 hours, the reaction mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was CH₂cl₂and precipitated again in methanol. The methanol was removed from the polymer by filtration to give a white powder. TSC = 54.99 ° C.

SEC: Mw = 184,678, Mn = 2446, Mp = 54,732, Mw / Mn = 7.56.

31st example

Preparation of Polymer from Ethyl 1-Methacryloxyoxyethyl Carbonate by Emulsion Polymerization

6.5 mg (0.023 mmol) of sodium dodecyl sulfate in 2.40 ml of water and 6.3 mg (0.028 mmol) of water in 0.82 ml

<img file="HUT69070A_D0007.tif" />

A mixture of potassium disulfite was heated to 60 ° C under nitrogen and 0.617 g (3.10 mmol, prepared as in Example 10) of ethyl 1-methacryloxyethyl carbonate was added. Polymerization was started by adding 0.54 mg (0.002 mmol) of potassium persulfate in 0.25 mL of water. The polymerization was continued at 60 ° C for 20 hours under nitrogen before the reaction mixture was cooled to 20 ° C.

32nd example

Preparation of 1-Chloro-1-phenylmethyl-vinyl carbonate

3.0 g (0.028 mol) of vinyl chloro carbonate ester and 4.14 g (0.0039 mol) of benzaldehyde are dissolved in 30 ml of 1,2-dichloroethane, and 0.1 g (1 g) is added dropwise to the stirred solution. Pyridine (28 mol) was added. The resulting solution was stirred at 80 ° C for 1 day, washed with water (25 mL), and the aqueous layer was extracted with methylene chloride (25 mL). The combined organic layers (anhydrous MgSO₄ dried) and concentrated to give 3.0 g (50%) of the title product.

¹1 H-NMR (60 MHz, CDCl 3)?₃Δ: 4.55 (dd, 1H, CH)₂=), 4.95 (dd,

1H, CH₂=), 7.05 (dd, 1H, CH)₂= CH-), 7.25 (s, 1H,

CH-Ph), 7.40 (m, 5H, Ph).

33rd example

Preparation of 1-Acetoxy-1-phenylmethyl-vinyl carbonate

To a solution of 2.50 g (0.012 mol) of 1-chloro-1-phenylmethyl-vinyl carbonate prepared in Example 32 in 60 ml of DMF was added 2.0 g (0.012 mol) of silver acetate. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methylene chloride to give 0.56 g (20%) of the title product.

1 H-NMR (60 MHz, CDCl 3)?₃) S: 2.24 (s, 3H, CH)₃C = O), 4.60 (dd,

1H, CH₂=), 4.95 (dd, 1H, CH)₂=), 7.00 (dd, 1H, CH =),

7.50 (m, 5H, Ph), 8.00 (s, 1H, -CH-Ph).

34th Example 1: Free radical polymerization of 1-Acetoxy-1-phenylmethyl-vinyl carbonate

To a solution of 1.0 g of 1-acetoxy-1-phenylmethyl-vinyl carbonate prepared in Example 33 in 8 mL of dry THF was added 0.005 g (0.03 mol) of AIBN at 60 ° C under a dry nitrogen atmosphere. After 12 hours, the solvent was removed under reduced pressure. The resulting polymer was CH₂cl₂and then precipitated again in a suitable solvent. The polymer was separated from the solvent by filtration to give a white powder.

35th example

Preparation of O-Benzoyloxymethyl-S-ethylcarbonothioate

To a solution of potassium benzoate (5.94 g, 0.037 mol) in O-chloromethyl-S-ethylcarbonothioate (5.73 g, 0.037 mol) in DMF (20 ml)¹then 0.485 g (1.85 mmol) of 18-crown-6 in DMF (130 mL) was added and the reaction mixture was stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure. The residue was dissolved in chloroform (150 mL) and washed with water (5 x 20 mL) and

<img file="HUT69070A_D0008.tif" />

MgSO4₄ above). Removal of the solvent under reduced pressure and purification by flash chromatography (silica gel, eluting with chloroform) gave the title product (7.16 g, 81%).

³1 H-NMR (60 MHz, CDCl 3)?₃δ: 1.3 (t, 3H, CH₃), 2.9 (q, 2H,

CH₂CH₃), 6.1 (s, 2H, OCH)₂O), 7.3-7.7 (m, 3H, Ph), 8.0-8.2 (m, 2H, Ph).

36th example

Preparation of benzoyloxymethyl chloro-carbonic acid ester

7.13 g (0.030 mole) of O-benzoyloxymethyl-S-ethylcarbonothioate prepared in Example 35 at 0-5 ° C with stirring for 15 minutes were treated with 4.03 g (0.030 mole) of S0.₂cl₂and the reaction mixture was stirred at room temperature for 2 hours. Evaporation of EtSCl at room temperature and 146.6 Pa yielded 5.30 g (83%) of a yellow liquid.

