CN102491994A - Preparation method of phosphocholine alkyl ester - Google Patents
Preparation method of phosphocholine alkyl ester Download PDFInfo
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- CN102491994A CN102491994A CN2011104024340A CN201110402434A CN102491994A CN 102491994 A CN102491994 A CN 102491994A CN 2011104024340 A CN2011104024340 A CN 2011104024340A CN 201110402434 A CN201110402434 A CN 201110402434A CN 102491994 A CN102491994 A CN 102491994A
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Abstract
The invention relates to a preparation method of phosphocholine alkyl ester. The method comprises the following steps of: a. carrying out an esterification reaction on cetyl alcohol and phosphorus oxychloride in an organic solvent under the action of an alkaline substance at (-20)-50 DEG C to obtain a substance A; b. carrying out a sufficient cyclization reaction on the substance A and ethylene glycol in an organic solvent under the action of an alkaline substance at (-20)-50 DEG C, carrying out solid-liquid separation on the obtained reaction liquid, concentrating the obtained liquid phase and dissolving in a solvent, washing with water and concentrating to obtain an intermediate B; and c. carrying out a sufficient ring-opening substitution reaction on the intermediate B obtained in the step b and trimethylamine in an organic solvent in a closed environment, carrying out solid-liquid separation on the obtained reaction liquid, and refining the obtained solid phase with a solvent to obtain a product. In the synthetic route adopted by the preparation method provided by the invention, no byproduct is generated in the final-step reaction, and the high-purity product can be obtained by a simple pulping and recrystallizing method after the reaction is finished; and the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic chemistry, relate to a kind of preparation method of esters of oxyacids of phosphorus, specifically is a kind of preparation method of phosphocholine alkyl ester.
Background technology
Miltefosine; Be Hexadecylphosphocholine, D-18506; Be a kind of phosphocholine alkyl ester, Chinese is miltefosine, Mi Tefuxin or Mi Tefuxin, chemistry hexadecyl 2-by name (trimethylammonium is amino) ethyl phosphonic acid ester; It has anti-tumor activity, is used to treat tropical communicable disease--leishmaniasis in the market.Eibl doctor H by Max-Planck-Inst studies its anti-tumor activity the earliest, and it delivered synthetic chromatographically pure Hexadecylphosphocholine to measure its iso-electric point character in 1980.
The preparation method of this phosphocholine alkyl ester (hereinafter to be referred as Mi Tefuxin) can represent through reaction formula as follows:
Specify in the face of above-mentioned preparation method down:
Method A--esterification methylates:
1, Eibl etc. discloses the method for being prepared as follows at EP0225608: hexadecanol and phosphorus oxychloride reaction generate the dichloro hexadecanyl phosphate; This ester is purified without separating, and promptly gets hexadecyl ethylamino-SULPHOSUCCINIC ACID ESTER bullion with the thanomin reaction through esterification (getting hexadecyl-ciliatine ester), open loop; Methylate through methyl-sulfate and generate the Mi Tefuxin bullion, bullion is through silica gel column chromatography, and the solvent crystallization method is purified, total recovery 70%;
Method B--esterification, the Trimethylamine 99 ammoniumization
1, Chemistry and Physics of Lipids, 109 (2), 203-207; 2001 disclose the method for being prepared as follows: hexadecanol and 2-bromotrifluoromethane-dichloro phosphide react behind hexadecyl-2-bromotrifluoromethane SULPHOSUCCINIC ACID ESTER; Generate the Mi Tefuxin bullion with Trimethylamine 99 reaction, bullion is through the post layer, solvent (chloroform-acetone) crystallization; De Mitefuxin, yield 44%.
Method C--is with the choline esterification
1, EP 0521297A1 has reported following method: embodiment 1; Hexadecanol and Phosphorus Oxychloride reaction generate the dichloro hexadecanyl phosphate; Generate Mi Tefuxin behind SULPHOSUCCINIC ACID ESTER and the acetylcholine response, the bullion yield is 87%, and bullion handles with ion-exchange resin and solvent crystallization is purified; De Mitefuxin, yield are 53% (by cetyl alcohol).
