JPH11513682A - Oxidation of phosphorus compounds - Google Patents

Abstract

  (57) [Summary] A phosphite triester compound comprising oxidizing a residue of an ethylenically unsaturated alcohol to form a corresponding phosphoric triester. The product can be reacted in a later step to form a zwitterionic compound, such as a phosphorylcholine derivative. In a particularly preferred embodiment of this method, the oxidizing agent is a tertiary amine oxide and the starting phosphite triester is a cyclic compound capable of reacting with the amine by-product of the oxidation reaction to open the ring. is there.

Description

DETAILED DESCRIPTION OF THE INVENTION                             Oxidation of phosphorus compounds   The present invention relates to a method for oxidizing a phosphite triester compound to prepare a corresponding phosphate ester. To a method of forming a derivative of phosphorus, ie, a phosphorus V compound. This method uses an oxidizing agent Use tertiary amine oxides as the Or as a reactant in a later step such as replacement of a halogen atom.   For oxidizing the phosphite compound to form the corresponding phosphorus V compound There are various synthesis methods. For example, various starting materials starting with phosphorus trichloride The synthesis method involves the production of a phosphate ester through a phosphite intermediate in a multi-step process. Form a product. Such methods include phospholipid derivatives, glycolipid derivatives and nucleic acids Used in the synthesis of 1,3,2-dioxaphosphorane and 1,3,2-dioxaphos Cyclic diesters such as holinan are oxidized to form the corresponding 2-oxo derivatives can do. Edmundson et al., Chem. And Ind (1966), pp. 1828-1829, Successful use of molecular oxygen as an oxidant in benzene, especially for phosphoranes It is stated that. Nitrous oxide has also been used as an oxidizing agent.   In nucleic acid synthesis, phosphite triesters are generally pyridine or 2,6- Oxidized using aqueous iodine in the presence of thidine, the corresponding phosphate triester To form Iodine cannot be used in non-aqueous systems and therefore has water-sensitive substituents. It is useless for oxidizing phosphorus III compounds. For example, Edm in the above book oxidizes phosphorane or phosphorinane compounds as described by undson It is useless for it.   Other oxidants oxidize phosphite compounds in nucleic acid synthesis Some of them can be used in non-aqueous solvent systems. For nucleic acid synthesis Examples of non-aqueous oxidizing agents used in the art include catalytic amounts of trimethylsilyl triflate. Tom-Chloroperbenzoic acid, dimethyl sulfoxide, trimethylamine,N-E Oxide, pyridine-N-oxide, N-methylmorpholine-N-oxide, iodobenze Diacetate, tetraperiodatenTetraacid in the presence of -butylammonium Nitride, tert-butyl hydroperoxide, tert-butyl hydroperoxy , Cumene hydroperoxide, hydrogen peroxide, bis- (trimethylsilyl) peroxide Oxide, as well as oxygen in the presence of a free radical generator. But nucleo Iodized water is the reagent of choice for the oxidation of triphosphite triesters.   Noyori and co-workers, Tet. Lett (1986) 27 (35), 4191-94 (Hayakawa et al.) Amine oxide compound, trimethylamine N-oxide, N-methylmorpholine-N- Various non-phosphorous triesters, including oxides and pyridine-N-oxides Describes the hydroxylation method. The first and third mentioned amine oxide yields are , Very low despite the long reaction time. The yield of the second compound is , Was theoretical. Amine oxide as oxidizing agent, giving high phosphate ester yield It would be desirable to provide a method for using SIDs.   