Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1996-05-23
1998-04-21
Ambrose, Michael G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
558100, 558166, 558169, 558170, 558172, 558173, 558174, C07F 909
Patent
active
057419230
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 USC 371 and is based upon PCT International Application No. PCT/GB94/02571, filed Nov. 23, 1994.
The present invention relates to an improved process for producing ethylenically unsaturated phosphate ester compounds. The process is suitable as part of a process for producing polymerisable monomers for use in the production of polymers which mimic cell surfaces. In particular the process involves a two-stage reaction, the successive stages being conducted in the presence of organic solvents. The present invention provides improved products which can be used to form clear polymer products, of particular use for ophthalmological applications, in the manufacture of contact lenses, for example.
The first published route (J.P. Appl. No. 60-21599, Kobunshi Ronbunshu 1978, 35, 7, 423) to 2-(methacryloyloxy ethyl)-2'(trimethylammonium ethyl) phosphate, inner salt (Hema-PC) is illustrated in Scheme I ##STR1##
The bromoethyldichlorophosphate (1), obtained from bromoethanol and phosphorus oxychloride, was treated with 2-hydroxyethylmethacrylate to give the phosphate diester chloride (2). Hydrolysis gave the acid analogue (3) which, on reaction with trimethylamine in methanol, gave the phosphorylcholine derivative (4). Conversion to the hydroxide salt (5) was effected using methanolic silver carbonate. The product (5) was isolated using column chromatography on silica-gel and the overall yield was under 5%.
In addition to the low overall yield, purification by column chromatography is inconvenient and expensive, particularly on a larger scale, and the product from this process was isolated in a hydrated form which may not be appropriate for some applications of the product or indeed, for the facile isolation of the product, a point subsequently accepted by the authors (Polymer Journal 1990, 22, 5, 355).
Synthetic processes for producing phosphoryl choline containing lipids, by a two step reaction, in the first step of which a hydroxyl substituted starting material is reacted with a halophospholane, followed by a ring opening reaction with a trialkylamine has been described by Chabrier and colleagues in -FR-A-2,270,887 and Bul. Soc. Chim. de France (1974) 667-671. The first step is carried out in an organic solvent selected from benzene, ether and tetrahydrofuran. The second step is carried out in an aprotic solvent selected from acetone and acetonitrile. Dong & Butcher in Tetrahedron Letters (1991) 32, 5291-5294 also used the reaction of a hydroxyl group containing compound with a halophospholane, followed by ring opening using trimethylamine to make a synthetic sphingomyelin. The former step was carried out in benzene, with the latter step being carried out in a mixed solvent of benzene and acetonitrile.
An analogous two stage reaction has also been described for producing HEMA-PC, by Nakaya et al, as depicted in scheme 2. The process is described in JP-A-58-154591, 1983 and Makromol. Chem., Rapid Commun., 1982, 3, 457), which involved coupling of 2-hydroxyethylmethacrylate to the chlorophospholane (6) to give intermediate (7) which was trimethylaminated under pressure to give the diester (8). ##STR2##
For the first stage of the reaction the authors describe the use of etheral solvents such as diethylether and tetrahydrofuran. Triethylamine hydrochloride, a byproduct of the reaction, precipitated from these solvents and was removed by filtration to give a solution of the phospholane (7). The solvent was then removed by distillation and the residual material dissolved in acetonitrile and heated with trimethylamine to give the product (8) after concentration. Precipitation of chloroform solution of (8) from acetone was the described means of purification. This basic chemical process is described in our earlier publication no. WO-A-92-07885.
We have now found that the product (8), prepared and purified in this way, may not be of the desired purity for certain applications, such as the production of co-polymers intended for fabricating or coating medical devices, for example. In particu
REFERENCES:
Chemical Abstracts, vol. 105, No. 12, 22 Sep. 1986, Abstract No. 098087, T. Nakaya et al.
Chemical Abstracts, vol. 100, No. 9,27 Feb. 1984, Abstract No. 068530, T. Nakaya.
Bull. Soc. Chim. de France, 1974, No. 3-4, pp. 667-671, P. Chabrier et al.
Tetrahedron Letters, vol. 32, No. 39, pp. 5291-5294, 1991, Z. Dong et al.
Makromal. Chem., Rapid Commun. vol. 3, pp. 457-459, 1982, T. Umeda et al.
Polymer Journal, vol. 22, No. 5, pp. 355-360, 1990, K. Ishihara et al.
Kobunishi Ronbunshu 1978, vol. 35, No. 7, pp. 423-424.
Driver Michael John
Jackson Deborah Jane
Ambrose Michael G.
Biocompatibles Limited
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