2, Chinese patent CN1068331 (applying date 1992.7.3; A mandate day 1997.3.6) require the following method of protection: the product that alphanol and phosphorus oxychloride reaction obtain reacts with choline salt under inert solvent, alkaline matter existence condition; Form the phosphodiester muriate, hydrolysis discharges the phosphocholine alkyl ester; For obtaining the purifying thing, also need ion exchange resin to purify.
More than three kinds of preparing method's final steps reaction except that generating product, also can generate other organic salt by products, this can cause the product purification difficulty, need be refining with column chromatography, therefore be not suitable for suitability for industrialized production.These methods must be separated and purification midbody product and use alkylating reagent; Perhaps use chromatographic process to come work and purification of crude product, perhaps use during recrystallization acid, alkalescence or amphoteric ion exchange resin to purify.
In addition, Mi Tefuxin can also prepare (Bull. Chem. Soc. Jpn., 78 (8), 1558-1564 through method D shown in the following reaction formula; 2005):
Aforesaid method need prepare chloro-cyclic SULPHOSUCCINIC ACID ESTER formula (D-I), and a lot of unfavorable factors are arranged here, unstable, the purity difference of this midbody at first, and preparation manipulation is difficult for.Secondly, the preparation the first step (D-I) need be used severe toxicity, dangerous big phosphorus trichloride, is difficult for the industriallization operation; The second step oxidizing reaction is dangerous big, and yield is low.In addition, we find in repeating above-mentioned operational process of craft: midbody (D-II) purity difference; Midbody (D-I) is not refining, directly carries out next step reaction, causes final product of poor quality, is difficult to make with extra care; The finished product are done recrystallization after need handling with column chromatography again.
R.L.Magolda once used the path of preparing alkyl phosphate choline shown in the following reaction formula (alkyl phoshorylcholines, this invention abbreviates Cn-PC as) (Tetrahedron Letters, 26 (9), 1167-70; 1985),
Summary of the invention
The technical problem that the present invention will solve is to provide that a kind of technology is simple to operation, safe and reliable, the preparation method of a kind of phosphocholine alkyl ester of being suitable for suitability for industrialized production.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of preparation method of phosphocholine alkyl ester, this method comprises the following steps:
A, in organic solvent, esterifications take place in-20 ~ 50 ℃ and obtain substance A in cetyl alcohol and POCl3 under the alkaline matter effect;
B, in organic solvent, ring-closure reactions take place to sufficient reacting in-20 ~ 50 ℃ in substance A and terepthaloyl moietie under the alkaline matter effect, the gained reaction solution carries out solid-liquid separation, the liquid phase that obtains is dissolved in the solvent after concentrating, and through washing, concentrate, obtains intermediate B;
C, under closed environment, the open loop substitution reaction takes place in intermediate B that the b step obtains and Trimethylamine 99 in organic solvent, to sufficient reacting, the gained reaction solution carries out solid-liquid separation, the solid phase that obtains obtains product after solvent treatment.
Substance A is the dichloro hexadecanyl phosphate, and intermediate B is the hexadecyl annular phosphate.
As preferably, the organic solvent described in step a and the step b is selected from THF, dioxane, t-butyl methyl ether, sherwood oil, toluene, YLENE, ETHYLE ACETATE, methylene dichloride, acetone, acetonitrile, MIBK (MIBK), ketopentamethylene or the normal hexane one or more independently of one another.One of preferred following: acetone, acetonitrile, THF, dioxane.