Bull.Soc.Chim.Fr. (1974), 3-4 edition, pages 677-680, Branlet and Chabrier Is the oxidation of a cyclic phosphite triester, followed by simultaneous ring opening and the corresponding Amination of phosphoric triesters to form phosphorylcholine derivatives It has been described. Phosphorous triesters include ethoxy, O-acetylphenoxy, Selected from enoxy and methoxy Alkylene optionally substituted by a third alkoxy group Or diesters of 1,3-propanediol. This oxidizing agent is Luamine oxide. C.R.Acad.Sci.Paris, Ser C (CHDCAQ) (1973), 276 (13), 1 At 135-7, Chabrier and Branlt further diverged using tertiary amine oxides. Discloses the oxidation of a monomethoxy cyclic phosphite triester.   In the novel method of the present invention for forming phosphotriester compounds: Formula I   Where R⁷Is a linear or branched alkylene, oxoalkylene or oligo- An oxaalkylene chain, and B is     Where:     R is hydrogen or C₁-C_FourAn alkyl group;     A is -O- or -NR⁸-(Where R⁸Is hydrogen or C₁-C_FourAn alkyl group) And;     K is a group-(CH_Two) pOC (O)-,-(CH_Two) pC (O) O-,-(CH_Two) pOC (O) O-,-(CH_Two) pNR⁹-,-(C H_Two) pOC (O) NR⁹-,-(CH_Two) pNR⁹C (O) NR⁹-(Wherein the group R⁹Are the same or different), -(CH_Two) pO-,-(CH_Two) PSO_Three-Or is a valence bond, and p is 1-12 And R⁹Is hydrogen Or C₁-C_FourAn alkyl group;   An ethylenically unsaturated polymerizable group selected from the group consisting of:   R^FourAnd R^FiveAre the same or different and are unsubstituted or aryl groups, hydro Xyl group, halogen atom, amine (mono-, di- or tri-alkyl-substituted Amines), sulfonium, thiol, carboxylic acid or phosphonium Each of which may be substituted by_1-40Linear or branched -alkyl group,- Selected from alkenyl and -alkynyl, or R^FourAnd R^FiveIs Together with the oxygen and phosphorus atoms attached thereto and a 5- to 15-membered heterocycle Forming a formula ring, optionally further adding heteroatoms and / or substituents to the ring May contain elemental and / or nitrogen atoms (if any), Is oxidized with an oxidizing agent in solution to give the corresponding formula II   Where BR⁷, 4 and R^FiveIs as defined for formula I, To form a phosphoric acid triester of   Used in the prior art to oxidize phosphite triesters, and Conventional oxidizing agents as described in the prior art discussion can also be used, Some of these were found to attack the ethylene bond of group B. This In a preferred aspect such as, the oxidizing agent is a tertiary amine oxide Z → O, The corresponding tertiary amine Z is a by-product And generate. This allows the compound of formula II and the tertiary amine to be reacted together in a later step. Let formula III   Where R⁷Is as defined above for formula I, and Y is -O^-Or OH And then R⁶Is R^FourOr R^FiveAnd R⁶The acids that are bound to them Linked together with elemental and phosphorus atoms to form a heterocyclic ring in the compound of formula II; Where Y is -O in formula III^-Or OH,   Base⁺ZR^FiveR^Four− (Where R^FourR^FiveRepresents a group as defined for compounds of formula II; Is the above tertiary amine, provided that Y is OR^FiveIf R⁶Is R^Fouris not ) Can be produced.   In view of this method, the tertiary amine used as an oxidizing agent for the phosphite triester The oxide can be any suitable tertiary amine oxide. Suitable amine oxide Examples include trialkylamine oxide (wherein the alkyl groups are For example, trimethylamine-N-oxide), or Unsaturated heterocyclic rings such as, or saturated ring systems such as N-lower alkyl morpholine rings May be a heterocyclic amine based on Thus, the tertiary amine oxide is pyridine-N -Oxide or N-methylmorpholine-N-oxide. Preferably third Amine oxide is trimethylamine-N-oxide.   