Methods for producing zwitterionic compounds

Abstract

To provide a production method that makes it possible to synthesize, by a simple process and in high yield, a zwitterionic ionic compound having a polymerizable moiety, a quaternary ammonium cation moiety and a phosphoric acid moiety.SOLUTION: A method for producing a zwitterionic ionic compound includes the step for reacting a compound H represented by the formula (1) with polyphosphoric acid to yield a zwitterionic ionic compound P represented by the formula (2) (R1 is a hydrogen atom or a methyl group, X1 is -O- or -N(Q1)-, Q1 is a hydrogen atom or C1-6 alkyl group, R2 is OH or O-, m is an integer of 1-12, n is an integer of 1-4).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for preparing zwitterionic compounds. [Background technology]

[0002] Artificial medical materials, such as artificial organs, have become indispensable in the medical field in recent years. It is important that artificial medical materials do not cause undesirable biological reactions in the body, and the development of such materials is being widely pursued. Polymer compounds such as polyethylene glycol (PEG) have been known to be useful as protein adsorption inhibitors and have been used as artificial medical materials. However, PEG chains are easily degraded by oxidation, making their long-term stable use in the body difficult. Therefore, there is a demand for materials that are resistant to degradation in the body and have a strong ability to inhibit protein adsorption.

[0003] For example, Non-Patent Document 1 discloses a polymer of 2-methacryloyloxyethyl phosphorylcholine (MPC), and shows that such a polymer has an excellent protein adsorption inhibitory effect.

[0004] Furthermore, Patent Document 1 discloses a zwitterionic compound having a structure in which a quaternary ammonium cation group and a phosphodiester group are interchanged in the phosphorylcholine (PC) group of MPC, in order to solve the problem that the hydrophilicity of MPC is easily reduced by a decrease in pH. A polymer of this zwitterionic compound is capable of exerting an excellent protein adsorption inhibitory effect over a wide pH range. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2021 / 107141 [Non-patent literature]

[0006] [Non-Patent Document 1] Vaisocherova, H. et al., Biosens. Bioelectron. 2009, 24, pp. 1924-1930 Summary of the Invention [Problem to be solved by the invention]

[0007] The zwitterionic compound disclosed in the aforementioned Patent Document 1 has an excellent inhibitory effect on protein adsorption, and therefore, efficient production of such a compound is extremely important in the field of medical materials, such as artificial medical materials. However, a method for efficiently synthesizing such a zwitterionic compound has not yet been established.

[0008] The present invention has been made in view of the above, and aims to provide a production method that can easily synthesize zwitterionic compounds, particularly zwitterionic compounds having a polymerizable moiety, a quaternary ammonium cation moiety, and a phosphate moiety, in good yield. [Means for solving the problem]

[0009] As a result of extensive research into achieving the above object, the present inventors have discovered that the above object can be achieved by reacting a specific compound H with polyphosphoric acid, thereby completing the present invention.

[0010] That is, the present invention includes, for example, the subject matter described in the following sections. Item 1 1. A method for producing a zwitterionic compound, comprising: The following general formula (1)

[0011] [ka]

[0012] (In formula (1), R 1 is a hydrogen atom or a methyl group, X 1is -O- or -N(Q 1 )- and Q 1 is a hydrogen atom or C 1-6 is an alkyl group, m is an integer from 1 to 12; n is an integer from 1 to 4. By reacting compound H represented by the formula: with polyphosphoric acid, The following general formula (2)

[0013] [ka]

[0014] (In formula (2), R 1 , X 1 , m and n are R in the formula (1), 1 , X 1 , m and n; R 2 is OH or O - is) A method for producing a zwitterionic compound, comprising the step of obtaining a zwitterionic compound P represented by the formula: Section 2 Item 2. The method for producing a zwitterionic compound according to Item 1, wherein the polyphosphoric acid contains polyphosphoric acid having an orthophosphoric acid equivalent of 105 to 120% by weight. Section 3 Item 3. The production method according to Item 1 or 2, wherein the reaction uses 0.5 to 1.5 moles of the compound H per mole of the polyphosphoric acid (calculated as P2O5). Section 4 Item 4. The method according to any one of Items 1 to 3, wherein the reaction is carried out in a solvent. Section 5 Item 5. The method according to any one of items 1 to 4, wherein the reaction is carried out at 50 to 100°C. [Effects of the Invention]

[0015] According to the production method of the present invention, a zwitterionic compound having a polymerizable moiety, a quaternary ammonium cation moiety, and a phosphate moiety can be synthesized in a simple manner with good yield. DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0023] In the present specification, the terms "contain" and "comprise" include the concepts of "contain," "comprise," "consist essentially of," and "consist only of."