As preferably, the alkaline matter described in step a and the b can independently be selected from mineral alkali or organic bases separately, and organic bases is pyridine, triethylamine or diisopropylethylamine, and mineral alkali is salt of wormwood, yellow soda ash or sodium hydroxide.Alkaline matter described in step a and the b is preferably pyridine, triethylamine or salt of wormwood.The molar ratio of described alkaline matter of step a and cetyl alcohol is 1 ~ 10:1, preferred 1-5:1; The molar ratio of described alkaline matter of step b and cetyl alcohol is 1 ~ 10:1, preferred 1 ~ 5:1.Select organic bases, mineral alkali commonly used, that molecular weight is little, can control reaction volume.Alkali at least 1 equivalent among the step a, the hydrogenchloride that absorption reaction generates; Alkaline condition reaction down is more thorough.Alkali diacidic base at least 1 equivalent among the step b, monoatomic base at least 2 equivalents.
As preferably, the temperature of reaction of esterification described in step a and the b and ring-closure reaction is controlled at-10 ~ 10 ℃.Ring-closure reaction is preferably in below 0 ℃.The reaction times of described cetyl alcohol and POCl3 is recommended as 1 ~ 30 hour, preferred 1-8 hour; The reaction times of dichloro hexadecanyl phosphate and terepthaloyl moietie is recommended as 1 ~ 30 hour, preferred 1 ~ 8 hour.The two-step reaction temperature is not high, needs the proper extension reaction times.
The reaction solution that the b step obtains can obtain bullion through conventional separation method (concentrating as filtering, filtrating), and the gained bullion is dissolved in solvent, washing, concentrated intermediate B, i.e. the hexadecyl annular phosphate of obtaining.As preferably, the solvent described in the b step is selected from toluene, ETHYLE ACETATE, t-butyl methyl ether, sherwood oil, primary isoamyl alcohol, pimelinketone or methylene dichloride.One of preferred following: toluene, ETHYLE ACETATE, methylene dichloride.Gained bullion after preferred solvent is handled can improve the bullion outward appearance, prevents to degenerate in the storage process.
As preferably, the molar ratio of the described cetyl alcohol of a step, POCl3, terepthaloyl moietie is 1:0.5 ~ 5:0.5 ~ 5, preferred 1:0.8 ~ 3:0.8 ~ 3.
As preferably, the open loop substitution reaction takes place in described intermediate B of c step and Trimethylamine 99 in organic solvent, specifically is under 0 ~ 150 ℃, the condition of 0.1 ~ 1.0MPa, to react 1 ~ 12h.Be preferable under 60-100 ℃, the condition of 0.2 ~ 0.5MPa and react 2-4h.Increase the confined reaction system pressure and help speeding speed of response,, can react completely though the Trimethylamine 99 large usage quantity owing to be to continue to feed, need not very high pressure.
As preferably, the organic solvent described in the c step is selected from acetonitrile, acetone, MIBK (MIBK), THF, dioxane, t-butyl methyl ether, toluene or N, dinethylformamide (DMF).One of preferred following: acetonitrile, acetone, THF, dioxane.Preferred solvent can reduce temperature of reaction well and shorten the reaction times.
As preferably; Solid phase described in the c step is successively to make with extra care through solvent D, solvent E respectively through solvent-refined process, and said solvent D and solvent E are selected from following a kind of or any several kinds combination independently of one another: water, chloroform, methylene dichloride, acetonitrile, methyl alcohol, ethanol, Virahol, acetone, t-butyl methyl ether, sherwood oil.Preferred following solvent: acetone, t-butyl methyl ether, sherwood oil, methylene dichloride, ethanol, water.The gained solid phase is the Mi Tefuxin bullion in the c step, and it is earlier after solvent D, the refining final product Mi Tefuxin that obtains of solvent E.Described solvent D and solvent E can be single solvent, also can be one or more mixed solvents.If make with extra care and to reach the product purity requirement for twice, can increase refining number of times; Indication utilizes solvent treatment among the present invention, includes but not limited to utilize solvent to carry out recrystallization, making beating.
As preferably, the said Trimethylamine 99 of c step continues to feed, and keeps reaction system at certain pressure.
