CN1202899A - Synthesis of polymerable phosphodiester - Google Patents

Abstract

The ethylenically unsaturated alcohol is phosphitylated by using a monofunctional or difunctional aminophosphite phosphoritylation agent, and the product can be oxidized to the corresponding phosphate ester, which can be further reacted to form a phosphorylcholine derivative. This method is very valuable in synthesizing 2-(methacryloyloxyethyl)-2'-(trimethylammonioethyl)phosphate inner salt. The advantage over the prior art methods is that the starting materials and intermediates are more stable and thus easier to handle.

Description

Synthesis of Polymerizable Phosphoric Diesters

The invention relates to a method for synthesizing a polymerizable ethylenically unsaturated phosphoric acid diester using a phosphite reactant.

Phospholipids are phosphodiester compounds in which one alcohol residue is typically a glycerol derivative and the other is a derivative of another alcohol, and may include nonionic, cationic or anionic (rarely) functional groups. Phospholipids and phospholipid-like compounds are now receiving increasing attention, for example, for their ability to mimic cell membrane surfaces, provide useful properties in terms of biocompatibility and hemocompatibility, and influence the reactions of various biomolecules with surfaces. In our previous publications such as EP-A-0032622, EP-A-0157469, EP-A-0555295, EP-A-0601041, EP-A-0593561, EP-A-0639989, WO-A-9416748 and Various synthetic phospholipids are described in WO-A-9416749 and their use in the manufacture of devices with biocompatible and hemocompatible surfaces. These specifications specifically describe zwitterionic phospholipids, in particular phosphorylcholine derivatives. Preferably, these phospholipids are prepared by total synthesis.

In Bull.Soc.Chim.de France (Bulletin of the French Chemical Society) 1974 (3 to 4) 667 to 670 pages and FR-A-2270887, Thuong and Chabrier describe the synthesis of phosphorylcholine derivatives, the method first React 2-chloro-2-oxo-1,3,2-dioxaphospholane (CCP) with alcohol, and then use trimethylamine to ring-open it in an organic solvent to form a zwitterionic diester compound . The phospholane compound is according to Edmundson in Chem.and Ind. (Chemistry and Industry) (1962) 1828 to 1829 described method, the corresponding 2-chloro-1,3,2-dioxaphospholane prepared by alkoxylation. The starting phospholane starting material is formed by reacting ethylene glycol with phosphorus trichloride.

Nakaya et al first described the use of a similar method in JP-A-58-154591 (1983) for the synthesis of polymerizable phospholipids, and thereafter, in our common pending patents WO-A-9514701 and WO-A-9514702 A modification of the method described by Nakaya was made in . All of these publications describe the synthesis of 2-(methacryloyloxyethyl)-2'-(trimethylammonio)ethyl phosphate inner salt (HEMA-PC). The compound can thereafter be polymerized or copolymerized with other polymerizable ethylenically unsaturated monomers to form polymers.

HEMA-PC itself was first described by Nakabayashi et al. in JP-A-54-063025 (1979). In this publication, the synthesis method involves reacting 2-hydroxyethyl methacrylate with 2-bromoethyl phosphoryl dichloride followed by amination of the bromine substituents of the phosphodiester. Although the method described by Nakaya has made some improvements to the original synthesis method of Nakabayashi et al., the synthesis method still has some difficulties. Especially the halophospholane intermediate (CCP) is very unstable. Furthermore, as a multi-step process, different solvents are used in each step to achieve optimal yields, requiring solvent removal between steps. Also, the reaction can be slow and the product yields low.

In recent years, phosphoramidite chemistry has been greatly developed for the synthesis of oligonucleotides. These synthetic methods are generally carried out on insoluble supports to which nucleosides are covalently linked. As first described by Beaucage and Caruthers in Tet.letts. (Tetrahedron Letters) 22, 1859 (1981) and Mcbride and Caruthers in Tet.letts. (Tetrahedron Letters) 24, 245 pages (1983), the use of nucleoside aminoimides Phosphate esters act as relatively stable monofunctional phosphitylating agents to synthesize fiber sequences plus nucleotides. Initially, the intermediate was prepared by reacting chloro-N,N-dimethylaminomethoxyphosphine with an appropriately protected nucleotide, which was later replaced by a different alkyl group to replace the methyl group on the amine nitrogen atom base, N,N-dimethylamino was replaced by N,N-diisopropylamino, morpholinyl, pyrrolidinyl and 2,2,6,6-tetramethylpiperidinyl, and by Beaucage et al. Various other groups described in Tetrahedron (1992) 48(12), pages 2223-2311. In addition, the methoxy protecting group of the phosphorus atom was replaced with a modified protecting group such as β-cyanoethoxy (Sinha et al., Tet. letts (Tetrahedron Letters) 24, p. 5843 (1983)). Other phosphate protecting groups have also been used, such as those reported by Beaucage et al.

In Chemical Abstracts (Chemical Abstracts) 72 (14) 107309 (1970) and full-text reference Khim.Khim.Telchol. (21WWAB), 68, 18-25 (1958), Podashova et al. Hydroxyalkyl methacrylates are phosphorylated and the phosphite product is polymerized, resulting in polymers that are said to have extremely low flammability.

For the synthesis of polymerizable phosphoric acid diester compounds such as HEMA-PC, it is best to use relatively stable raw materials or intermediates that do not need to be synthesized and used immediately. Phosphitylation agents have achieved this goal.

According to the novel method of the present invention comprises alcoholysis step, formula I compound

Wherein R ₁ can be the same or different, each R ₁ represents a straight chain or branched chain alkyl (including cycloalkyl), or forms a heterocyclic ring together with their attached nitrogen atoms, optionally containing other heteroatoms, which can be Saturated or unsaturated, and NR ₂ ¹ is optionally in quaternized form,

Y is a phosphate protecting group, and

其中：Z is NR ₂ ² , wherein R ² is selected from the same group as R ¹ and may be the same or different from NR ₂ ¹ , or Z is an OR ³ group, wherein R ³ is selected from C _1-40 -straight chain or Branched chain alkyl, ^alkenyl and alkynyl, or R and Y together with the oxygen atom and phosphorus atom to which they are attached (respectively) form a 5 to 15 membered heterocyclic ring, optionally containing additional heteroatoms and/or Or there are substituents on the ring carbon and/or nitrogen atom (if any), in any case, the ^R3 group can be aryl, hydroxyl, halogen atom, amino (including one, two or trialkyl Substituted amino group), sulfonium group or phosphonium group, in solution react with alcohol of formula BR ⁷ OH, wherein R ⁷ is linear or branched chain alkylene, oxaalkylene or oligomeric oxaalkylene chain, B is an ethylenically unsaturated polymerizable group selected from and

in:

R is hydrogen or C ₁ -C ₄ alkyl;

A is -O- or -NR ⁸ -, wherein R ⁸ is hydrogen or C ₁ -C ₄ alkyl; and

K is -(CH ₂ ) _p OC(O)-, -(CH ₂ ) _p CO(O)-, -(CH ₂ ) _p OC(O)O-, -(CH ₂ ) _p NR ⁹ -, - (CH ₂ ) _p OC(O)NR ⁹ -, -(CH ₂ ) _p NR ⁹ C(O)NR ⁹ - (wherein R ⁹ groups may be the same or different), -(CH ₂ ) _p O-, - (CH ₂ ) _p SO ₃ -group, or a covalent bond, and p is from 1 to 12, R ⁹ is hydrogen or C ₁ -C ₄ alkyl,

其中Z、Y、R⁷和B代表与式I化合物和醇中相同的基团。Formation of the compound of formula II

Wherein Z, Y, R ⁷ and B represent the same groups as in the compound of formula I and alcohol.

In one embodiment of the method, Z is ^OR3 . In this embodiment, although ^R may be alkyl, alkenyl or alkynyl, such as C _1-6 alkyl, it is preferred that ^R and Y are joined together to form a heterocyclic ring together with the phosphorus and oxygen atoms , preferably they represent C _2-12 , preferably C _2-4 alkylene chains, most preferably (CH ₂ ) ₂ .

In another embodiment, Z is a NR ₂ ² group, after the first step phosphitylation i), in the second step ii), the compound of formula II is combined with the second alcohol R in solution in the presence of a weak acid ⁴ OH reaction, wherein R ⁴ is selected from BR ⁷ (as defined above) and C _1-40 straight chain or branched chain alkyl, alkenyl and alkynyl, in any case, all can be unsubstituted or with aromatic group, halogen atom, hydroxyl group, amino group (including one, two or three alkyl substituted amino groups), sulfonium group, phosphonium group substitution,

其中R⁴、Y、R⁷和B如各自原料中所述。Formation of the compound of formula III

Wherein R ⁴ , Y, R ⁷ and B are as described in the respective raw materials.