³1 H-NMR (60 MHz, CDCl 3)?₃δ: 6.1 (s, 2H, OCH)₂O), 7.3-7.7 (m, 3H, Ph), 8.0-8.2 (m, 2H, Ph).

37th example

Preparation of N- (3-aminopropyl) methacrylamide

To a solution of 1,3-diaminopropane in 200 mL of methylene chloride was added methacryloyl chloride (8.0 g, 0.078 mmol) in methylene chloride (10 mL) at 0 ° C. After stirring at 0 ° C for 15 minutes and then at 25 ° C for 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue (silica gel, 8: 2 chloroform / methanol)

<img file="HUT69070A_D0009.tif" />

Purification by flash chromatography gave the title compound (yield: 72%).

<td>1 H-NMR (60 MHz,</td><td>CDCl₃/ d₆-aceton) δ: 1.70 (m, 2H, CH)₂CH₂CH₂),</td>

<td>2.00 (s,</td><td>3H, CH₃C), 2.30 (s, 2H, NH)₂), 2.98 (m, 2H,</td>

<td>ch₂nh₂),</td><td>3.35 (m, 2H, NHCH)₂), 5.35 (m, 1H, CH)₂=),</td>

<td>5.80 (m,</td><td>1H, CH₂=), 7.45 (m, 1H, NH).</td>

38th example

Preparation of N- (3-methacrylamidoylpropyl) -O- (benzoyloxymethyl) carbamate in molar equivalent of a 0.1 M solution of N- (3-aminopropyl) methacrylamide in methylene chloride at 0 ° C 1 molar equivalent of benzoyloxymethylchloro carbonate ester was added. After 15 minutes at 0 ° C and then 25 ° C for a suitable period, the reaction mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give the desired N- (3-methacrylamidoylpropyl) -O-benzoyloxymethylcarbamate.

39th example

Free radical polymerization of N- (3-methacrylamidoylpropyl) -O-benzoyloxymethylcarbamate in solution molar equivalent of N- (3-methacrylamidoylpropyl) -O-benzoyloxymethylcarbamate in THF To a 0.5 mol / l solution of the compound prepared at 0 ° C was added 3/100 molar equivalents of AIBN at 60 ° C. After 24 hours at 60 ° C, the reaction mixture was cooled to 25 ° C and concentrated under reduced pressure to dryness. THE • ·

SEC analysis of 53 crude products shows polymer formation.

40th example

Preparation of Chloromethylmorpholine-4-carboxylate To a 0.1 molar solution of chloromethylchlorocarbonate ester in methylene chloride is slowly added 1 molar equivalent of morpholine at low temperature. After the reaction mixture was kept at low temperature for 15 minutes, then kept at 25 ° C for a sufficient time, it was filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give chloromethyl-morpholine-4-carboxylate.

41st example

Preparation of methacryloxy-oxymethyl-morpholine-4-carboxylate

To a solution of 1.1 molar equivalents of the calcium salt of methacrylic acid in DMF, containing 2/100 molar equivalents of 18-crown-6, 1 molar equivalent of chloromethylmorpholine-4-carboxylate was added at 0 ° C. After the reaction mixture was kept at 0 ° C for 15 minutes and then at a sufficiently elevated temperature, it was filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give the desired methacryloxy-oxymethyl-morpholine-4-carboxylate.

42nd example

Free Cryo-Polymerization of Methacryloxymethyl-Morpholine-4-Carboxylate to a 0.5 M Solution of Methacryloxymethyl-Morpholine-4-Carboxylate in THF at 60 ° C for 3/100 molar equivalents of AIBN- t added. After 24 hours at 60 ° C, the reaction mixture was cooled to 25 ° C and concentrated under reduced pressure to dryness. Indicates SEC polymer formation.

43rd example

Preparation of O-methacryloxy-oxymethyl-S-ethylcarbonothioate

1 molar equivalent of calcium salt of methacrylic acid in DMF containing 0/100 molar equivalents of 18-crown-6 at 0 DEG C., 1 molar equivalent of O-chloromethyl-S-ethylcarbonothioate¹We added. The reaction mixture was kept at 0 ° C for 15 minutes and then at an elevated temperature for a sufficient time, then filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give the desired O-methacryloxy-oxymethyl-S-ethylcarbonothioate.