[0017] The method for producing the zwitterionic compound of the present invention comprises: The following general formula (1)

[0018] [ka]

[0019] (In formula (1), R 1 is a hydrogen atom or a methyl group, X 1 is -O- or -N(Q 1 )- and Q 1 is a hydrogen atom or C 1-6 is an alkyl group, m is an integer from 1 to 12; n is an integer from 1 to 4. By reacting compound H represented by the formula: with polyphosphoric acid, The following general formula (2)

[0020] [ka]

[0021] (In formula (2), R 1 , X 1 , m and n are R in the formula (1), 1 , X 1 , m and n are synonymous with each other, and R 2 is OH or O - is) This step is hereinafter referred to as "Step A."

[0022] The production method of the present invention, which includes the above-mentioned step A, can easily synthesize a zwitterionic compound having a polymerizable moiety, a quaternary ammonium cation moiety, and a phosphate moiety in high yield, and in particular, can obtain a zwitterionic compound that is a phosphate monoester with higher purity. Here, the polymerizable moiety refers to a (meth)acryloyl group moiety, as is clear from the above-mentioned formula (2). In this specification, "(meth)acry" refers to "acrylic" or "methacrylic."

[0023] Step A is a step for reacting the compound H with polyphosphoric acid. This reaction produces the target zwitterionic compound P.

[0024] (Compound H) Compound H is a compound represented by formula (1) and is a raw material for obtaining zwitterionic compound P. As represented by formula (1), compound H is a cationic compound.

[0025] In formula (1), X 1 -N(Q 1 )-, then Q 1 is C 1-6 It is an alkyl group, that is, an alkyl group having 1 to 6 carbon atoms. Examples of such alkyl groups include a methyl group, an ethyl group, a propyl group (n-propyl group or i-propyl group), and a butyl group (n-butyl group, i-butyl group, s-butyl group, t-butyl group). 1 is preferably a hydrogen atom or C 1-4 is an alkyl group, more preferably a hydrogen atom or C 1-3 It is an alkyl group.

[0026] In formula (1), X 1 is preferably —O— or —N(H)—, more preferably —O—. 1 When is -N(H)-, it is less susceptible to bond cleavage than -O- and can be stable even under harsh conditions such as high temperatures.

[0027] In formula (1), m can be appropriately selected depending on the solubility in the solvent, etc. m is preferably an integer of 4 to 12 from the viewpoint of improving the solubility in the organic solvent, and on the other hand, m is preferably an integer of 1 to 3 from the viewpoint of improving the water solubility.

[0028] In formula (1), n is preferably an integer of 1 to 3, and more preferably 1 or 2.

[0029] Compound H may have a counter ion, for example Cl - , Br - as a counter ion.

[0030] There is no particular limitation on the method for producing Compound H. For example, Compound H can be obtained by a known production method, or Compound H can be obtained from a commercially available product, etc.

[0031] Compound H can be produced by reacting a compound represented by the following formula (3) with a compound represented by the following formula (4).

[0032] [ka]

[0033] Here, in equation (3), L 1 is a halogen atom, and in formula (4), R 1 , X 1 , and m are R in the formula (1), respectively. 1 , X 1 , and m.

[0034] The amount of the compound represented by formula (4) used is, for example, 0.5 to 2.0 mol, preferably 0.9 to 1.1 mol, and usually about 1 mol, relative to 1 mol of the compound represented by formula (3).

[0035] The reaction between the compound represented by formula (3) and the compound represented by formula (4) can be carried out in a solvent. Examples of the solvent include polar aprotic solvents, and specific examples thereof include haloalkanes such as dichloromethane and dichloroethane, diethyl ether, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric triamide. These solvents can be used alone or in combination of two or more.

[0036] The reaction temperature and reaction time of the compound represented by formula (3) and the compound represented by formula (4) are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 10 to 150°C, preferably 20 to 120°C, and the reaction time is, for example, 1 to 48 hours, preferably 2 to 36 hours.