The concrete preparation method of described Mi Tefuxin that recommends of the present invention carries out according to following steps:
A, in organic solvent, cetyl alcohol and POCl3 under the alkaline matter effect in-10 ~ 10 ℃ of resultant of reaction matter A dichloro hexadecanyl phosphates;
B, substance A are fully reacted in-10 ~ 10 ℃ under the alkaline matter effect without separation and purification and terepthaloyl moietie, and the gained reaction solution concentrates through filtering, filtrating, and the gained enriched material is dissolved in solvent, obtain intermediate B hexadecyl annular phosphate through washing, concentrating;
It is one of following that organic solvent among the said step a is selected from: acetone, acetonitrile, THF, dioxane; It is one of following that alkali among said step a, the b independently is selected from separately: pyridine, triethylamine, salt of wormwood; It is one of following that solvent among the step b is selected from: toluene, ETHYLE ACETATE, methylene dichloride;
Hexadecyl annular phosphate that c, step b make and Trimethylamine 99 react 2 ~ 4 h under 60 ~ 100 ℃, the condition of 0.1 ~ 0.5MPa in organic solvent; The gained reacting liquid filtering obtains the Mi Tefuxin bullion, and the gained bullion earlier obtains described Mi Tefuxin after solvent D, solvent E are refining; It is one of following that described organic solvent is selected from: acetonitrile, acetone, THF, dioxane; Described solvent D and solvent E independently are selected from following a kind of or any several kinds combination separately:: acetone, t-butyl methyl ether, sherwood oil, methylene dichloride, ethanol, water.
Compare with existing technology, beneficial effect of the present invention is:
A) compare with method A, B or C, the synthetic route that the present invention adopts, final step instead would not produce any other by product, and therefore, only need simply pull an oar in reaction end back, the method for recrystallization can obtain high purity product, is fit to suitability for industrialized production.
B) compare with method D, this route final step synthetic route is consistent with the present invention.The synthetic route that the present invention adopts need not passed through midbody chloro-cyclic SULPHOSUCCINIC ACID ESTER formula (D-I); Directly obtain hexadecyl annular phosphate compound (being D-II) with two-step reaction; And this two-step reaction can be accomplished in one pot, operates very simple; Secondly synthetic route of the present invention is raw materials used safer with reagent hexadecanol, POCl3, terepthaloyl moietie, Trimethylamine 99, and low price; What is more important; The present invention is through the control to step a, step b reaction; Improved the purity of intermediate B hexadecyl annular phosphate compound; And can make with extra care improving its purity the intermediate B hexadecyl annular phosphate compound that obtains, thereby operation is greatly simplified, be suitable for industrialized production.
Embodiment
With specific embodiment technical scheme of the present invention is done further explanation below, but protection scope of the present invention is not limited thereto.
Embodiment 1
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 500ml four-hole bottle, drop into POCl3 27.9g (1.1eq), exsiccant THF 100ml; Stir, cryosel is bathed cooling reaction to below-5 ℃, drips hexadecanol 40g (1eq)-triethylamine 25g (1.5eq)-THF 100ml solution simultaneously; About 2h dropwises; Continue at-5 ℃ of left and right sides insulation reaction 0.5h then, filter, filter cake washs with the 20ml THF;
Filtrating and washing lotion go back in the four-hole bottle, stir, and are cooled to about-5 ℃; Begin to drip the solution of terepthaloyl moietie 10.3g (1eq) and triethylamine 40 g (2.4eq)-THF 40ml, about 1h dropwises, and reaction is spent the night; Primitive reaction is complete; Filter, the washing of filter cake 40ml THF, filtrate decompression is revolved evaporate to dryness;
Add methylene dichloride 250ml in the gained residue, dissolving, 50ml water washing 2-3 time, anhydrous magnesium sulfate drying, decompression is revolved dried, and the gained residue is an intermediate B hexadecyl annular phosphate compound, directly is used for next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound Shi Mitefuxin
With step 1 products obtained therefrom formula intermediate B hexadecyl annular phosphate compound 42g, drop in the 500ml autoclave, add the 15ml acetonitrile, the sealing autoclave; Feed Trimethylamine 99 gas, stir, be warmed up to 78-82 ℃; The interior pressure is about 0.2Mpa, reaction 3.5h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
Gained Mi Tefuxin bullion is used the 40ml*2 washing with acetone, drops into then in the 500ml four-hole bottle, adds acetone 300ml, in about 20-30 ℃ of stirring to pulp 3h, filters, and gets filter cake, weight in wet base 37.5g;
Filter cake is used the 40ml*2 washed with dichloromethane, and the gained filter cake is dropped in the 500ml four-hole bottle, adds methylene dichloride 300ml recrystallization; Repeating above-mentioned acetone making beating and methylene dichloride recrystallization two goes on foot 2 times; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 30g, yield 44.6% (equivalence ratio, yield are all in hexadecanol).