44th EXAMPLE 1 Free Radical Polymerization of O-Methacryloxymethyl-S-Ethyl Carbonothioate to a Molecular Equivalent Solution of O-Methacryloxymethyl-S-Ethyl Carbonothioate in THF at 0.5 ° C at 3/100 molar equivalents of AIBN were added. After 24 hours at 60 ° C, the reaction mixture was cooled to 25 ° C and concentrated under reduced pressure to dryness. It shows the formation of SEC polymer.

45th example

Free radical copolymerization of N- (2-hydroxypropyl) methacrylamide with N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide in solution

0.430 g (3.0 mmol) of N- (2-hydroxypropyl) methacrylamide² and 0.778 g (3.0 mmol) of N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide (prepared in Example 17) was dissolved in THF (10 mL) and heated to 55 ° C. To the solution was added AIBN (0.0207 g, 0.126 mmol), and the reaction mixture was stirred at 55 ° C for 3 days to give a clear gel. This gel was dissolved in THF and the solvent removed under reduced pressure to give 1.33 g of a white powder.

It showed SEC polymer formation.

46th example

Enzyme-catalyzed hydrolysis of the polymer prepared from methacryloxyloxymethyl benzoate was charged with 50 mg of the polymer (prepared in Example 23) and 20 ml of 0.9% w / w aqueous NaCl solution as a finely divided powder. One ampoule of 0.1 ml esterase (Sigma E-3128, 250 U) from porcine liver was added at a concentration of 3.2 M (NH).₄) ₂S0₄crosslinked. An additional ampoule contains 0.1 ml of a 3.2 M solution (NH₄)₂S0₄solution. Using a radiometer-type pH regulator, the vials were maintained at pH 8.0 by the addition of 0.1 M NaOH. The NaOH consumption was recorded by calculating the rate of hydrolysis. At 37 ° C for 45 hours, the hydrolysis of the polymer in the presence of esterase was 11 times faster than that of esterase-free (NH)₄)₂SALT₄- in a control medium. As shown in Figure 1 attached, the hydrolysis did not occur in the control assay with the polymer in 0.9% w / w NaCl. The abscissa of FIG. 1 shows the test time in minutes, while the ordinate shows the consumption of 0.1 M NaOH in mL. Substance (s) added to 20 ml of 0.9% w / w NaCl solution in each ampoule is as follows:

(a) Polymer and esterase, 0,1 ml at a concentration of 3,2 mol / l (NH₄)₂S0₄crosslinked

(b) polymer and 0.1 ml of a 3.2 M solution (NH₄)₂S0₄solution and

(c) polymer only.

5th spreadsheet

0.1M NaOH in mL of 0.9% NaCl in polymer and

0.1 ml ampoule containing esterase in 3.2 M (NH4) 2SO4-0Date

<td>Time (minutes)</td><td>PH</td><td>volume (ml) of added 0,1 mol / l NaOH solution</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 100</td><td> 8,00</td><td> 0,080</td>

<td> 220</td><td> 8,00</td><td> 0,142</td>

<td> 355</td><td> 8,00</td><td> 0,239</td>

<td> 2670</td><td> 8,00</td><td> 1,101</td>

<td> 2710</td><td> 8,00</td><td> 1,105</td>

• · • · · ·

6th spreadsheet

Consumption of 0.1 M NaOH in 20 mL 0.9 wt.% NaOH in a control vial containing polymer and 0.1 mL of 3.2 M (NH4) 2SO4.

<td>Time (minutes)</td><td>PH</td><td>volume (ml) of added 0,1 mol / l NaOH solution</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 120</td><td> 8,00</td><td> 0,012</td>

<td> 240</td><td> 8,00</td><td> 0,030</td>

<td> 4316</td><td> 8,00</td><td> 0,130</td>

<td colspan="3">Table 7 Consumption of 0.1 M NaOH solution Polymer in 20 ml of 0.9% NaCl solution</td>

<td></td><td colspan="2">containing a control vial</td>

<td>Time (minutes)</td><td>PH</td><td>volume (ml) of added 0,1 mol / l NaOH solution</td>

<td> 0</td><td> 8,4</td><td> 0,000</td>

<td> 115</td><td> 8,0</td><td> 0,002</td>

<td> 250</td><td> 8,0</td><td> 0,002</td>

<td> 300</td><td> 8,0</td><td> 0,002</td>

<td> 1600</td><td> 8,0</td><td> 0,002</td>

¹ [Folkmann M. and Lund FJ: Synthesis, 1159 (1990)] ² [J. Stroholm and J. Kopecek, Angew. Macromol. Chemie 70, 109 (1978)].³ [Benneche T., Strandé P. and Wiggen U .: Acta Chem. Scand. 43, 74 (1988)].