[0037] (Polyphosphate) The polyphosphoric acid used in step A is a raw material for introducing a phosphate moiety into compound H. n+2 P n O 3n+1 (n is an integer of 2 or more). By using polyphosphoric acid in step A, the target zwitterionic compound P contains a high proportion of phosphoric acid monoesters, and the amount of by-products (e.g., diesters) can be reduced.

[0038] The polyphosphoric acid used in step A preferably contains polyphosphoric acid having an orthophosphoric acid equivalent amount of 105 to 120% by weight. The use of such polyphosphoric acid increases the reaction efficiency of phosphorus in the polyphosphoric acid, facilitating the reaction in step A, allowing the target zwitterionic compound P to be obtained in a higher yield, and also allowing the phosphoric acid monoester to be obtained with a higher purity. The orthophosphoric acid equivalent amount of the polyphosphoric acid is more preferably 110% by weight or more, more preferably 120% by weight or less, and even more preferably 118% by weight or less. Two or more polyphosphoric acids having different orthophosphoric acid equivalent amounts may be used in combination in step A.

[0039] The polyphosphoric acid used in step A can be polyphosphoric acid having an orthophosphoric acid equivalent of 105 to 120% by weight alone, or polyphosphoric acid having an orthophosphoric acid equivalent outside the range of 105 to 120% by weight can be used in combination. The polyphosphoric acid used in step A preferably contains polyphosphoric acid having an orthophosphoric acid equivalent of 105 to 120% by weight in an amount of 80% by weight or more, more preferably 90% by weight or more, even more preferably 95% by weight or more, and particularly preferably 99% by weight or more. In step A, orthophosphoric acid, phosphorus pentoxide, water, etc. can also be used in combination with polyphosphoric acid.

[0040] Polyphosphoric acid may be in the form of a salt, such as an alkali metal salt of polyphosphoric acid, an alkaline earth metal salt of polyphosphoric acid, an ammonium salt of polyphosphoric acid, or an organic amine salt of polyphosphoric acid. More specifically, examples of the salt of polyphosphoric acid include sodium polyphosphate, potassium polyphosphate, ammonium polyphosphate, calcium polyphosphate, and ferric polyphosphate. The polyphosphoric acid used in step A may be a mixture of non-salt polyphosphoric acid and a salt of polyphosphoric acid.

[0041] The polyphosphoric acid may be, for example, a linear polymer, or a cyclic or branched polymer, or a mixture thereof.

[0042] Polyphosphoric acid can be obtained, for example, by production using known methods, or can be obtained from commercially available products, such as 116% polyphosphoric acid and 105% polyphosphoric acid manufactured by Rasa Kogyo Co., Ltd., as well as various polyphosphoric acids manufactured by Nippon Chemical Industry Co., Ltd., Taihei Chemical Industry Co., Ltd., and Fujifilm Wako Pure Chemical Industries Co., Ltd.

[0043] (Process A) In step A, the compound H is reacted with the polyphosphoric acid.

[0044] In the reaction, it is preferable to use 0.3 to 2 moles of the compound H per mole of the polyphosphoric acid (calculated as P2O5). In this case, the target zwitterionic compound P can be obtained in high yield. The amount of the compound H used per mole of the polyphosphoric acid is more preferably 0.4 moles or more, even more preferably 0.5 moles or more, and more preferably 2.0 moles or less, even more preferably 1.5 moles or less.

[0045] The reaction between compound H and polyphosphoric acid is preferably carried out in a solvent. Examples of the solvent include aprotic solvents, such as acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, hexane, benzene, toluene, and xylene. These solvents can be used alone or in combination of two or more.

[0046] When a solvent is used in the reaction of step A, the ratio of the solvent to each raw material is not particularly limited. For example, the amount of polyphosphoric acid used can be 0.1 to 100 g per 100 mL of solvent.

[0047] The reaction temperature between compound H and polyphosphoric acid is not particularly limited as long as the reaction proceeds, and is, for example, 10 to 150° C., preferably 50 to 100° C., and more preferably 60 to 80° C. The reaction time can be appropriately set depending on the reaction temperature, and is, for example, 0.1 to 20 hours, and preferably 0.5 to 12 hours.