其中Y、R⁷和B代表与起始亚磷酸三酯原料相同的基团，且R¹³是R³或是R⁴。The method further comprises the step of oxidizing the compound of formula III or the compound of formula II wherein Z is OR ³ to form the corresponding phosphoric acid ester of formula IV

Wherein Y, R ⁷ and B represent the same group as the starting phosphite triester raw material, and R ¹³ is R ³ or R ⁴ .

In this method, the oxidation step is generally followed by the following steps: iv) the compound of formula IV is deprotected, and the substituent Y is replaced by ^O- or OH.

When the alcohol BR ⁷ OH used in the first step phosphitylation reaction is an acrylic ethylenically unsaturated alcohol, R is preferably hydrogen, methyl or ethyl, more preferably methyl, so that the alcohol BR ⁷ OH is a Acrylic, methacrylic or ethacrylic acid derivatives.

When the alcohol ^BR7OH used is a styrene derivative in which K is a group (ie not a covalent bond), p is preferably from 1 to 6, more preferably 1, 2 or 3, most preferably p is 1. When K is -(CH ₂ ) _p NR ⁹ -, O(CH ₂ ) _p NR ⁹ C(O)-, -(CH ₂ ) _p C(O)NR ⁹ -, -(CH ₂ ) _p NR ⁹ C (O)O-, -(CH ₂ ) _p OC(O)NR ⁹ - or O(CH ₂ ) _p NR ⁹ C(O)NR ⁹ -, then R ⁹ is preferably hydrogen, methyl or ethyl, More preferred is hydrogen. In such compounds, the vinyl group is preferably in the para position to ^-KR7OH .

Preferred ^R7 is:

An alkylene group of formula -(CR ₂ ¹⁰ ) _a , wherein -(CR ₂ ¹⁰ )- groups can be the same or different, and in each -(CR ₂ ¹⁰ )- group, R ¹⁰ is a group that can be the same or different, and each ^R group is hydrogen, fluorine or C _1-4 alkyl or fluoroalkyl, preferably hydrogen, a is from 1 to 12, preferably 1 to 6;

Oxaalkylene groups such as alkoxyalkyl groups, wherein the alkyl moiety has 1 to 6 carbon atoms, more preferably -CH ₂ O-(CH ₂ ) ₄ -; or

The formula -[(CR ₂ ¹¹ ) _b O] _c (CR ₂ ¹¹ ) _b -oligooxyheteroalkylene, wherein -(CR ₂ ¹¹ )-groups can be the same or different, and each -(CR ₂ ¹¹ )-In the group, R ¹¹ can be the same or different, each R ¹¹ group is hydrogen or C _1-4 alkyl, preferably hydrogen, b is from 1 to 6, preferably 2 or 3, c is from 2 to 11, preferably 2 to 5.

Preferred R ⁷ groups include alkylene, oxaalkylene or oligooxaalkylene groups of up to 12 carbon atoms, preferably (CH ₂ ) _2-6 .

The first alcohol is more preferably a hydroxyalkyl methacrylate compound, preferably hydroxyethyl methacrylate.

When the Z group of the compound of formula I is NR ₂ ² groups, that is, the compound of formula I is a difunctional phosphitylation agent, and when the product compound will contain an ethylenically unsaturated moiety, then in step 1, the method adopted is that only one of the NR ₂ ¹ and NR ₂ ² groups is replaced by an alcohol moiety. When _NR21 and _NR22 are different, this can be achieved by employing reaction conditions ^{such that} only one group reacts.

Any alcoholysis step is easily carried out in the presence of weak acid.

When the NR ₂ ¹ and NR ₂ ² groups are the same, by selecting a weak acid activator suitable for the NR ₂ ¹ and NR ₂ ² groups, in the presence of a solvent suitable for the reaction step, a corresponding diaminophosphite of formula I is achieved Compounds are selectively activated, for example, an acid that activates the first NR ₂ ¹ or NR ₂ ² group is used in the first step, while in the second step, a different acid is used to activate the second NR ₂ ¹ or NR ₂ ² groups.

It is believed that it is a new method to prepare zwitterionic phosphodiesters with a difunctional phosphitylation agent. According to a second aspect of the present invention, a method comprising the steps is provided: v) a compound of formula V

其中R²、R³和Y的定义与式V化合物和第一个醇中相同；vi)然后将式VI化合物与第二个醇R⁴OH反应，其中R⁴选自C_1-40直链或支链烷基、链烯基和链炔基，任一种情况下，均可以是未取代的，或用芳基、羟基、卤原子、胺基(包括一、二或三烷基取代胺基)、锍基或鏻基取代，但R³和R⁴至少一个应代表有卤原子、锍基、氨基或鏻基取代的C_1-10烷基，反应在弱酸存在且基本无水条件下进行，形成式VII化合物其中R³、R⁴和Y的定义与式VI化合物和第二个醇中相同；vii)式VII化合物被氧化，形成式VII化合物

其中R³、R⁴和Y的定义同式VII化合物；viii)将式VIII化合物解保护，使Y取代基被O^-或OH置换，若需要的话，可将阳离子取代基引入R³或R⁴基团，形成一个两性离子磷酸二酯产物化合物。Wherein R ¹ and R ² can be the same or different, and each represents a straight chain or branched chain alkyl group (including cycloalkyl), or the R ₁ group and the R ¹ /R ² group form a group with the nitrogen atom attached to each The heterocycle, optionally containing other heteroatoms, may be saturated or unsaturated, and the NR ₂ ¹ and NR ₂ ² groups may be in quaternized form, Y is a phosphate protecting group, in solution with the second An alcohol R ³ OH reaction, wherein R ³ is selected from C _1-40 straight chain or branched chain alkyl, alkenyl and alkynyl, in any case, all can be unsubstituted, or with aryl , hydroxyl, halogen atom, amino group (including one, two or three alkyl substituted amino groups), sulfonium group or phosphonium group substitution, the reaction is carried out under substantially anhydrous conditions to form the compound of formula VI

wherein R ² , R ³ and Y are as defined in the compound of formula V and the first alcohol; vi) the compound of formula VI is then reacted with the second alcohol R ⁴ OH, wherein R ⁴ is selected from C _1-40 straight chain or branched chain alkyl, alkenyl and alkynyl groups, in either case, may be unsubstituted, or substituted with aryl, hydroxyl, halogen, amine (including mono-, di- or tri-alkyl substituted amine group), sulfonium group or phosphonium group, but at least one of ^R3 and ^R4 should represent a _C1-10 alkyl group substituted by a halogen atom, sulfonium group, amino group or phosphonium group, and the reaction is carried out in the presence of a weak acid and under anhydrous conditions Carry out, form formula VII compound wherein R ³ , R ⁴ and Y are as defined in the compound of formula VI and the second alcohol; vii) the compound of formula VII is oxidized to form the compound of formula VII

wherein the definitions of R ³ , R ⁴ and Y are the same as those of the compound of formula VII; viii) deprotecting the compound of formula VIII so that the substituent Y is replaced by ^O- or OH, and if necessary, a cationic substituent can be introduced into R ³ or R ⁴ group, forming a zwitterionic phosphodiester product compound.

In this regard, when both ^R3 or ^R4 groups do not contain sulfonium, amino (including ammonium soluble) or phosphonium groups, but contain halogen substituents, it is necessary to introduce cationic groups. The reaction typically involves amination of the haloalkyl compound with a tertiary amine to provide a quaternary ammonium group.

When the product of step vii) is to be reacted to introduce cationic groups, the deprotection step (step viii) and cationic group introducing step can usually be combined. For example, when one of ^R3 or ^R4 is a haloalkyl group, it can be aminated with a tri-lower alkylamine, such as the same base used in the deprotection step, to replace the halogen atom with a quaternary ammonium group . The same solvents are suitable.

This aspect of the invention is of particular value for the preparation of phosphonium-based derivatives. In a particularly preferred embodiment of the second aspect of the invention, the cationic group is a phosphonium group, which group is usually a substituent for one of the alcohols ^R3OH or ^R4OH , which is very convenient. In this embodiment, it is not necessary to introduce cationic substituents in step viii).

This aspect of the invention is also very valuable for the synthesis of phospholipids, ie glyceryl derivatives. In this aspect, at least one of R ³ OH and R ⁴ OH is a disubstituted glycerol, preferably an α,β-disubstituted glycerol, such as α,β-diacyl, α,β-dialkyl, α,β-disubstituted Alkenyl, α,β-dialkynylglycerol. Acyl, alkyl, alkenyl, alkynyl groups are generally 12-24 carbon atoms long, preferably 12 to 18 carbon atoms, and may be different from each other, but are preferably identical to each other.