In the preferred embodiment of the present invention, a two-step process, in-situ instantaneous oxidation Intermediates can be further reacted with by-products of the oxidation reaction in additional steps . A further step may be a base-catalyzed protection step in which the protecting group R^Five Is removed from the phosphate ester. Alternatively, for example, the reaction is a halo-substituted alkyl Group R^FourMay be subjected to an amination reaction to produce a corresponding quaternary ammonium compound. In a further example, a tertiary amine is used simultaneously in the deprotection and amination reaction, If the group R⁶And R^FiveAre connected to each other to form an oxygen atom to which they are bonded and Forming a heterocyclic ring with the phosphorus atom, thereby forming the group R⁶Is a quaternary ammonium group Wachi R^FourR^FiveZ⁺Is formed to form a ring-opened phosphoric diester.   In such a subsequent step, it is preferable to further include a tertiary amine reactant. This tertiary amine reactant is usually the same as the tertiary amine by-product. Again Adding a medium and / or removing some or all solvent from the first step Is preferred. Preferably, however, no solvent is removed after the first step.   R^FourIs preferably lower substituted by unsubstituted lower alkyl or halogen. Alkyl or R^FiveTogether with to form a 5-7 membered ring.   In the present invention, the group R^FiveIs preferably C_1-6An alkyl group or an aryl group; Preferably, a halogen atom, a nitro group, a cyano group, a sulfonyl group and an aryl (he (Including teroaryl) groups. R^Five Substituents further add steric hindrance (e.g., a 1,1-dialkyl substituent on the alkyl group). Can be provided. R^FiveCan represent a methyl group, but preferably Lower alkyl groups with electron-withdrawing substituents such as phenolic, cyano or vinyl groups Represents Preferably the group R^FiveIs allyl, benzyl, phenyl, phenylsulfoethyl Le, Mech Ru-sulfoethyl, para-nitrophenylethyl, 2,2,2-trihaloethyl (especially Trichloro- and tribromo-ethyl), 2,2,2-trihalo-1,1-dialkylethyl (Especially 2,2,2-trichloro-1,1-dimethylethyl, 2′- and 4′-pyridylethyl,m- Methylbenzyl,p-Orm-Halobenzyl,m, p-Dichlorobenzyl, pentahalo Phenyl (especially pentafluoro- and pentachloro-phenyl) 2,6-dimethylphenyl Phenyl and 2,4-dinitrophenyl and most preferably beta-cyanoethyl It is. In another preferred aspect of the invention, a group R^FiveIs the group R^FourLinked with ethylene or Forms higher poly (methylene) groups.   R^FourIs preferably an unsubstituted lower alkyl (C_1-6-Alkyl) or halogen Is a lower alkyl substituted with Alternatively, R^FourAnd R^FiveAre together-(CH_Two)_2-6- , Preferably-(CH_Two)_Two-Yes.   In the compounds of the formula I, B is preferably of the formula CH_Two= C (R) -CO-A-. Preferred Alternatively, R is hydrogen or methyl, preferably methyl. A is -NR⁸-But good More preferably -O-. R⁷Is preferably-(CH_Two)_2-6-, Preferably -CH_Two-CH_Two-Is .   Suitable solvents for the oxidation step include nitrile derivatives of lower carboxylic acids, especially Cetonitrile, and dimethylformamide and dimethylacetamide And other aprotic solvents. When the oxidizing agent is a tertiary amine oxide, The use of acetonitrile gives excellent yields and low levels of by-product formation, Aspects of consideration by Hayakawa et al. (Supra) where such solvents produce poor results. Is surprising.   