[0048] In step A, hydrolysis can be carried out subsequently to the reaction of compound H with polyphosphoric acid. For example, hydrolysis can be carried out by mixing water with the reaction product obtained by the reaction of compound H with polyphosphoric acid. For example, hydrolysis can be carried out by separating the by-product generated by the reaction of compound H with polyphosphoric acid by an appropriate method and then mixing with water.

[0049] In the hydrolysis, the amount of water used is not particularly limited, and can be, for example, 5 to 100 parts by mass per 100 parts by mass of the product.

[0050] After the reaction in Step A or after hydrolysis following the reaction, the resulting product can be purified by an appropriate method. This can further increase the yield and purity of the target zwitterionic compound P. The purification method is not particularly limited, and examples include filtration, chromatography, reprecipitation, and concentration, which can be used alone or in combination multiple times.

[0051] The target product, zwitterionic compound P, is produced through step A. In step A, compound H and polyphosphoric acid are used as raw materials for the reaction, so zwitterionic compound P can be obtained in high yield, with a particularly high proportion of phosphoric acid monoester and a small amount of by-products (e.g., diester). Furthermore, the production of insoluble matter during the reaction in step A can be suppressed.

[0052] In the past, phosphoric acid diesters could not be easily removed, and therefore, purification treatment using silica gel, ion exchange resins, etc. was required to reduce the amount of phosphoric acid diesters. However, in the production method of the present invention, by including step A, the amount of phosphoric acid diesters is extremely small, and therefore, there is little need for purification treatment as in the past.

[0053] From this viewpoint, the proportion of the phosphoric acid monoester in the zwitterionic compound P obtained in step A is preferably 80 mol % or more, more preferably 90 mol % or more, even more preferably 95 mol % or more, and particularly preferably 99 mol % or more. The content of the phosphoric acid monoester can be calculated by a known method, and specifically, 31 It can be calculated from the integral value of P-NMR.

[0054] (Zwitterionic Compound P) The zwitterionic compound P obtained by the production method of the present invention is a compound represented by the above formula (2). The zwitterionic compound P is a polymerizable compound. A polymer of the zwitterionic compound P has, for example, a protein adsorption inhibitory effect and can therefore be suitably used as a protein adsorption inhibitor. In other words, the zwitterionic compound P obtained by the production method of the present invention can be suitably used as a raw material for producing a protein adsorption inhibitor.

[0055] The zwitterionic compound P is a compound represented by X in formula (2) in that it is likely to improve the protein adsorption suppression function of the polymer. 1 is preferably -O- or -N(H)-, and more preferably -O-. For the same reason, it is preferable that n in formula (2) of zwitterionic compound P is 1 or 2. In order to improve the solubility in organic solvents, m in formula (2) is preferably an integer of 4 to 12, and in order to improve water solubility, m is preferably an integer of 1 to 3. In addition, it is preferable that R 2 is preferably OH.

[0056] An example of a zwitterionic compound P is (2-(methacryloyloxy)ethyldimethylammonio)ethyl phosphate.

[0057] The zwitterionic compound P may have a counterion. + Counter ions for the terminal phosphate moiety in zwitterionic compound P include, for example, ions of alkali metals such as Na and K, and alkaline earth metals such as Mg and Ca. In addition, tertiary amines and quaternary amines can also be used as counter ions.

[0058] In a polymer obtained by polymerization of zwitterionic compound P, the content of structural units based on zwitterionic compound P contained in the polymer is not particularly limited. For example, in order to facilitate improvement of the protein adsorption inhibitory function, the content of structural units based on zwitterionic compound P in the polymer can be 10 mol % or more, preferably 20 mol % or more, more preferably 30 mol % or more, even more preferably 40 mol % or more, and particularly preferably 50 mol % or more. Alternatively, the content of structural units based on zwitterionic compound P in the polymer may be 100 mol %.

[0059] The polymer may contain structural units other than those based on the zwitterionic compound P. Examples of monomers for forming the other structural units include monomers having an ethylenically unsaturated double bond, and specific examples include monofunctional monomers such as unsaturated carboxylic acids or salts, esters, or amides thereof; vinyl ethers; vinyl esters; and styrene sulfonic acid or salts thereof.