In the method of the present invention, the ^R1 and ^R2 groups represent any groups which have been used in the synthesis method of phosphoramidite-based nucleic acid. Although these groups may all be methyl or other lower alkyl groups, it is preferred that each group represents an alkyl group of at least 3 carbon atoms, usually a branched chain alkyl group, or ^{an R} group and its attached Nitrogen atom (and/or R ² and their connected nitrogen) represent saturated or unsaturated heterocyclic group, like this, R ¹ or R ² group can represent a straight chain or branched C _2-12 alkylene, For example a (CH ₂ ) _2-12 group, or an alkylene group intercalated with a heteroatom such as oxygen, sulfonium or N-lower alkyl nitrogen atom. Preferred examples of the radicals R ₂ ¹ and R ₂ ² N are N,N-diisopropylamino, morpholinyl, pyrrolidinyl, triazolyl, tetrazolyl, imidazolyl and 2,2,6,6- Tetramethylpiperidinyl.

Among the preferred quaternized derivatives of phosphitylating agents, the quaternized groups can have the same or different ^R1 or ^R2 groups ^, examples ^{of quaternized derivatives of NR21} _{and NR22} groups It is N, N, N-trimethylammonium and N, N, N-triisopropylammonium. Preferred unsaturated heterocyclic groups NR ₂ ¹ or NR ₂ ² are pyridinium and 2,6-lutylpyridinium.

Any weak acid used in phosphodiester synthesis can be used in each phosphorylation step, such as 1H-triazole, 1,2,4-triazole, 3-chlorotriazole or diisopropylammonium tetrazolide or 4,5-dichloroimidazole.

We have surprisingly found that other weak acids, such as organic acids, preferably carboxylic acids, which may be monobasic or dibasic, work well with less expensive and more readily available weak acids than those commonly used in the phosphorylation of phosphoramidites. Elemental acid.

The use of such acids in phosphoramidite phosphorylation reactions is believed to be novel.

According to the method provided in another aspect of the present invention, the compound of the following formula Wherein the ^R groups can be the same or different, each representing a branched or linear alkyl group (including a cycloalkyl group), or forming a heterocyclic ring with their connected nitrogen atoms, optionally containing other heteroatoms, which can be Saturated or unsaturated, and NR ₂ ¹ is optionally in the form of a quaternary ammonium,

Y is a phosphate protecting group, and

Z is NR ₂ ² , wherein R ² is selected from the same group as R ¹ and may be the same or different from NR ₂ ¹ , or Z is an OR ³ group, wherein R ³ is selected from C _1-40 straight chain or branched Alkyl, ^alkenyl and alkynyl, or R and Y together with the oxygen atom and phosphorus atom to which they are attached (respectively) form a 5 to 15 membered heterocyclic ring, optionally containing additional heteroatoms and/or There are substituents on the ring carbon and/or nitrogen atom (if any), in any case, ^R3 can be substituted with aryl, hydroxyl, halogen, amine (including mono, di or trialkyl substituted amine base), sulfonium and phosphonium groups, react in solution with alcohol of formula R ³ OH, wherein R ³ is selected from C _1-40 straight chain or branched chain alkyl, alkenyl and alkynyl, in any case , can be unsubstituted, or substituted with aryl group, hydroxyl group, halogen atom, amino group (including one, two or three alkyl substituted amino groups), sulfonium group or phosphonium group, and the reaction is neutralized in an almost anhydrous organic solvent carried out in the presence of a weak acid and removes the amine HNR ₂ ¹ from the reaction mixture, characterized in that the weak acid is a carboxylic acid soluble in organic solvents and capable of forming a salt with the amine HNR ₂ ¹ insoluble in organic solvents, the salt precipitated from the product mixture Remove from liquid.

Weak carboxylic acids may be, for example, monobasic acids such as benzoic acid, or preferably dibasic alkanedioic or aromatic diacids such as glutaric, phthalic, adipic or cyanuric acids.

In the oxidation reaction step of step iii) and step vii), conventional oxidation systems and reagents can be used. If the substituent does not include a water-sensitive group, it is suitable to carry out the oxidation reaction with iodine water and 2,6-lutyl or pyridine catalyst. Alternatively, organic oxidizing agents can be used, such as peroxy compounds, such as tert-butyl hydroperoxide, di-tert-butyl hydroperoxide, bis(trimethylsilyl)hydroperoxide, perbenzoic acid derivatives such as m-chloroperbenzene Formic acid, or iodobenzene diacetate. Alternatively, ozone or molecular oxygen in benzene or other dry organic solvent may be used, optionally with a free radical initiator, or dinitrogen tetroxide or other nitrogen oxide oxidizing agents such as tertiary amine oxides may be used.

The use of amine oxide oxidizing agents is preferred, especially when the alcohol to be phosphorylated is BR ⁷ OH, since the use of such oxidizing agents results in higher yields of the desired product without the formation of by-products, especially due to the absence of attacking radicals. A by-product formed by the side reaction of the ethylenic bond in group B.

Suitable solvents for steps i), v) and vi) are tetrahydrofuran, 1-methyl-2-pyrrolidone, chloroform or preferably dichloromethane or acetonitrile. Since phosphite compounds are generally sensitive to water, the reaction mixture of steps i) and ii) should be reacted under substantially anhydrous conditions, the reagents and solvents need to be dried, and/or the reaction should be carried out under dry inert gas.

Y is a protecting group which is preferably removed from the product of oxidation step iii) and step vii) with a base in a subsequent step when the process includes it. Y is usually -OR ⁵ , wherein R ⁵ is C _1-6 alkyl or aryl, preferably substituted with electron-withdrawing groups such as halogen, nitro, sulfonyl and aryl (including heteroaryl). The substituents in R ⁵ may additionally be sterically hindered (eg 1,1-dialkyl substituents on alkyl). Although R ⁵ may represent a methyl group, it is preferably a lower alkyl group with electron withdrawing substituents such as aryl, cyano, vinyl. Preferred ^R groups are allyl, benzyl, phenyl, benzenesulfonylethyl, methanesulfonylethyl, p-nitrophenethyl, 2,2,2-trihaloethyl (especially Trichloro and tribromoethyl), 2,2,2-trihalo-1,1,-dialkylethyl (especially 2,2,2-trichloro-1,1-dimethylethyl) , 2'- and 4'-pyridylethyl, m-methylbenzyl, p- or m-halogenated benzyl, m-, p-dichlorobenzyl, pentahalogenated phenyl (especially pentafluoro and pentachlorophenyl) , 2,6-dimethylphenyl and 2,4-dinitrophenyl, more preferably β-cyanoethyl.

The deprotection steps, step iv) and step viii) are carried out by conventional methods. Although it is possible to use sulfonium alkoxides, for example using the methods described by Daub et al. in JACS, 99, 3526 (1977) and Andreus et al. in Tet. Letts, 29, 5479 (1988), preferably by using organic The base, especially a tri-lower alkylamine, usually trimethylamine, avoids the later difficulty of recovering the product from, for example, phenylsulfonol. Suitable solvents are acetonitrile, and mixtures of acetonitrile and dichloromethane, methanol/chloroform mixtures, or even lower alcohol-water mixtures.

When Z is OR ³ and Y and R ³ groups are joined together in the compound of formula I, the deprotection step effectively opens the ring to an -O- and a group derived from YR ³ -O-, such a ring opening step The terminal end of the Y moiety can also be aminated to form an amine group, usually a quaternary ammonium group. This simultaneous reaction involves reaction with a trialkylamine in an organic solvent similar to that described by Thuong and Chabrier (book), Nakaya et al. and our co-pending patents WO-A-9514701 and WO-A-9514702 open-loop steps.

The present inventors have found that the use of phosphoramidite phosphoritylation reagents enables the process of the invention to be performed in greater than 90% or higher yields, whereas the use of phosphorochloridized phosphorous acid phosphites as described by Podashova et al. Phosphorylation reagents can only obtain lower yields, such as 60%. In addition, the reaction of the present invention is also easier to control.

The following examples serve to illustrate the invention.

Example 1

2-(Methacryloyloxyethyl)-2′-(trimethylammoniumethyl)phosphate inner salt

Hydroxyethyl methacrylate (0.43g, 3.32mmol) and 4,5-dichloroimidazole (0.45g, 3.32mmol) were stirred in dry acetonitrile (10ml) in the presence of 4A molecular sieves (1g). Add bis(diisopropylamino)cyanoethyl phosphite (1 g, 3.32 mmol) into the above mixture, and stir under nitrogen atmosphere at room temperature for 4 hours to obtain crude monophosphorous acid ester.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.18(d), 1.94(s), 2.62(t),

3.60(m), 3.84(m), 4.30(t), 5.60(s), 6.14(s)

Bromoethanol (redistilled, 0.41 g, 3.32 mmol), 4,5-dichloroimidazole (0.45 g, 3.32 mmol) and 4A molecular sieves (1 g) were added to the above reaction mixture, and stirred at room temperature for 16 hours. A certain amount of bromomethanol (redistilled, 0.05g0.40mmol) was added, and the mixture was stirred at 40°C for 4 hours. After filtering through celite and a 0.2 μm glass fiber filter, the solvent was removed to obtain crude phosphite triester.