Suitable solvents for the method steps after the oxidation step are acetonitrile and acetonitrile. Mixture of lyl and dichloromethane, methanol / chloroform Or a more aqueous lower alcohol mixture.   The present invention is further specifically described in the following examples.   Examples 3-5 demonstrate the use of oxidizing agents other than tertiary amine oxides in the first step of the method. Represent. These are the speeds of the oxidation step of the preferred embodiment of the present invention using amine oxides. The degree and yield of meta-chloroper ammonium, a commonly used non-aqueous oxidizing agent, Compared to methods using benzoic acid, nitrous oxide and tertiary butyl hydroperoxide Indicates that they are enemies. This result also indicates that, in a preferred embodiment of the present invention, the amine Use of oxide oxidizer facilitates further reaction steps and separates reaction intermediates Indicates that it is not necessary to do so.Example 1 2- ( (Methacryloyloxyethyl) -2'-trimethylammoniumethyl) phosphe Large-scale production of salts and inner salts 1.1 N, N-diisopropylaminoethylene phosphite   Diisopropylamine (463 g, 4518 mmol) was stirred for 1 hour. 2-chloro-1,3,2-dioxaphospholane (distilled, 115.8 g, 915 mmol) solution ( (In 4000 ml of anhydrous ether) at −10 ° C. under nitrogen. Bring the mixture to room temperature, Stir for 16 hours and filter to remove diisopropylammonium chloride. And the filter bed was washed with ether (400 ml). About 500 filtrate and washings evaporate to ml and the mixture is re-filtered and the filter bed is washed with ether (140 0ml) Was. The solvent was removed to give a free flowing liquid, which was filtered through a sinter funnel and fractionated. Distilled (40 ° C, 0.1 mbar) to give pure N, N-diisopropylaminoethylenephos Fit, 104.2 g, 545 mmol, 60% yield.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.17 (d), 3.46 (m ), 3.89 (m), 4.14 (m)1.2 2-[(methacryloyl) ethyloxy] -1,3,2-dioxaphosphorane   4,5-dichloroimidazole (70 g, 511 mmol) and 2-hydroxyethyl meta A mixture of acrylate (68.0 g, 523 mmol) was dissolved in dry acetonitrile (500 ml). I understand. N, N-diisopropylaminoethylene phosphite (100 g, 523 mmol) ( (In 100 ml of dry acetonitrile) at room temperature under nitrogen atmosphere for 1 hour And then stirred for 10 minutes. The mixture was filtered through a bed of Celite tightly packed. And the pad washed with acetonitrile (200 ml) to give 2-[(methacryloyl) ethyl [Loxy] -1,3,2-dioxaphospholane solution was obtained and used immediately.1.3 2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphora N   2-[(methacryloyl) ethyloxy] -1,3,2-dioxaphosphorane solution (A (In 800 ml of cetonitrile) was cooled to -10 ° C and anhydrous trimethylamine-N-oxide (35.4 g, 471 mmol) solution (in 200 ml of acetonitrile) under nitrogen for 90 minutes Dripped. The mixture was warmed to room temperature and the solvent was evaporated to about 800 ml and 2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphorane solution Which was used immediately. The sample is¹Analyzed by H-nmr.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.97 (s), 4.43 (m ), 5.66 (s), 6.21 (s)   The Tlc of the product indicated that it was clean but contained some by-products.1.4 2- (methacryloyloxyethyl) -2'-trimethylammoniumethyl) Phosphate inner salt   2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphorane solution Was treated with trimethylamine (49.9 g, 845 mmol) in 200 ml of acetonitrile. And stirred at 50 ° C. for 16 hours. The mixture is cooled to ambient temperature and excess Some of the methylamine was removed under reduced pressure. Warm the solution to 80 ° C and Celite under nitrogen Filtered through the bed. After cooling, a total of 300 ml of acetonitrile was removed under reduced pressure. After crystallization and the solid is isolated after crystallization to give pure 2- (methacryloyloxyethyl ) -2'-trimethylammoniumethyl) phosphate, inner salt, 35.0 g, 119 ml Limol was obtained from 2-hydroxyethyl methacrylate in 23% yield.