[0060] The method for preparing the polymer is not particularly limited, and for example, a wide variety of known polymerization methods can be employed.

[0061] The structure of the polymer is not particularly limited, and examples thereof include a wide range of known structures such as linear, comb, star, and ladder structures. The polymer can be formed into a molded article, as disclosed in Patent Document 1, or a polymer brush. The method for forming the molded article and the polymer brush is not particularly limited, and the same method as that described in Patent Document 1 can be used.

[0062] The polymer has an excellent protein adsorption suppression function and is therefore suitable as a biocompatible material, and for example, by applying it to the surface of a material, it can impart biocompatibility to the material or improve the biocompatibility of the material. A "biocompatible material" refers to a material that has the property of being difficult for proteins, cells, etc. to adhere to.

[0063] Examples of such biocompatible materials include surface covering materials (or surface coating materials) for medical materials such as artificial blood vessels, catheters, artificial organs, artificial joints, artificial dialysis membranes, artificial skin, artificial bones (joints, etc.), contact lenses, adhesive plasters, and bandages; preservative solutions for contact lenses; surface modifiers for diagnostic medical devices such as biochips and microarray chips; cell culture sheets; preservatives for blood, proteins, and cells; anticoagulants for proteins; moisturizers, pack materials (cosmetics), etc. [Example]

[0064] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0065] (Synthesis Example 1) 2-(Dimethylamino)ethyl methacrylate (0.5 mL, 3.0 mmol), 2-bromoethanol (0.2 mL, 3 mmol), and acetonitrile (6 mL) were added to a nitrogen-purged flask with a navel and stirred at room temperature (25 °C) for 24 hours. The solution was concentrated to obtain the crude product as a colorless viscous liquid. The crude product was dissolved in chloroform and reprecipitated in ethyl acetate. After filtration and washing with ethyl acetate, a white solid (0.81 g, 96%) was obtained. 1 H NMR (400 MHz,CD3OD): δ=1.97(s, 3H, CH3-), 3.276(s, 6H, -N + (CH3)2-), 3.613(m, 2H, -N + (CH3)2-CH2-CH2-OH), 3.88(m, 2H, -O-CH2-CH2-), 4.028(m, 2H, -CH2-OH), 4.641(m, 2H, -O-CH2-), 5.717, 6.162(2s, 2H, C=CH2) The obtained white solid 1 From the results of 1 H NMR measurement (400 MHz, CD3OD), it was confirmed that 2-cholinium methacrylate bromide (hereinafter referred to as CMB) represented by the following formula (1a) was produced. [ka]

[0066] Example 1 A flask with a navel under a nitrogen atmosphere was charged with Compound H (100 mmol, 28.2 g) obtained in Synthesis Example 1 and dry acetonitrile (100 mL). While adjusting the temperature inside the flask to 50°C using an oil bath, "116% polyphosphoric acid" (100 mmol (PO equivalent), 17.7 g) manufactured by Rasa Industries, which has an orthophosphoric acid equivalent of 116% by weight, was added to the flask. After the addition, the reaction was carried out at 70°C for 5 hours. Water (30 mL) was then added dropwise to the flask, and the mixture was stirred at 70°C for 3 hours and freeze-dried to obtain a crude product. The crude product was dissolved in methanol and added dropwise to dehydrated acetone under a nitrogen atmosphere to obtain a precipitate. This reprecipitation procedure was repeated three times to obtain a precipitate. The obtained precipitate was dissolved in a small amount of acetonitrile, and the insoluble matter was removed by filtration. The mixture was then added dropwise to dehydrated acetone under a nitrogen atmosphere to obtain the product (70 mmol, 19.7 g). 1 H NMR (400 MHz, DMSO -d6): δ=1.899 (s, 3H,C H 3-), 3.148 (s, 6H, -N + (C H 3)2-), 3.484 (m, 2H, -N + (CH3)2-C H 2-CH2-OP), 3.760 (m, 2H, -O-CH2-C H 2-N), 4.262 (m, 2H, -C H 2-OP), 4.515 (m, 2H, -OC H 2-), 5.758, 6.081 (s, 2H, C=CH2)(purity 99.9%) 31 P NMR (400 MHz, DMSO-d6): δ=-0.656 (99.9% purity) The above-mentioned obtained product 1From the results of H NMR measurement (400 MHz, DMSO-d6), it was confirmed that (2-(methacryloyloxy)ethyldimethylammonio)ethyl phosphate (hereinafter referred to as MCHP) represented by the following formula (2a) was produced. [ka]

[0067] Example 2 MCHP was obtained in the same manner as in Example 1, except that the amount of polyphosphoric acid used was changed to 150 mmol (P2O5 equivalent).