Embodiment 2
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 500L reaction kettle, drop into POCl3 11.5kg (1.5eq), exsiccant dioxane 50L; Stir, cryosel is bathed cooling reaction to below-10 ℃, drips hexadecanol 12kg (1eq)-salt of wormwood 15.2kg (2.2eq)-dioxane 100L solution simultaneously; About 2h dropwises; Continue at-10 ℃ of left and right sides insulation reaction 0.5h then, filter, filter cake washs with the 3L dioxane;
Filtrating and washing lotion go back in the four-hole bottle, stir, and are cooled to about-10 ℃; Begin to drip terepthaloyl moietie 4.66kg (1eq) and salt of wormwood 15.2kg (2.2eq) and be dissolved in the solution of dioxane 100L, about 1h dropwises, reaction 12h; Primitive reaction is complete; Filter, the washing of filter cake 3L dioxane, filtrate decompression is revolved evaporate to dryness;
Add toluene 200L in the gained residue, dissolving, water washing 2-3 time, decompression is revolved dried, gets the 15.4kg solid, and the gained residue is an intermediate B hexadecyl annular phosphate compound, directly is used for next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound Mi Tefuxin
With step 1 gained intermediate B hexadecyl annular phosphate compound 2.2kg, drop in the 10L autoclave, add 3L acetone, the sealing autoclave; Stir, feeding contains Trimethylamine 99 gas, is warmed up to 56-62 ℃; The interior pressure is about 0.4MPa, reaction 2h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
The Mi Tefuxin bullion is used the 0.5L*2 washing with alcohol, drop into then in the 10L reaction kettle, add ethanol 3L, in about 20-30 ℃ of stirring to pulp 3h, filter; Filter cake is used the 0.5L*2 washed with dichloromethane, and the gained filter cake is dropped in the 10L reaction kettle, adds methylene dichloride 5L recrystallization; Repeating above-mentioned ethanol making beating and methylene dichloride recrystallization two goes on foot 1 time; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 1.9kg, yield 65.9% (equivalence ratio, yield are all in hexadecanol).
Step 2 ': by formula intermediate B hexadecyl annular phosphate compound Mi Tefuxin
With step 1 gained intermediate B hexadecyl annular phosphate compound 2.2kg, drop in the 10L autoclave, add the 4L ketopentamethylene, the sealing autoclave; Stir, feeding contains Trimethylamine 99 gas, is warmed up to 90 ℃; The interior pressure is about 0.6MPa, reaction 2h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
The Mi Tefuxin bullion is used the 0.5L*2 washing with acetone, drop into then in the 10L reaction kettle, add acetone 5L, in about 20-30 ℃ of stirring to pulp 2h, filter; Filter cake is used the 0.5L*2 washing with alcohol, and the gained filter cake is dropped in the 20L reaction kettle, adds ethanol 12L recrystallization; Repeating above-mentioned acetone making beating and ethyl alcohol recrystallization two goes on foot 1 time; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 1.7kg, yield 59% (yield is in hexadecanol).