¹ H-nmr, 200MHz, (CDCl ₃ )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 phosphite triester was dissolved in dichloromethane (20ml) and treated with m-chloroperbenzoic acid (0.57g, 3.32mmol) and stirred at room temperature for 10 minutes. The above solution was extracted with saturated aqueous sodium bicarbonate (4 x about 20 ml). After the aqueous phases were combined, back-extracted with dichloromethane (about 40 ml), then combined with the organic phase from the previous step, and extracted with saturated aqueous sodium bicarbonate (2 x about 20 ml). The mixture was dried over magnesium sulfonate and evaporated to give crude phosphate triester, 1.18 g, 3.19 mmol, 96% yield based on hydroxyethyl methacrylate.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=2.00(s), 2.80(t), 3.54(t),

4.37(m), 5.65(s), 6.19(s)

Crude phosphate triester (1.18 g, 3.19 mmol) was dissolved in dry acetonitrile (about 30 mL), treated with trimethylamine (1.57 g, 26.5 mmol), and heated at 75°C for 48 hours. Add 4A molecular sieve (1.5h) to the mixture, continue heating for 2 hours, filter through diatomaceous earth and 2μm glass fiber filter, distill off the solvent, dissolve the residue in methanol, and elute with silica gel (about 20g) column chromatography methanol Purify. Fractions containing product were combined and evaporated to dryness to give pure 2-(methacryloyloxyethyl)-2'-(trimethylammoniumethyl)phosphate inner salt, 0.29g, 0.97mmol, 30% yield Rate.

¹ H-nmr, 200MHz, (D ₂ O)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)

The total yield of 2-(methacryloyloxyethyl)-2'-(trimethylammoniumethyl)phosphate inner salt based on hydroxyethyl methacrylate was 29%. Example 2

2-(Methacryloyloxyethyl)-6'-(triphenylphosphoniumylethyl)phosphate inner salt

Bis(isopropylamino)cyanoethylphosphine (0.75g, 2.49mmol) in dry acetonitrile (5ml) was added dropwise to tetrazolide diisopropylamine (0.43g, 2.49mmol) in dry dichloromethane (70ml) followed by 6-Hydroxyhexyltriphenylphosphonium bromide (1.1 g, 2.49 mmol) in acetonitrile (3.3 ml) was added. The mixture was stirred at room temperature under argon atmosphere for 40 minutes. The solvent was distilled off, and the triphenylphosphonium salt was analyzed by ¹ H-nmr before being used in the next step.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.16(m), 1.29(m), 1.43(d),

1.66(m), 2.63(t), 2.39-3.87(m), 4.11(m), 4.30(m),

7.74(m)

Triphenylphosphonium salt in acetonitrile (75ml) was treated with tetrazole (0.18g, 2.49mmol) and ethylhydroxyethylmethacrylate (0.43g, 3.32mmol) and stirred at room temperature for 18 hours. The solvent was distilled off, and the residue was distributed among dichloromethane/chloroform (9:1, about 60ml) and water (about 60ml), and the organic layer was extracted with water (2×about 60ml), and crude methacrylic acid (sub-methacrylic acid) was obtained after evaporation. Phosphate (triphenylphosphonium) ester, 1.8g.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.29(m), 1.63(m), 1.89(s),

2.66(t), 3.80(m), 4.03(m), 4.29(m), 5.60(s), 6.11(s),

7.73(m)

Crude triphenylphosphonium methacrylate (1.8 g, about 2.5 mmol) was dissolved in dichloromethane:chloroform (1:1, 80 mL) and treated with m-chloroperbenzoic acid (0.69 g, 2.8 mmol). The mixture was stirred at room temperature for 1 hour, then extracted with saturated sodium bicarbonate solution (3 x 80ml). Evaporation of the organic layer gave crude (triphenylphosphonium phosphate) methacrylate without further purification.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.29(m), 1.59(m), 1.91(s),

2.76(t), 3.71(m), 4.01(m), 4.26(m), 5.60(s), 6.14(s),

7.70(m)

(Triphenylphosphonium phosphate)methacrylate was dissolved in methanol (15ml) and treated with ammonia (5%, 35ml) and stirred at room temperature for 30 minutes. The solvent was evaporated, the residue was azeotropically distilled with benzene (2 x 100ml), and dried over diphosphonium pentoxide under vacuum for 16 hours. The crude residue was purified by column chromatography on silica gel (31 g) eluting with chloroform:methanol (4:1). The product-containing fractions were combined, evaporated in vacuo and dried to give [2-(methacryloyloxyethyl)-6'-triphenylphosphonium hexyl]phosphate inner salt, 0.34g, 0.61ml, according to bromide 6- The overall yield based on hydroxyhexyl-1-triphenylphosphonium was 25%.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.34(m), 1.53(m), 1.83(s),

3.31(m), 3.86(m), 4.09(m), 4.20(m), 5.46(s), 6.03(s),

7.71 (m) Example 3 Large-scale preparation of 2-(methacryloyloxyethyl)-2'-(trimethylammoniumethyl)phosphate inner salt 3.1N, N-diisopropylaminophosphite ethylene

Diisopropylamine (463g 4518mmol) was added dropwise to stirred 2-chloro-1,3,2-dioxaphospholane (distilled, 115.8g, 915mmol) in anhydrous Solution in diethyl ether (4000 mL) over 1 h. The mixture was warmed to room temperature and stirred for 16 hours, diisopropylammonium chloride was filtered off and the filter bed was washed with diethyl ether (400ml). The filtrate and washings were evaporated to about 500ml, the mixture was filtered again and the filter bed was washed with diethyl ether (1400ml). The solvent was removed to obtain a liquid, which was filtered through a glass sintered funnel and fractionated (40°C, 0.1mbar) to obtain pure N,N-diisopropylaminophosphite ethylene, 104.2g, 545mmol, 60% yield .

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.17(d), 3.46(m), 3.89(m),

4.14(m)3.2 2-[(Methacryloyl)ethoxy]-1,3,2-dioxaphospholane

A mixture of 4,5-dichloroimidazole (70 g, 511 mmol) and 2-hydroxyethyl methacrylate (68.0 g, 523 mmol) was dissolved in dry acetonitrile (500 ml). Ethylene N,N-diisopropylaminophosphite (100 g, 523 mmol) in dry acetonitrile (100 ml) was added dropwise under nitrogen atmosphere at room temperature over 1 hour and then stirred for 10 minutes. The mixture was filtered through a tightly packed bed of celite and the plug was washed with acetonitrile (200ml) to give 2-[(methacryloyl)ethoxy]-1,3,2-dioxaphospholane which was ready to use alkane solution. 3.3 2-[(Methacryloyl)ethoxy]-2-oxo-1,3,2-dioxaphospholane

A solution of 2-[(methacryloyl)ethoxy]-1,3,2-dioxaphosphopentane in acetonitrile (800ml) was cooled to -10°C, and N-trimethoxy A solution of the amine (35.4 g, 471 mmol) in acetonitrile (200 mL) was added dropwise over 90 minutes. The mixture was brought back to room temperature, and the solvent was evaporated to about 800 ml to obtain 2-[(methacryloyl)ethoxy]-2-oxo-1,3,2-dioxaphospholane which could be used immediately solution. Samples were analyzed by 'H-nmr.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.97(s), 4.43(m), 5.66(s),

6.21(s)3.4 2-(Methacryloyloxyethyl)-2'-trimethylammoniumethyl)phosphate inner salt

A solution of 2-[(methacryloyl)ethoxy]-2-oxo-1,3,2-dioxaphospholane was treated with trimethylamine (49.9 g, 845 mmol) in dry acetonitrile (200 mL) , stirred at 50 °C for 16 hours. The mixture was cooled to room temperature, and excess trimethylamine was removed under reduced pressure. The solution was heated to 80°C and filtered through a bed of celite under a nitrogen atmosphere. After cooling, a total amount of 300ml of acetonitrile was removed under reduced pressure. After crystallization, the solid was separated to obtain pure 2-(methacryloyloxyethyl)-2'-trimethylammonium ethyl) phosphate internal salt, 35.0g, 119mmol , The yield of 2-hydroxyethyl methacrylate is 23%.