¹ H-nmr, 200 MHz, (D_TwoO) δ = 1.94 (s), 3.21 (s) , 3.66 (m), 4.17 (m), 4.31 (m), 4.39 (m), 5.76 ( s), 6.19 (s)¹³ C-nmr, 50.1 MHz, (D_TwoO) δ = 20.2, 56.8, 62.3 , 66.7, 67.3, 68.8, 129.9, 138.7, 172.4Example 2 2-[( Methacryloyl) ethyloxy] -1,3,2-dioxaphosphorane   4,5-dichloroimidazole (7.16 g, 52.3 mmol) and 2-hydroxyethyl Mix a mixture of methacrylate (6.8 g, 52.3 mmol) with dry acetonitrile (100 ml) Was dissolved. N, N-diisopropylaminoethylene phosphite (10 g, 52.3 mmol Was added under a nitrogen atmosphere at room temperature and stirred for 10 minutes. Mixture Celite Filter through a tightly packed bed and wash the pad with acetonitrile (about 20 ml). To give 2-[(methacryloyl) ethyloxy] -1,3,2-dioxaphosphorane solution, This was used immediately.¹ Hnmr, 200 MHz, (CDCl_Three) Δ = 1.97 (s), 4.01 (m ), 4.25 (m), 5.62 (s), 6.20 (s)2-[( Methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphorane   2-[(methacryloyl) ethyloxy] -1,3,2-dioxaphosphorane solution (acetonate (In 25 ml of tolyl) was cooled to 0 ° C. and trimethylamine-N-oxide (3.54 g, 47 .1 mmol) solution (in 10 ml of acetonitrile) was added dropwise under nitrogen. Bring the mixture to room temperature Warm to 2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphorane Which was used immediately. The sample is¹Analyzed by H-nmr.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.96 (s), 4.43 ( m), 5.63 (s), 6.21 (s)   The product Tlc indicates that the product is clean without significant by-products Indicated.2- ( (Methacryloyloxyethyl) -2'-trimethylammoniumethyl) phosphe Salt, inner salt   2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2-dioxaphosphorane solution Was dried with acetonitrile (20 ml) using trimethylamine (4.64 g, 78.0 mmol). ) And stirred at 50 ° C. for 48 hours. Cool the mixture to ambient temperature and To about half the volume. The mixture was cooled to -20 C over 16 hours. The mixture was filtered through filter paper under nitrogen and washed with acetonitrile (13 ml) . Isolate solid after crystallization And pure 2- (methacryloyloxyethyl) -2'-trimethyl-ammonium methyl Le) phosphate, inner salt, 4.16 g, 14.1 mmol, 27% yield from 2-hydroxy Obtained from ethyl methacrylate.¹ H-nmr, 200 MHz, (D_TwoO) δ = 1.94 (s), 3.21 (s) , 3.67 (m), 4.17 (m), 4.30 (m), 4.39 (m), 5.75 ( s), 6.19 (s)   The second crop was crystallized and purified by column chromatography on silica (150 g). And purified by elution with methanol, 3.87 g, 13.0 mmol, 25% The yield was obtained from 2-hydroxyethyl methacrylate.¹ H-nmr, 200 MHz, (D_TwoO) δ = 1.93 (s), 3.19 (s) , 3.64 (m), 4.14 (m), 4.29 (m), 4.39 (m), 5.74 ( s), 6.19 (s)   The overall yield (based on 2-hydroxyethyl methacrylate) was 52%.Example 3 2- (methacryloyloxyethyl) -2 using oxidized metachloroperbenzoic acid '-Trimethylammoniumethyl) phosphate, inner salt   2-hydroxyethyl methacrylate (0.43 g, 3.32 mmol) and 4,5-dichloro Loimidazole (0.45 g, 3.32 mmol) was added to 4A in dry acetonitrile (10 ml). Was stirred in the presence of a molecular sieve (1 g). Mix bis (diisopropylamino) -cyanoethylphosphine (1 g, 3.32 mmol) The mixture was stirred at room temperature under nitrogen for 4 hours to remove the crude monophosphoramidite. Obtained.