[0068] Example 3 MCHP was obtained in the same manner as in Example 1, except that the amount of polyphosphoric acid used was changed to 50 mmol (P2O5 equivalent).

[0069] (Comparative Example 1) MCHP was synthesized as follows according to Synthesis Example 1 described in the aforementioned Patent Document 2. N,N-Dimethyl-4-aminopyridine (0.18 g, 1.5 mmol) was placed in a flask with a navel under a nitrogen atmosphere. Dehydrated dichloromethane (27 mL), dehydrated triethylamine (3.0 mL, 22 mmol), and 2-bromoethanol (1.0 mL, 15 mmol) were added. Diethyl chlorophosphate (2.9 mL, 20 mmol) was added dropwise to this solution and stirred at 0°C for 1 hour. The resulting reaction mixture was warmed to room temperature (25°C) and stirred overnight. The resulting triethylamine hydrochloride was then filtered off, and the filtrate was transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The resulting organic layer was washed with water, brine, and then 2N HCl. The resulting organic layer was further washed with water and brine, dehydrated over anhydrous magnesium sulfate, filtered, and concentrated to yield a colorless liquid (3.16 g, 81%). 1H NMR (400 MHz,CDCl3): δ=1.35-1.37(t, J=6.87, 7.16, 6H, CH3-CH2), 3.53-3.56(t, J=6.30, 2H, CH2-Br), 4.12-4.18(quin, J=6.87, 7.16, 4H, PO-CH2-CH3), 4.29-4.33(dt, J=6.30, 2H, Br-CH2-CH2-OP) The obtained viscous liquid was 1 The results of 1 H NMR measurement (400 MHz, CD3OD) confirmed that diethyl 2-bromoethylphosphate was produced.

[0070] Diethyl 2-bromoethylphosphate (1.04 g, 4 mmol), 2-(dimethylamino)ethyl methacrylate (0.76 mL, 4.5 mmol), and acetonitrile (7 mL) were stirred at room temperature (25 °C) for 3 days. The solution was concentrated to give the crude product as a colorless liquid. The crude product was reprecipitated with ethyl acetate and washed with ethyl acetate to give a colorless viscous liquid (1.43 g, 64%). 1 H NMR (400 MHz,DMSO-d6): δ=1.24-1.28 (dt,J=0.91, 7.02, 6H,CH3CH2-OP), 1.90 (s, 3H,CH3-), 3.19 (s, 6H, -N + (CH3)2-), 3.79-3.83 (m, 4H, CH2-N + (CH3)2-CH2-CH2-OP), 3.83 (dq, 4H, CH3CH2-OP), 4.43-4.67 (q, J=3.4, 6.12, 2H, -N-CH2-CH2-OP), 4.53 (br, 2H, C(O)-O-CH2-), 5.717, 6.162 (t, 2H, C=CH2) The above-mentioned viscous liquid obtained 1 The results of H NMR measurement (400 MHz, CD3OD) confirmed that (2-(methacryloyloxy)ethyldimethylammonio)ethyl diethyl phosphate was produced.

[0071] The above (2-(methacryloyloxy)ethyldimethylammonio)ethyl diethylphosphate (0.61 g, 1.5 mmol) was placed in a flask with a navel under a nitrogen atmosphere. Dehydrated acetonitrile (15 mL) was added. Bromotrimethylsilane (1.2 mL, 9.0 mmol) was added dropwise to the solution, which was then stirred at 0°C for 9 hours. The solution was concentrated to give a crude product as a viscous liquid (yield: 61%). Methanol was added to the crude product, which was stirred for 9 hours. Purification was performed on a strong acid cation exchange resin (H type) (DOWEX 50Wx8, 50-100 mesh), followed by two washes with a mixed solvent of water and acetone (water:acetone = 9:1), to give a colorless liquid. The liquid was then concentrated to remove the acetone, and the resulting solution was freeze-dried overnight. Finally, the freeze-dried product was dissolved in a small amount of dehydrated methanol and added dropwise to dehydrated acetone under a nitrogen atmosphere to obtain a white powder precipitate. This reprecipitation procedure was repeated three times to obtain MCHP.