¹ H-nmr, 200MHz, (D ₂ O)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 ₂ O) δ=20.2, 56.8, 62.3, 66.7, 67.3,

68.8, 129.9, 138.7, 172.4 Example 4 uses dinitrogen tetroxide oxidizing agent to prepare 2-[(methacryloyl) ethoxyl group]-2-oxo-1,3,2-dioxaphospholane

Dinitrogen tetroxide was purified by the method of MS Anson and C McGuigan (J. Chem. Soc. Perkin Trans. 1, 1989, 715). At -60°C, a solution of dinitrogen tetroxide (0.175g, 1.92mmol) in dry dichloromethane (12ml) was added dropwise to 2-[(methacryloyl)ethoxy]-1,3,2- Dioxaphospholane (prepared as in Example 7.2) (1.69 g, 7.68 mmol) in solution in dry dichloromethane. After standing for 5 minutes, the mixture was warmed to room temperature and the solvent was distilled off to obtain crude 2-[(methacryloyl)ethoxy]-2-oxo - 1,3,2-Dioxaphospholane (1.86 g, 7.8 mmol).

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.97(s), 4.44(m), 5.63(s),

6.21(s) Example 5 Preparation of 2-[(methacryloyl)ethoxy]-2-oxo-1,3,2-dioxaphospholane using tert-butyl hydroperoxide oxidation reagent

At 0°C, a solution of tert-butyl hydroperoxide in decane (5.5M, 1.40ml, 7.68mmol) in dry dichloromethane (15ml) was added dropwise to 2-[(methacryloyl)ethoxy A solution of -1,3,2-dioxaphospholane (1.69 g, 7.68 mmol) (prepared in Example 7.2) in dry dichloromethane (15 mL). After standing for 5 minutes, the mixture was heated to room temperature, the solvent was distilled off, and the residue was dried in vacuo to obtain crude 2-[(methacryloyl)ethoxy]- 2-Oxo-1,3,2-dioxaphospholane.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.97(s), 4.46(m), 5.63(s),

6.21 (s) Example 61-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-trimethylethylammonium hydroxide inner salt})-2-dimethylpropane

2,2-Dimethylpropanol-1 (0.44g, 5.0mmol) and tetrazolide diisopropylammonium (0.43g, 2.5mmol) were dissolved in dry dichloromethane (25ml) and stirred under nitrogen atmosphere. Bis(diisopropylamino)cyanoethylphosphite (1.66 g, 5.5 mmol) was added and stirring was continued for 1 hour. The mixture was diluted with dichloromethane (100mmol), extracted with aqueous sodium carbonate (2%, 2 x 125ml) and washed with saturated sodium chloride solution (125ml). The combined aqueous phases were back extracted with dichloromethane (125 ml), and the organic phase was decanted and dried over sodium sulfonate at 4°C for 1 hour. The mixture was filtered to remove solids and washed with dry dichloromethane (50ml). The solvent was removed by evaporation to give (2,2-dimethylpropyl-1) phosphite adduct (1.46 g, 5.0 mmol, theoretical recovery).

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.91(s), 1.21(d), 2.68(t),

3.26(m), 3.60(m), 3.85(m)

Under nitrogen, (2,2-dimethylpropyl-1) phosphite adduct (1.46 g, 5.0 mmol) was added to bromoethanol (0.95 g, 7.6 mmol) and 1H-tetrazole (sublimed , 0.18g, 2.5mmol) in a mixture in dry acetonitrile, stirred at room temperature for 16 hours. Additional bromoethanol (0.16 g, 1.3 mmol) and 1H-tetrazole (0.09 g, 1.3 mmol) were added and the mixture was stirred for 30 minutes. The solvent was distilled off, the residue was dissolved in dichloromethane (about 75ml), extracted with aqueous sodium carbonate solution (2%, 2 x about 100ml), and washed with saturated sodium chloride solution (about 100ml). The combined aqueous phases were back extracted with dichloromethane (about 100ml). The organic phase was decanted and dried over sodium sulfonate for 1 hour at 4°C. After the mixture was filtered to remove solids, it was washed with dry dichloromethane (about 50ml), and the solvent was distilled off to obtain crude phosphorous acid (2,2-di Methylpropyl-1) bromoethyl ester adduct, it was purified by chromatographic column with hexane: acetone: trimethylamine (63:32:5) to obtain pure material (1.09g, 3.5mmol, 69% yield).

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.94(s), 2.71(t), 3.53(d),

3.56(t), 4.12(m)

(2,2-Dimethylpropyl-1) bromoethyl phosphorous acid adduct (1.23g, 3.9mmol) was dissolved in dry dichloromethane (about 15ml), and m-chloroperbenzoic acid (0.68 g, 3.9 mmol), and the mixture was stirred at room temperature for 10 minutes, then m-chloroperbenzoic acid (0.07 g, 0.4 mmol) was added, and stirring was continued for 15 minutes. The solution was extracted with aqueous sodium bicarbonate (1M, 2 x about 30ml) and washed with saturated sodium chloride solution (about 30ml). After the combined aqueous phases were back extracted with dichloromethane (ca. 30ml), the organic phase was decanted, dried over sodium sulfonate, and the solid was filtered off and washed with dry dichloromethane (ca. 15ml). The solvent was distilled off to obtain crude (2,2-dimethylpropyl-1)bromoethyl phosphoric acid adduct (1.12 g, 3.4 mmol, 87% yield).

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.96(s), 2.79(t), 3.56(t),

3.76(d), 4.34(m)

mass spec.: C.I., m/2=328 (3%)

EI, m/2 = 328 (14%).

(2,2-Dimethylpropyl-1)bromoethyl phosphoric acid adduct (0.2g, 0.61mmol) and trimethylamine (0.87g, 14.6mmol) in anhydrous acetonitrile (about 30ml) at 46 After heating at ℃ for 16 hours, the solvent and excess trimethylamine were distilled off. The residue was purified by column chromatography on silica gel (about 10 g) eluting with methanol. Fractions containing product were combined and evaporated to give 1-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-trimethylethylammonium hydroxide inner salt}) 1-dimethyl Propane (0.1 g, 0.40 mmol, 65% yield).

¹ H-nmr, 200MHz, (CDCl ₃ /CD ₃ OD)δ=0.94(s), 3.22(s),

3.54(d), 3.63(m), 4.24(m)

mass spec.: C.I., m/2=254 (32%).

Based on the raw material phosphorous acid ester, the total The yield is 39%. Example 71, 3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy) 1-N,N,N-trimethylethylammonium hydroxide inner salt }) 2-Methylpropane

Dissolve 1,3-bis(hexadecyloxy)-2-(hydroxymethyl)-2-methylpropane (0.38 g, 0.66 mmol) and tetrazolide diisopropylammonium in dry dichloromethane (25 ml) , stirred under a nitrogen atmosphere. Add bis(diisopropylamino)cyanoethyl phosphite (0.2 g, 0.66 mmol) and continue stirring for 3 hours. The solvent was distilled off to obtain a crude dialkyl phosphite adduct.

The crude dialkyl phosphite adduct was added to a mixture of bromoethanol (0.15 g, 1.16 mmol) and 1H-tetrazole (literally, 0.035 g, 0.50 mmol) in dry acetonitrile (10 ml) at room temperature The mixture was stirred for 64 hours. The solvent was distilled off, the residue was dissolved in dichloromethane (about 30ml), and extracted with aqueous sodium carbonate solution (2%, about 2×30ml) and saturated sodium chloride solution (about 30ml). After combining the aqueous extracts, back-extract with dichloromethane (about 30ml), pour off the organic phase, dry over sodium sulfonate and evaporate to obtain crude dialkyl phosphite, 0.30g, 0.37mmol, 56% yield

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.88(t), 0.94(s), 1.20(m),

1.53(m), 2.68(t), 3.22(s), 3.38(t), 3.53(m), 3.74(t),

4.12(m)

m-Chloroperbenzoic acid (0.064 g, 0.37 mmol) in dry dichloromethane (about 5 ml) was added to crude dialkyl phosphite (0.30 g, 0.37 mmol) in dry dichloromethane (5 ml) . The mixture was stirred at room temperature for 15 minutes, and after standing at 4°C for 16 hours, it was extracted with saturated sodium bicarbonate solution (2 x about 15 ml) and saturated sodium chloride solution (about 15 ml). The combined aqueous phases were back extracted with dichloromethane (about 15ml), and the decanted organic phase was dried over sodium sulfonate, filtered and evaporated to give crude dialkyl phosphate, 0.25g, 0.31mmol, 83% yield.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.88(t), 0.97(s), 1.24(m),

1.53(m), 2.76(t), 3.24(s), 3.38(t), 3.56(t), 3.74(t),

4.00(m), 4.29(m)

Dialkyl phosphate adduct (0.25 g, 0.31 mmol) and trimethylamine (0.66 g, 11.2 mmol) in anhydrous acetonitrile were heated at 46°C for 48 hours, and the solid precipitated was filtered off and washed with acetonitrile. The solid was dissolved in chloroform and purified by column chromatography on silica gel (about 10 g) eluting with chloroform to chloroform:methanol:ammonia (25%) (690:270:64). Fractions containing product were combined and evaporated to give 1,3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-trimethyl Ethylammonium hydroxide·inner salt})-2-methylpropane (0.126 g, 0.17 mmol, 56% yield).