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.18 (d), 1.94 ( s), 2.62 (t), 3.60 (m), 3.84 (m), 4.30 (t), 5.6 0 (s), 6.14 (s)   Bromoethanol (redistilled, 0.41 g, 3.32 mmol), 4,5-dichloroimida Reaction mixture of sol (0.45 g, 3.32 mmol) and 4A molecular sieve (1 g) And stirred at room temperature for 16 hours. Additional bromoethanol (re-steamed) (0.05 g, 0.40 mmol) was added and the mixture was stirred at 40 ° C. for 4 hours. After filtration through Celite and a 0.2 μm glass fiber filter, the solvent was removed. Removal gave crude triphosphite.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.43 (d), 1.94 (s), 2.68 (t), 3.50 (t), 4.11 (m), 4 .34 (t), 5.62 (s), 6.17 (s)   The crude triphosphite is dissolved in dichloromethane (20 ml) andmeta-Chloro Treat with perbenzoic acid (0.57 g, 3.32 mmol) and stir at room temperature for 10 minutes did. The solution was extracted with saturated aqueous sodium bicarbonate (4 x about 20ml). The combined aqueous layers were extracted back into dichloromethane and extracted (about 40 ml). Pooled with the previous organic fraction and re-extracted with saturated aqueous sodium bicarbonate (2 X about 20 ml). The mixture is dried over magnesium sulfate and evaporated to give Sulfate, 1.18 g, 3.19 mmol, 96% yield, Obtained from Relate.¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 2.00 (s), 2.80 ( t), 3.54 (t), 4.37 (m), 5.65 (s), 6.19 (s)   The product, Tlc, shows significant by-products, with oxidants attacking ethylenically unsaturated groups. Probably due to living things. Thus, the product uses an amine oxide oxidizing agent. It was not as clean as when used.   Crude triphosphate (1.18 g, 3.19 mmol) in dry acetonitrile (about 30 ml) Dissolve and use trimethylamine (1.57 g, 26.5 mmol) in a closed vessel Treated and heated at 75 ° C. for 48 hours. Mix 4A molecular sieve (1.5g) And heating was maintained for a further 2 hours before Celite and 0.2 μm glass Filtered through a fiber filter. The solvent is evaporated and the residue is methanol And purified by column chromatography on silica gel (about 20 g). And eluted with methanol. The fractions containing the product are combined and evaporated to dryness to give Trendy 2- (methacryloyloxyethyl) -2 '-(trimethylammoniumethyl) pho Sphate, inner salt, 0.29 g, 0.97 mmol, 30% yield.¹ H-nmr, 200 MHz, (D_TwoO) δ = 1.96 (s), 3.23 (s) , 3.67 (m), 4.17 (m), 4.31 (m), 4.40 (m), 5.76 ( s), 6.20 (s)   2- (methacryloyloxyethyl) from 2-hydroxyethyl methacrylate -2 '-(trimethylammoniumethyl) phosphate, total yield of inner salt is 29% Met.Example 4 2-[(methacryloyl) ethyloxy] -2-oxo-1, using nitrous oxide oxidizing agent 3,2-dioxaphosphorane   Nitrous oxide was prepared according to the method of MS Anson and C McGuigan (J. Chem. Soc. s. 1, 1989, 715). Dissolution of nitrous oxide (0.175 g, 1.92 mmol) Liquid (in 12 ml of dry dichloromethane) with 2-[(methacryloyl) ethyloxy] -1,3,2- Dioxaphosphorane solution (prepared in Example 1.2) (1.69 g, 7.68 mmol) (dry (In dichloromethane) at -60 ° C. After 5 minutes, warm the mixture to room temperature, Then the solvent is evaporated to give crude 2-[(methacryloyl) ethyloxy] -2-oxo-1,3,2- Dioxaphospholane (1.86 g, 7.8 mmol) was obtained and used immediately (eg, (Corresponding to Example 1.4).¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.97 (s), 4.44 ( m), 5.63 (s), 6.21 (s)   The Tlc of this product is cleaner than the products of Examples 1 and 2. Not shown.Example 5 t- 2-[(methacryloyl) ethyloxy using butyl hydroperoxide oxidizing agent [S] -2-oxo-1,3,2-dioxaphosphorane   In Deccantert-Butyl hydroperoxide solution (5.5 M, 1.40 ml, 7.68 mmol )) (In 15 ml of dry dichloromethane) with 2-[(methacryloyl) ethyloxy] -1,3,2 -Dioxaphosphorane solution (1.69 g, 7.68 mmol) (prepared in Example 7.2) (dry (In 15 ml of dry dichloromethane) at 0 ° C. After 5 minutes, bring the mixture to room temperature Warm and evaporate the solvent and dry the residue under vacuum to dry the crude 2-[(methacrylic acid). Loyl) ethyloxy] -2-oxo-1,3,2-dioxaphospholane, which is commonly used (E.g., in a step corresponding to Example 1.4).¹ H-nmr, 200 MHz, (CDCl_Three) Δ = 1.97 (s), 4.46 ( m), 5.63 (s), 6.21 (s)   The Tlc of this product is less clean than the products of Examples 1 and 2. It has been shown.Example 6 2- ( (Methacryloyloxyethyl) -2 '-(trimethylammoniumethyl) phosphe Production of salt   2-chloro-1,3,2-dioxaphosphorane solution in acetonitrile (4.9 g, 0.04 M) Was added 2,6-dimethylpyridine (4.0 g, 0.04 M) over 20 minutes. While cooling, it was cooled to -10 ° C under a nitrogen atmosphere. The mixture is stirred at -10 ° C for a further 20 minutes. Stirred. A solution of 2-hydroxyethyl methacrylate (4.4 g, 0.033 M) in acetonitrile (In 8 ml of tolyl) was added at -10 ° C over 15 minutes. Warm the mixture to 0 ° C and And filtered. The filtrate was cooled to −10 ° C. and trimethylamine N-oxide (2.4 g , 0.32M) in 25 ml of acetonitrile. Trimethylamine (3 .3 g) solution (in 10 ml of acetonitrile) was added. Add the mixture in a closed system at 45 ° C for 16 hours Heating gives the desired product, which concentrates the reaction mixture and crystallizes at 0 ° C. By isolation.   By Tlc of this product, the product is clean and contaminated with small amounts of by-products. It was shown that.¹ H-nmr, 200 MHz, (D_TwoO) δ = 1.94 (s), 3.21 (s) , 3.66 (m), 4.17 (m), 4.31 (m), 4.39 (m), 5.76 ( s), 6.19 (s)¹³ C-nmr, 50.1 MHz, (D_TwoO) δ = 20.2, 56.8, 62.3 , 66.7, 67.3, 68.8, 129.9, 138.7, 172.4

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, G E, HU, IL, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, P L, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, US, UZ, VN (72) Inventor Brown, Judith Elizabeth             UK Sally             El Farnham Waydon Rain Hu             Arnam Business Park Frencham             House Bio Compatibles Limited             Do

Claims (1)

[Claims] 1. A method for forming a phosphotriester compound, comprising: Formula I   Where R⁷Is a linear or branched alkylene, oxoalkylene or oligo- An oxaalkylene chain, and B is     Where:     R is hydrogen or C₁-C_FourAn alkyl group;     A is -O- or -NR⁸-(Where R⁸Is hydrogen or C₁-C_FourAn alkyl group) And;     K is a group-(CH_Two) pOC (O)-,-(CH_Two) pC (O) O-,-(CH_Two) pOC (O) O-,-(CH_Two) pNR⁹-,-(C H_Two) pOC (O) NR⁹-,-(CH_Two) pNR⁹C (O) NR⁹-(Wherein the group R⁹Are the same or different), -(CH_Two) pO-,-(CH_Two) PSO_Three-Or is a valence bond, and p is 1-12 And R⁹Is hydrogen or C₁-C_FourAn alkyl group;   An ethylenically unsaturated polymerizable group selected from the group consisting of:   R^FourAnd R^FiveAre the same or different and each is unsubstituted or aryl Group, hydroxyl group, halogen atom, amine (mono-, di- or tri- Alkyl-substituted amine) group, sulfonium, C which may be substituted by an all, carboxylic acid or phosphonium group_1-40Straight chain Or branched -alkyl, -alkenyl and -alkynyl groups Or R^FourAnd R^FiveTogether with the oxygen atom and And a 5- to 15-membered heterocyclic ring, and in some cases further Adding a terrorist atom and / or substituent to a ring carbon and / or nitrogen (if any) May include Is oxidized with an oxidizing agent in solution to give the corresponding formula II   Where R⁷, B, R^FourAnd R^FiveIs as defined for formula I, Form a phosphoric acid triester of The above forming method. 