Embodiment 3
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 20L reaction kettle, drop into POCl3 0.75kg (0.8eq), exsiccant acetone 2L; Stir, cryosel is bathed cooling reaction to below-8 ℃, drips hexadecanol 1.5kg (1eq)-pyridine 0.7kg (1.4eq)-acetone 6L solution simultaneously; About 1h dropwises; Continue at-8 ℃ of left and right sides insulation reaction 0.5h then, filter, filter cake is used the 3L washing with acetone;
Filtrating and washing lotion go back in the four-hole bottle, stir, and are cooled to about-8 ℃, begin to drip the solution that terepthaloyl moietie 0.8kg (2eq) and pyridine 1kg (2eq) are dissolved in acetone 2L; About 1h dropwises, reaction 12h, and primitive reaction is complete; Filter, filter cake 0.5L washing with acetone, filtrate decompression is revolved evaporate to dryness;
Add pimelinketone 1L in the gained residue, dissolving, water washing 2-3 time, decompression is revolved dried, gets the 1.86kg solid, and the gained residue is an intermediate B hexadecyl annular phosphate compound, directly is used for next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound Mi Tefuxin
With step 1 gained intermediate B hexadecyl annular phosphate compound 1.86kg, drop in the 10L autoclave, add the 3L THF, the sealing autoclave; Stir, feeding contains Trimethylamine 99 gas, is warmed up to 75 ℃; The interior pressure is about 0.3MPa, reaction 3h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
The Mi Tefuxin bullion with the washing of 0.2L*2 t-butyl methyl ether, is dropped in the 10L reaction kettle then, add t-butyl methyl ether 5L,, filter, the gained filter cake is dropped in the 20L reaction kettle, add ethanol 10L recrystallization in 20-30 ℃ of stirring to pulp 1h; Repeating above-mentioned t-butyl methyl ether making beating and ethyl alcohol recrystallization two goes on foot 1 time; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 1.25kg, yield 49.6% (equivalence ratio, yield are all in hexadecanol).
Embodiment 4
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 20L reaction kettle, drop into POCl3 1.9kg (2.0eq), exsiccant toluene 10L; Stir, cryosel is bathed below the cooling reaction to 0 ℃, drips hexadecanol 1.5kg (1eq)-triethylamine 1.25 (3.0eq)-toluene 3L solution simultaneously; About 0.5h dropwises; Continue at 0 ℃ of left and right sides insulation reaction 0.5h then, filter, filter cake is used the 2L toluene wash;
Filtrating and washing lotion go back in the four-hole bottle, stir, and are cooled to about 0 ℃, begin to drip the solution of terepthaloyl moietie 0.77kg (5eq)-triethylamine 1.25kg (4eq)-toluene 2L; About 1h dropwises, reaction 10h, and primitive reaction is complete; Filter, filter cake 0.5L toluene wash, filtrate decompression is revolved evaporate to dryness;
Add ETHYLE ACETATE 500ml in the gained residue, dissolving, water washing 2-3 time, decompression is revolved dried, gets the 1.83kg solid, and the gained residue is an intermediate B hexadecyl annular phosphate compound, directly is used for next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound Mi Tefuxin
With step 1 gained intermediate B hexadecyl annular phosphate compound 1.83kg, drop in the 10L autoclave, add 3L toluene, the sealing autoclave; Stir, feeding contains Trimethylamine 99 gas, is warmed up to 100 ℃; The interior pressure is about 0.8MPa, reaction 5h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
The Mi Tefuxin bullion is used the 0.2L*2 petroleum ether, drop into then in the 10L reaction kettle, add sherwood oil 5L,, filter, the gained filter cake is dropped in the 20L reaction kettle, add ethanol 10L recrystallization in 20-30 ℃ of stirring to pulp 1h; Repeating above-mentioned sherwood oil making beating and ethyl alcohol recrystallization two goes on foot 1 time; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 1.3kg, yield 52.0% (equivalence ratio, yield are all in hexadecanol).