¹ H-nmr, 200MHz, (CDCl ₃ /CD ₃ OD) δ=0.91(t), 0.97(s), 1.26

(m), 1.54(m), 3.29(t, s), 3.35(s), 3.65(m), 3.75(m),

4.24(m)

mass spec.: +ve FAB, m/2=735(m+1).

According to the raw material phosphorous acid ester, 1,3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-trimethylethylammonium The total yield of hydroxide·inner salt})-2-methylpropane was 39%. Example 81, 3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-quinuclidinylethylammonium hydroxide salt})-2-methylpropane

Bromoethyl dialkyl phosphate (0.558g, 0.69mmol) (prepared in the third step of Example 2) was mixed with quinuclidine (0.76g, 6.9mmol) in a mixture of acetonitrile and dichloromethane (1:1, 10ml) ) treatment, heated at 45°C for 16 hours. The solid precipitate was filtered off, and after the mother liquor was distilled off, the residue was dissolved in acetonitrile (about 10ml), and the obtained solid was filtered and added to the previously separated material to obtain a crude product (0.59g), which was washed with silica gel (15g ) column chromatography by eluting with chloroform to chloroform:methanol:water (65:25:4). Fractions containing product were combined and evaporated to give the title compound, 0.28g, 0.48mmol, 69% yield.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.88(t), 0.96(s), 1.26(m),

1.51(m), 2.01(m), 2.16(m), 3.29(s), 3.35(t), 3.78(m),

4.27(m)

¹³ C-nmr, 75MHz (CDCl ₃ ), δ=14.1, 17.1, 19.7, 22.7, 24.1,

26.2, 29.7, 31.9, 40.8, 56.0, 58.3, 64.6, 68.5, 71.6, 73.0.

³¹ P-nmr, 84.5 MHz, (CDCl ₃ ), δ=0.695 (s).

Mass spec.: C.I.m/2＝786(1.3%)，+ve FAB m/2＝788(m+1，

50%)

The overall yield of this compound was 59% based on 1,3-bis(hexadecyloxy)-2-(hydroxymethyl)-2-methylpropane. Example 91, 3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-triphenylphosphonium hexahydroxide inner salt })-2-Methylpropane

A mixture of 6-bromohexanol-1 (18.5 g, 102 mmol) and triphenylphosphine (26.9 g, 102 mmol) in dry acetonitrile (360 mL) was heated at 70°C for 184 hours. The solvent was evaporated, and the residue was dissolved in chloroform (270ml) and added dropwise to diethyl ether (910ml) with stirring. After stirring for 1 hour, the solid was filtered off, washed with diethyl ether (100 mL), and dried under vacuum for 16 hours to give 6-hydroxyhexyltriphenylphosphonium bromide, 35.6 g, 80.3 mmol, 79% yield.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.51(m), 1.69(m), 3.68(m),

3.77(m), 7.80(m)

6-Hydroxyhexyl-1-triphenylphosphonium bromide (35.6 g, 80.3 mmol) was dissolved in dichloromethane (about 300 ml), and dried at 70° C. for 16 hours through a Dean and Stark trap. A sample (0.29g, 0.65mmol) was removed in dichloromethane (4ml) and mixed with 1H-tetrazole (literized, 0.046g, 0.65mmol) and diisopropylamidophosphite ( Prepared according to the first step method of Example 7) (0.5 g, 0.65 mmol) were mixed and stirred at room temperature for 16 hours. The product was analyzed by ¹ H-nmr and used immediately in the next step.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.88(t), 0.90(s), 1.29(m),

1.46(d), 1.63(m), 2.63(t), 3.23(s), 3.36(t), 3.40-

3.90(m), 3.97(m), 7.78(m)

A solution of triphenylphosphonium phosphite containing the diisopropylammonium salt was treated with m-chloroperbenzoic acid (0.11 g, 0.65 mmol) in dichloromethane (10 mL) and stirred for 15 minutes. The solvent was evaporated, the residue was dissolved in dichloromethane (about 20ml) and extracted with saturated sodium bicarbonate solution (3 x about 20ml). The combined aqueous layers were back extracted with dichloromethane (about 50ml), the organic phase was poured off, dried over magnesium sulfonate, filtered and evaporated to give triphenylphosphonium phosphate triester compound, 0.53g, 0.47mmol, according to bromide Based on 6-hydroxyhexyl-1-triphenylphosphonium, the yield was 72%.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.84(t), 0.91(s), 1.23(m),

1.56(m), 2.77(t), 3.20(s), 3.31(t), 3.57-4.29(m),

7.71(m)

Triphenylphosphine triphosphate (0.53g, 0.47mmol) was dissolved in methanol (40ml) and chloroform (7ml), and treated with ammonia (5%, 9ml, 25mmol) for 4 hours at room temperature. The solvent was evaporated, and the residue was azeotropically distilled with benzene (×5) and dried under high vacuum to obtain the crude product. The material was purified by column chromatography on silica gel (40 g) eluting with chloroform to chloroform:methanol (3:1). Fractions containing product were combined and evaporated to give pure 1,3-bis(hexadecyloxy)-2-(hydroxymethyl-{[(hydroxyphosphinyl)oxy]-N,N,N-triphenyl Hexaphosphonium hydroxide inner salt})-2-methylpropane, 2.6g, 0.26mmol, 56% yield.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=0.87(t,s), 1.23(m), 1.46(m),

3.25(s, t), 3.53-3.97(m), 7.74(m)

Mass spec.: FAB (+ve) 994 (m+1, 100%) Example 10

2-Hydroxyethyl methacrylate (0.15 g, 1.03 mmol) and 1H-tetrazole (0.07 g, 1.03 mmol) in dry acetonitrile (ca. 10 mL) were added to the reaction mixture and stirred at room temperature for 16 hours. After filtering through celite, the solvent was removed to obtain crude phosphite triester.

¹ H-nmr, 200MHz, (CDCl ₃ )δ=1.45(d), 1.94(s), 2.68(t),

3.52(t), 4.14(m), 4.35(t), 5.65(s), 6.17(s)

The crude phosphite triester was dissolved in dichloromethane (about 20 mL), treated with m-chloroperbenzoic acid (0.18 g, 1.03 mmol), and stirred at room temperature for 10 minutes. The solution was extracted with saturated aqueous sodium bicarbonate (2 x about 20 mL). The organic phase was dried over magnesium sulfonate and evaporated to give crude phosphoric acid triester, 0.35 g, 91% yield based on hydroxyethyl methacrylate.

¹ H-nmr, 200 MHz (CDCl ₃ ) 8 = 1.98(s), 2.80(t), 3.52(t), 4.35(m),

5.64(s), 6.17(s).

Crude phosphate triester (0.35 g, 0.95 mmol) was dissolved in dry acetonitrile (about 10 mL), treated with trimethylamine (0.31 g, 5.2 mmol), and heated at 75°C for 16 hours. The solvent was distilled off, the residue was dissolved in methanol, and purified by column chromatography on silica gel (about 30 g) eluting with methanol. The product-containing fractions were combined and evaporated to dryness to give pure 2-(methacryloyloxyethyl)2'-(trimethylammonioethyl)phosphate inner salt, 0.99 g, 0.31 mmol, 30% yield.

¹ H-nmr, 200MHz, (D ₂ O)8=1.97(s), 3.22(s), 3.68(m), 4.17(m),

4.32(m), 4.41(m), 5.82(s), 6.23(s)

The total yield of 2-(methacryloyloxyethyl)-2'-(trimethylammonioethyl)phosphate inner salt based on hydroxyethyl methacrylate was 30%. Example 1111.1 Chloride 2-[N-(2,6-dimethyl)pyridinium]-1,3,2-dioxaphospholane

Anhydrous lutidine (0.313g, 2.92mmol) was added to cooled (-10°C) 2-chloro-1,3,2-dioxaphospholane (0.369g, 2.92mmol) in dry d ₃ -Acetonitrile (4ml) in a stirred solution. The resulting solution was stirred at -10°C for 1 hour and analyzed by NMR spectroscopy.

¹ HNMR (CD ₃ CN) δ8.10 (1H, t, J=6), 7.48 (2H, d, J=6), 4.65-3.95 (4H, m),

2.75 (6H, s). 11.2 Preparation of inner salt of 2-(methacryloyloxyethyl)-2'-(trimethylammoniumethyl)phosphate

Under nitrogen atmosphere, the acetonitrile solution of 2-chloro-1,3,2-dioxaphospholane (4.9g, 0.04M) was cooled to -10°C, and 2,6-lutidine (4.0 g, 0.04M) for 20 minutes and the mixture was stirred for a further 20 minutes at -10°C. A solution of 2-hydroxyethyl methacrylate (4.4 g, 0.033 M) in acetonitrile (8 ml) was added over 15 minutes at -10°C. The mixture was heated to °C and filtered. The filtrate was cooled to -10°C and treated with a solution of trimethylamine N-oxide (2.4g, 3.2M) in acetonitrile (25ml). A solution of trimethylamine (3.3 g) in acetonitrile (10 ml) was added. The mixture was heated at 45°C for 16 hours in a closed system. The reaction mixture was concentrated and crystallized at 0°C to isolate the desired product.