2. The oxidizing agent is a tertiary amine oxide Z → O, whereby the corresponding tertiary amine 2. The method according to claim 1, wherein Z is formed as a by-product. 3. The compound of formula II and the tertiary amine by-product are reacted together in a later step to form a compound of formula II I   Where B and R⁷Is the same group as in the compound of formula II, and Y is -O^- Or OH or OR^Five(Where R^FiveIs as defined in claim 1), And R⁶Is R^FourOr R^FiveAnd R^FourAre the oxygen and And a phosphorus atom to form a heterocyclic ring in the compound of formula II; Is -O of compound III^-Or, if it is OH, the group⁺ZR^FiveR^Four-(Where R^FourR^FiveIs of formula II Represents a group as defined for compounds, and Z is as defined above for tertiary amine oxide Where Y is OR^Five, R⁶Is R^Fouris not , 3. The method according to claim 2, wherein the compound of formula (1) is produced. 4. After the above step, the protecting group OR^FiveIs O^-Or OH (ie Y is O^-Or 4. A method according to claim 3, comprising a base-catalyzed deprotection step, which is replaced by OH). The method described in. 5. After the above process, R^FourReacting compound II, which represents a halo-alkyl group, Claims comprising an amination reaction for substituting an ammonium group for a logogen atom. Item 5. The method according to item 3 or 4. 6. R^FourAnd R^FiveAtoms and phosphorus atoms which are linked to each other by To form a heterocyclic ring together with a compound of formula III wherein R⁶Is Group R^FourR^FiveZ⁺Which is a simultaneous ring opening and amination reaction to produce Item 4. The method according to Item 3. 7. The solvent in the oxidation step and the subsequent steps described above is the same, and preferably The method according to any of claims 3 to 6, wherein the method is tonitrile. 8. Z → O is a trialkylamine oxide (preferably each alkyl group is a lower alkyl group) Or a saturated or unsaturated heterocyclic ring Formula amine oxide, preferably pyridine-N-oxide or N-lower alkyl A rufoline-N-oxide, most preferably trimethylamine-N-oxide, A method according to any of claims 2 to 7, wherein the method comprises: 9. R^FiveIs a halogen atom, a nitro group, a cyano group, a sulfonyl group and an aryl ( Preferably substituted by one or more electron withdrawing groups such as heteroaryl groups) C_1-6Any of the preceding claims, which is an alkyl or aryl group The method described in Crab. 10. R^FiveIs allyl, benzyl, phenyl, phenylsulfoethyl, methyl-s Rufoethyl, para-nitrophenylethyl, 2,2,2-trihaloethyl (especially (Rolol- and tribromo-ethyl), 2,2,2-trihalo-1,1-dialkylethyl (particularly 2,2,2-trichloro-1,1-dimethylethyl, 2'- and 4'-pyridylethyl,m-Me Tylbenzyl,p-Orm-Halobenzyl,m, p-Dichlorobenzyl, pentahalov Phenyl (especially pentafluoro- and pentachloro-phenyl) 2,6-dimethylphen Nil and 2,4-dinitrophenyl and most preferably beta-cyanoethyl 10. The method according to claim 9, wherein the method is selected from: 11. B is the formula   Wherein R is hydrogen or methyl, preferably methyl, and A is preferably Is -O-; and   R⁷Is (CH_Two)_2-6, Preferably (CH_Two)_TwoIs, A method according to any of the preceding claims, wherein the group is 12. R^FourIs an unsaturated lower alkyl or halogen-substituted lower alkyl. A method according to any of the preceding claims, wherein the method is alkenyl. 13. R^FourAnd R^FiveTogether, (CH_Two)_2-6, Preferably (CH_Two)_TwoClaims that are Item 7. The method according to Item 1 or 6.