Embodiment 5
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 20L reaction kettle, drop into POCl3 2.37kg (2.5eq), exsiccant methylene dichloride 10L; Stir, cryosel is bathed below the cooling reaction to 5 ℃, drips hexadecanol 1.5kg (1eq)-pyridine 3.1kg (5.0eq)-toluene 3L solution simultaneously; About 0.5h dropwises; Continue at 0 ℃ of left and right sides insulation reaction 0.5h then, filter, filter cake is used the 2L washed with dichloromethane;
Filtrating and washing lotion go back in the four-hole bottle, stir, and are cooled to about 0 ℃, begin to drip the solution of terepthaloyl moietie 1.54kg (4eq)-pyridine 3.1kg (5eq)-methylene dichloride 2L; About 1h dropwises, reaction 5h, and primitive reaction is complete; Filter, filter cake 0.5L washed with dichloromethane, filtrate decompression is revolved evaporate to dryness;
Add primary isoamyl alcohol 500ml in the gained residue, dissolving, water washing 2-3 time, decompression is revolved dried, gets the 1.8kg solid, and the gained residue is an intermediate B hexadecyl annular phosphate compound, directly is used for next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound Mi Tefuxin
With step 1 gained intermediate B hexadecyl annular phosphate compound 1.8kg, drop in the 10L autoclave, add the 3L acetonitrile, the sealing autoclave stirs, and feeds to contain Trimethylamine 99 gas, is warmed up to 80 ℃, and interior pressure is about 0.1MPa, reaction 5h, reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, the De Mitefuxin bullion;
The Mi Tefuxin bullion is used the 0.2L*2 water washing, drop into then in the 10L reaction kettle, add entry 5L,, filter, the gained filter cake is dropped in the 20L reaction kettle, add methylene dichloride 10L recrystallization in 20-30 ℃ of stirring to pulp 1h; Repeating above-mentioned water making beating and methylene dichloride recrystallization two goes on foot 1 time; Filter is done, and 50 ℃ of oven dry of filter cake in vacuum get white solid 1.51kg, yield 60.0% (equivalence ratio, yield are all in hexadecanol).
Claims (9)
1. the preparation method of a phosphocholine alkyl ester is characterized in that comprising the following steps:
A, in organic solvent, esterifications take place in-20 ~ 50 ℃ and obtain substance A in cetyl alcohol and POCl3 under the alkaline matter effect;
B, in organic solvent, ring-closure reactions take place to sufficient reacting in-20 ~ 50 ℃ in substance A and terepthaloyl moietie under the alkaline matter effect, the gained reaction solution carries out solid-liquid separation, the liquid phase that obtains is dissolved in the solvent after concentrating, and through washing, concentrate, obtains intermediate B;
C, under closed environment, the open loop substitution reaction takes place in intermediate B that the b step obtains and Trimethylamine 99 in organic solvent, to sufficient reacting, the gained reaction solution carries out solid-liquid separation, the solid phase that obtains obtains product after solvent treatment.
2. the preparation method of phosphocholine alkyl ester as claimed in claim 1 is characterized in that: the organic solvent described in step a and the step b is selected from THF, dioxane, t-butyl methyl ether, sherwood oil, toluene, YLENE, ETHYLE ACETATE, methylene dichloride, acetone, acetonitrile, MIBK (MIBK), ketopentamethylene or the normal hexane one or more independently of one another.
3. the preparation method of phosphocholine alkyl ester as claimed in claim 1; It is characterized in that: the alkaline matter described in step a and the b can independently be selected from mineral alkali or organic bases separately; Organic bases is pyridine, triethylamine or diisopropylethylamine, and mineral alkali is salt of wormwood, yellow soda ash or sodium hydroxide.