[0072] (Comparative Example 2) A nitrogen-purged three-neck flask was charged with CMB (28.2 g, 100 mmol) obtained in Synthesis Example 1 as Compound H and dry acetonitrile (100 mL). The flask was placed in an ice bath, and while the temperature inside the flask was adjusted to 10°C, phosphoryl chloride (28 mL, 300 mmol) was added dropwise over 1 hour. After 1 hour, deionized water (28 mL) was added and stirred for 1 hour. The solution was concentrated and then dried under reduced pressure to obtain a crude product as a yellow liquid. The crude product was isolated by reverse-phase silica column chromatography (0.1% by mass TFA aqueous solution:acetonitrile = 95:5 (v / v)) to obtain MCHP.

[0073] (Comparative Example 3) CMB (100 mmol, 28.2 g) obtained in Synthesis Example 1 as Compound H and dry acetonitrile (100 mL) were placed in a flask with a navel under a nitrogen atmosphere. While adjusting the temperature inside the flask to 50°C using an oil bath, phosphoric anhydride (diphosphorus pentoxide) (100 mmol, 14.2 g) as polyphosphoric acid was added to the flask. After the addition, the reaction was carried out at 70°C for 5 hours. Water (30 mL) was then added dropwise to the flask, and the mixture was stirred at 70°C for 3 hours. Insoluble matter was generated during the reaction. The insoluble matter was removed by filtration and then freeze-dried to obtain a crude product. The crude product was dissolved in methanol and added dropwise to dehydrated acetone under a nitrogen atmosphere to obtain a precipitate. This reprecipitation procedure was repeated three times, and a precipitate was obtained. The obtained precipitate was dissolved in ion-exchanged water, adsorbed onto a strongly acidic cation exchange resin (H type) (DOWEX 50W x 850-100 mesh), and eluted with an acetic acid solution to obtain MCHP.

[0074] [Table 1]

[0075] Table 1 shows the results of MCHP synthesis carried out in each of the Examples and Comparative Examples (monoester proportion after reaction, yield, and whether or not insoluble matter was precipitated).

[0076] The yield of MCHP is calculated using the following formula: (Yield of MCHP obtained / Amount of CMB charged) x 100 In Comparative Example 1, however, CMB was replaced with (2-(methacryloyloxy)ethyldimethylammonio)ethyl diethyl phosphate in the above formula. The monoester ratio after the reaction was calculated as follows: 31 The values were calculated from the integrals of the signals derived from the monoester and diester in P-NMR.

[0077] As can be seen from Table 1, when the production method including the step of reacting compound H with polyphosphoric acid as in the examples was employed, MCHP (zwitterionic compound P) could be synthesized in a higher yield than the method of the comparative examples, and no insoluble matter was observed during the reaction.

Claims

1. 1. A method for producing a zwitterionic compound, comprising: The following general formula (1) 【Chemical 1】 (In formula (1), R １ is a hydrogen atom or a methyl group, X １ is -O- or -N(Q １ ) - and Q １ is a hydrogen atom or C １－６ is an alkyl group, m is an integer from 1 to 12; n is an integer from 1 to 4. By reacting compound H represented by the formula: The following general formula (2) 【Chemistry 2】 (In formula (2), R １ , X １ , m and n are R in the formula (1), １ , X １ , m and n are synonymous with each other; R ２ is OH or O － is) A method for producing a zwitterionic compound, comprising the step of obtaining a zwitterionic compound P represented by the formula:

2. 2. The method for producing a zwitterionic compound according to claim 1, wherein the polyphosphoric acid contains polyphosphoric acid having an orthophosphoric acid equivalent of 105 to 120% by weight.

3. In the reaction, 1 mole of polyphosphoric acid (P ２ O ５ The method according to claim 1 or 2, wherein the compound H is used in an amount of 0.3 to 2 moles per mole (calculated as a mole of the compound H).

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in a solvent.

5. The method according to any one of claims 1 to 4, wherein the reaction is carried out at 50 to 100°C.

Images