TLC showed that the product was pure with a small amount of by-product contamination.

¹ H-nmr, 200MHz, (D ₂ O)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 ₂ O) δ=20.2, 56.8, 62.3, 66.7, 67.3,

68.8, 129.9, 138.7, 172.4

According to the above formula, when the product is used to react with HEMA in a method similar to the second step of Example 3, it is found that no acid activator needs to be added. Reaction. Example 12 Chloride 2-(N-pyridinium)-1,3,2-dioxaphospholane

Anhydrous pyridine (0.228g, 2.88mmol) was added to a cooled (-10°C) stirred solution of 2-chloro-1,3,2-dioxaphospholane in dry _d3 -acetonitrile (4ml) middle. The resulting solution was stirred at -10°C for 1 hour and analyzed by NMR spectroscopy.

¹ H NMR (CD ₃ CN) δ8.70 (2H, d, J=4), 8.38 (1H, t, J=6), 7.88 (2H, m),

4.65-3.95 (4H, m).

¹³ CNMR (CD ₃ CN) δ66, 56 (CH ₂ ), 124.81 (CH), 137.34 (CH), 150.04 (CH).

This product was used to react with HEMA as described in Example 11.2. Also, since phosphoramidites have a cationic charge, they can activate the reaction with alcohols without adding a weak acid activator. Example 13 2-(methacryloyloxyethyl)-2'-(trimethylammonioethyl)phosphate inner salt

2-Hydroxyethyl methacrylate (1.64 g, 12.5 mmol) and benzoic acid (1.52 g, 12.4 mmol) were stirred in dry acetonitrile (15 mL) for about 0.25 hours under nitrogen atmosphere at room temperature. A solution of 2-(N,N-diisopropylamino)-1,3,2-dioxaphospholane (2.50 g, 12.4 mmol) in dry acetonitrile (2.5 ml) was added dropwise to the above mixture over a period of 0.5 hours. After stirring was continued at room temperature for 2 hours, the mixture was cooled to about 0°C and filtered under nitrogen. The filter bed was washed with dry acetonitrile (2ml). A sample of the filtrate was evaporated to dryness and analyzed by TLC and ¹ H-nmr, showing the desired 2-(methacryloyloxyethoxy)-1,3,2-dioxaphospholane . Thus, benzoic acid is a weak acid activator with good effect on phosphoritylation agents.

The remainder of the material was cooled to -20°C and treated with a solution of trimethylamine N-oxide (0.89 g, 11 mmol) in dry acetonitrile (12 mL). After one hour, the mixture was warmed to about 21°C, sampled, evaporated and analyzed by ¹ H-nmr. ^{The 1} H-nmr spectrum indicated the presence of unoxidized material, so the contents of the reaction mixture were recooled to -20°C and a portion of trimethylamine N-oxide (0.23 g, 3.1 mmol) in dry acetonitrile (4 mL) was added. After 5 minutes, the mixture was warmed to about 21°C and a solution of trimethylamine (1.28g, 21.4mmol) in dry acetonitrile (4ml) was added. The mixture was heated to 45°C for 16 hours. The solution was filtered through celite and evaporated to give the crude product.

¹ Hnmr, 200MHz, (D ₂ O)δ6.2(IH, s), 5.8(IH, s), 4.4(2H, m),

4.3(2H,m), 4.2(2H,m), 3.7(2H,m), 3.2(9H,s) and 1.9

(3H,s) ppm. Example 14 Preparation of 2-(methacryloyloxyethoxy)-1,3,2-dioxaphospholane using carboxylic acid activator 14.1 using glutaric acid

2-Hydroxyethyl methacrylate (1 equivalent) and glutaric acid (0.5 equivalent) were heated to 40°C in acetonitrile, and 2-(N,N-diisopropylamino)-1,3,2-bis Oxaphospholane (1 eq.) was treated. The mixture was cooled to room temperature and filtered to give the title compound in solution. 14.2 Use of adipic acid

Reaction of 2-hydroxyacetic acid methacrylic acid and adipic acid with 2-(N,N-diisopropylamino)-1,3,2-dioxaphospholane gave the title compound in a similar manner to that described above.

These examples show that dibasic aliphatic carboxylic acids are good activators of phosphitylation agents. Example 15 (Comparative Example) 2-[(methacryloyl)ethoxy]-1,3,2-dioxaphospholane

2-Chloro-1,3,2-dioxaphospholane (0.425g, 3.36mmol) was added dropwise to cooled (-10°C) anhydrous pyridine (0.269g, 3.40mmol) and methacrylic acid 2- Hydroxyethyl ester (0.437g, 3.36mmol) was stirred in anhydrous ether (15ml). The mixture was warmed to room temperature, stirring was continued for 0.5 hours, and the pyridinium chloride salt was removed by filtration under nitrogen, and the filter bed was washed with another portion of anhydrous diethyl ether (2 x 25 mL). The 2-[(methacryloyl)ethoxy]-1,3,2-dioxaphospholane product was identified by thin layer chromatography.

TLC, silica gel, 10% ethyl acetate/dichloromethane, 1% KM _n O ₄ K aqueous solution: Rf=0.75. Numerous other spots were seen on the chromatogram, indicating that the mixture included a large amount of by-products. It can be seen that the inventive method using phosphoramidite raw material is much better than the prior art method using chlorophosphite phosphoritylation agent. The reaction of embodiment 16 (comparative example) 2-chloro-1,3,2-dioxaphospholane and 2-hydroxyethyl methacrylate

2-Chloro-1,3,2-dioxaphospholane (12.6 g, 0.1 M) in anhydrous acetonitrile (5 ml) was added dropwise to 2-hydroxylmethacrylic acid at -30 °C under nitrogen atmosphere Ethyl ester (13.0g, 1M) and N,N,N,N'-tetramethylethylenediamine (5.81g, 0.1M). The mixture was warmed to 0 °C over 0.5 h. The reaction mixture was filtered and a sample of the filtrate was evaporated in vacuo and determined by ¹ H and ³¹ P-nmr spectroscopy.

¹ H-nmr, 500 MHZ, (CDCl ₃ ), indicated that there was a large amount of other acrylate-related products along with the desired product.

³¹ P-nmr indicated that a number of other peaks including 140.9, 136.7, 18.9, 10.6, 9.6, and -24.8 ppm were present concurrently with the desired product (peak at 137.3 ppm).

Therefore, according to the prior art, the process using phosphoryl chloride phosphoritylation agent will result in a product which is not as pure as the product of the process of the present invention.

Claims (22)

1. method that comprises the alcoholysis step is with formula I compound

R wherein ₁Can be identical or different, each R ₁Representing straight or branched alkyl (comprising cycloalkyl), perhaps form a heterocycle with the nitrogen-atoms that they connected, choose wantonly and contain other heteroatoms, can be saturated or undersaturated, and NR ₂ ¹Optional is quaternized form,

Y be the phosphoric acid ester blocking group and

Z is NR ₂ ², R wherein ²Be selected from and R ¹Identical group, and can with NR ₂ ¹Identical or different, or Z is OR ³Group, wherein R ³Be selected from C _1-40-straight or branched alkyl, alkenyl and alkynyl group, or R ³Form 5 to 15 yuan of heterocycles with Y with Sauerstoffatom and the phosphorus atom that their institute'ss (difference) are connected, optionally contain other heteroatoms and/or on ring carbon and/or nitrogen-atoms (if the words that have), substituting group is arranged, under arbitrary situation, R ³Group can replace with aryl, hydroxyl, halogen atom, amido (comprise one, two or trialkyl substituted amido), sulfonium Ji Huo Phosphonium base, in solution with formula BR ⁷The reaction of OH alcohol, wherein R ⁷Be the straight or branched alkylidene group, oxa-alkylidene group or oligomeric oxa-alkylidene chain, B are the unsaturated groups that gathers of olefinic, are selected from

With Wherein:

R is hydrogen or C ₁-C ₄Alkyl;

A is-O-or-NR ⁸-, R wherein ⁸Be hydrogen or C ₁-C ₄Alkyl; With

K is-(CH ₂) _pOC (O)-,-(CH ₂) _pCO (O)-,-(CH ₂) _pOC (O) O-,-(CH ₂) _pNR ⁹-,-(CH ₂) _pOC (O) NR ⁹-,-(CH ₂) _pNR ⁹C (O) NR ⁹-(R wherein ⁹Group can be identical or different) ,-(CH ₂) _pO-,-(CH ₂) _pSO ₃-group, or a covalent linkage, and p is from 1 to 12, R ⁹Be hydrogen or C ₁-C ₄Alkyl forms formula II compound Wherein Z, Y, R ⁷With identical group in B representative and formula I compound and the alcohol.