4. the preparation method of phosphocholine alkyl ester as claimed in claim 1 is characterized in that: the temperature of reaction of esterification described in step a and the b and ring-closure reaction is controlled at-10 ~ 10 ℃.
5. the preparation method of phosphocholine alkyl ester as claimed in claim 1 is characterized in that: the solvent described in the b step is selected from toluene, ETHYLE ACETATE, t-butyl methyl ether, sherwood oil, primary isoamyl alcohol, pimelinketone or methylene dichloride.
6. the preparation method of phosphocholine alkyl ester as claimed in claim 1 is characterized in that: the molar ratio of the described cetyl alcohol of a step, POCl3, terepthaloyl moietie is 1:0.5 ~ 5:0.5 ~ 5.
7. the preparation method of phosphocholine alkyl ester as claimed in claim 1 is characterized in that: the open loop substitution reaction takes place in described intermediate B of c step and Trimethylamine 99 in organic solvent, specifically is under 0 ~ 150 ℃, the condition of 0.1 ~ 1.0MPa, to react 1 ~ 12h.
8. the preparation method of phosphocholine alkyl ester as claimed in claim 1; It is characterized in that: the organic solvent described in the c step is selected from acetonitrile, acetone, MIBK, THF, dioxane, t-butyl methyl ether, toluene or N, dinethylformamide.
9. the preparation method of phosphocholine alkyl ester as claimed in claim 1; It is characterized in that: for successively making with extra care through solvent D, solvent E respectively, said solvent D and solvent E are selected from following a kind of or any several kinds combination to the solid phase described in the c step independently of one another: water, chloroform, methylene dichloride, acetonitrile, methyl alcohol, ethanol, Virahol, acetone, t-butyl methyl ether, sherwood oil through solvent-refined process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110402434.0A CN102491994B (en) | 2011-12-07 | 2011-12-07 | Preparation method of phosphocholine alkyl ester |
Applications Claiming Priority (1)
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| CN201110402434.0A CN102491994B (en) | 2011-12-07 | 2011-12-07 | Preparation method of phosphocholine alkyl ester |
Publications (2)
| Publication Number | Publication Date |
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| CN102491994A true CN102491994A (en) | 2012-06-13 |
| CN102491994B CN102491994B (en) | 2014-10-15 |
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| CN111808137A (en) * | 2020-07-14 | 2020-10-23 | 江苏华盛锂电材料股份有限公司 | Preparation method of vinyl hydrocarbon phosphate, vinyl hydrocarbon phosphate and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4837023A (en) * | 1985-12-04 | 1989-06-06 | Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften | Compositions containing hexadecylophosphocholine and alkylglycerols and uses thereof |
| US20070264206A1 (en) * | 2006-05-11 | 2007-11-15 | Kimberly-Clark Worldwide, Inc. | Mucosal formulation |
| CN101475585A (en) * | 2009-01-07 | 2009-07-08 | 卫永刚 | New compound alkyl bilineurine phosphodiester (miltefosine)and preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4837023A (en) * | 1985-12-04 | 1989-06-06 | Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften | Compositions containing hexadecylophosphocholine and alkylglycerols and uses thereof |
| US20070264206A1 (en) * | 2006-05-11 | 2007-11-15 | Kimberly-Clark Worldwide, Inc. | Mucosal formulation |
| CN101475585A (en) * | 2009-01-07 | 2009-07-08 | 卫永刚 | New compound alkyl bilineurine phosphodiester (miltefosine)and preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111808137A (en) * | 2020-07-14 | 2020-10-23 | 江苏华盛锂电材料股份有限公司 | Preparation method of vinyl hydrocarbon phosphate, vinyl hydrocarbon phosphate and application |
| CN111808137B (en) * | 2020-07-14 | 2023-08-01 | 江苏华盛锂电材料股份有限公司 | Preparation method of ethylene phosphate |
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