2. by the method for claim, wherein Z is an X ' group, and further comprises solution and second pure R of II ⁴The step of OH reaction, wherein R ⁴Be selected from BR ⁷And C _1-40Under straight or branched alkyl, alkenyl and alkynyl group, any situation, all unsubstituted or replace with aryl, halogen atom, hydroxyl, amido (comprise one, two or trialkyl substituted amido), sulfonium Ji, Phosphonium base,

Form the formula III compound

Y wherein, R ⁷With the identical group in B representative and the formula II compound and second alcohol.

3. by the method for claim 1 or 2, wherein each alcoholysis step is all carried out in the presence of weak acid.

4. by the method for claim 2 or 3, wherein Z is NR ² ₂Group, and NR ² ₂With NR ¹ ₂Identical.

5. by the method for claim 4, wherein the first step and the 3rd goes on foot and uses different weak acid in the alcoholysis step.

6. by the method for claim 2 or 3, wherein Z is NR ² ₂Group, and NR ² ₂With NR ¹ ₂Different.

7. by the method for claim 6, when wherein the first step and second goes on foot alcoholysis, use identical weak acid.

8. by claim 3,5 and 7 each methods, weak acid wherein is selected from the 1H-tetrazolium, and 1,2,4-triazole, 3-chlorine triazole, tetrazolide diisopropyl ammonium and 4,5-dichloro-imidazole.

9. by the method for each claim of front, comprise that with formula III compound or Z be OR ³The subsequent step of formula II compound oxidation, form the corresponding phosphoric acid ester of general formula I V R wherein ¹³Be R ³Or R ⁴And Y, R ⁷Define with claim 1 or 2 with B.

10. press the method for claim 9, wherein, in oxidation step, reagent is a kind of organic oxidizing agent, be preferably selected from superoxide, (as tertbutyl peroxide, di-tert-butyl hydrogen peroxide, two (trimethyl silicane) hydrogen peroxide and peroxidation benzoic acid derivative such as metachloroperbenzoic acid) and iodobenzene diacetate, or ozone or molecular oxygen in benzene or other dry solvent, optional have radical initiator, or oxynitride (as nitrogen tetroxide) or tertiary amine oxide.

11. by each method of aforementioned claim, wherein B is following group

Wherein R is hydrogen or methyl, preferable methyl, and A is preferably-O-; And

R ⁷Be (CH ₂) _2-6, preferred (CH ₂) ₂

12. by each method of aforementioned claim, wherein Y is R ⁵O-, wherein R ⁵Be C _1-6Alkyl or aryl; preferably use drawing electron group; as halogen atom; nitro; alkylsulfonyl and aryl (comprising heteroaryl) replace; be selected from allyl group; benzyl; phenyl; the benzene sulfonyl ethyl; the methylsulfonyl ethyl; to the nitre styroyl; 2; 2; 2-three halogenated ethyls (particularly trichlorine and three bromomethyl); 2,2,2-three halogen-1; 1-dialkyl group ethyl (particularly 2; 2,2-three chloro-1,1-dimethyl ethyl); 2 ＇-and 4 '-the pyridyl ethyl; between methyl-benzyl; to or a halogeno-benzyl; between; right-dichloro benzyl; phenyl-pentahalide base (particularly five fluoro-and pentachloro--phenyl); 2; 6-3,5-dimethylphenyl and 2,4-dinitrophenyl, most preferably beta-cyano ethyl.

13. by each method of claim 9-12, further comprise formula IV compound separated the protection step, make substituting group Y be replaced as O ^-

14. by the method for claim 12, wherein Z is OR ³, and Y group and R in formula I compound ³Group connects heterocycle of formation, separates the effectively open loop of protection step, becomes-O ^-With from Y-R ³-O-deutero-group links to each other with phosphorus atom.

15. by the method for claim 14, wherein open loop is separated the protection step and is comprised simultaneously the Y group end amination away from phosphoryl group one side is formed amine groups, preferably a quaternary amines.

16. by each method of aforementioned claim, wherein Z is OR ³, and Y group and R ³Connect, become following formula: compound

R wherein ¹²Be C _2-4Alkylidene group, alkylene group or inferior alkynyl group, any is all unsubstituted or replace with one or more halogen atoms, hydroxyl, amine, alkyl or alkylidene group, is a closed hoop components of system as directed, R ¹Definition with claim 1.

17. the method for a synthetic amphoteric ion type phosphodiester comprises the steps: v) formula V compound R wherein ¹And R ²Can be identical or different, and respectively represent straight or branched alkyl (comprising cycloalkyl), perhaps R ₁Group and/or R ²Group forms a heterocycle with the nitrogen-atoms that is connected separately, and choose wantonly and contain other heteroatoms, can be saturated or undersaturated,

Y is the phosphoric acid ester blocking group.

In solution with first pure R ³OH reaction, wherein R ³Be selected from C _1-40Straight or branched alkyl, alkenyl and alkynyl group, under any situation, all can be unsubstituted, or replace with aryl, hydroxyl, halogen atom, amido (comprise one, two or trialkyl substituted amido), sulfonium Ji Huo Phosphonium base, be reflected under the substantially anhydrous conditions and carry out, form formula VI compound

R wherein ², R ³With identical in the definition of Y and formula V compound and first alcohol; Vi) then with formula VI compound and second pure R ⁴OH reaction, wherein R ⁴Be selected from C _1-40Straight or branched alkyl, alkenyl and alkynyl group under any situation, all can be unsubstituted, or replace with aryl, hydroxyl, halogen atom, amido (comprise one, two or trialkyl substituted amido), sulfonium Ji Huo Phosphonium base, but R ³And R ⁴The C that on behalf of halogen atom, sulfonium base, amino Huo Phosphonium base, at least one should replace _1-10Alkyl is reflected under weak acid existence and the substantially anhydrous conditions and carries out, and forms formula VII compound R wherein ³, R ⁴With identical in the definition of Y and formula VI compound and second alcohol; Vii) formula VII compound is oxidized, forms formula VIII compound

R wherein ³, R ⁴Definition cotype VII compound with Y;

Viii) formula VIII compound is separated protection, make the Y substituting group by O ^-Displacement if need, can be introduced R with cationic substituent ³Or R ⁴Group forms the product compound.

18. by the method for claim 17, wherein in v and the vi step, each step all carries out in the presence of weak acid, weak acid is preferably 1H-tetrazolium, 1,2,4-triazole, 3-chlorine triazole or tetrazolide diisopropyl ammonium, or be preferably 4, the 5-dichloro-imidazole.

19. by the method for claim 17 or 18, wherein Y is R ⁵O-, wherein R ⁵Be C _1-6Alkyl or aryl; preferably use drawing electron group; as halogen atom; nitro; alkylsulfonyl and aryl (comprising heteroaryl) replace; be selected from allyl group; benzyl; phenyl; the benzene sulfonyl ethyl; the methylsulfonyl ethyl; to the nitre styroyl; 2; 2; 2-three halogenated ethyls (particularly trichlorine and three bromomethyl); 2,2,2-three halogen-1; 1-dialkyl group ethyl (particularly 2; 2,2-three chloro-1,1-dimethyl ethyl); 2 ＇-and 4 '-the pyridyl ethyl; between methyl-benzyl; to or a halogeno-benzyl; between; right-dichloro benzyl; phenyl-pentahalide base (particularly five fluoro-and pentachloro--phenyl); 2; 6-3,5-dimethylphenyl and 2,4-dinitrophenyl, most preferably beta-cyano ethyl.

20. by each method of claim 17 to 19, wherein the oxygenant of step in vii) is a kind of organic oxidizing agent, be preferably selected from superoxide, (as tertbutyl peroxide, di-tert-butyl hydrogen peroxide, two (trimethyl silicane) hydrogen peroxide and peroxidation benzoic acid derivative such as metachloroperbenzoic acid) and iodobenzene diacetate, or ozone or molecular oxygen in benzene or other dry solvent, optional have radical initiator, or oxynitride (as nitrogen tetroxide) or tertiary amine oxide.

21. by the method for claim 17, wherein R ³And/or R ⁴You Phosphonium substituting group.

22. by each method of claim 17 to 20, wherein R ³OH and/or R ⁴OH is α, β-two substituted glycerol, preferred α, β-two C _12-24Acyl group, alkyl, alkenyl or alkynyl group glycerine.