CN102491994B - Preparation method of phosphocholine alkyl ester - Google Patents
Preparation method of phosphocholine alkyl ester Download PDFInfo
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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 a kind of preparation method of phosphocholine alkyl ester.
Background technology
Miltefosine, be Hexadecylphosphocholine, D-18506, it is a kind of phosphocholine alkyl ester, Chinese is miltefosine, D-18506 or D-18506, chemistry hexadecyl 2-by name (trimethylammonium is amino) ethyl phosphonic acid ester, it has anti-tumor activity, is used for the treatment of in the market tropical communicable disease--leishmaniasis.Eibl doctor H by Max-Planck-Inst studies its anti-tumor activity the earliest, and within 1980, it delivers synthetic chromatographically pure Hexadecylphosphocholine to measure its iso-electric point character.
The preparation method of this phosphocholine alkyl ester (hereinafter to be referred as D-18506) can represent by reaction formula as follows:
Below above-mentioned preparation method is specifically described:
method A--esterification, methylates:
1, Eibl etc. discloses at EP0225608 the method for being prepared as follows: hexadecanol and phosphorus oxychloride reaction generate dichloro hexadecanyl phosphate, this ester, without separating-purifying, reacts with thanomin through esterification (obtaining hexadecyl-ciliatine ester), open loop and obtains hexadecyl ethylamino-phosphoric acid ester crude product; Through methyl-sulfate, methylate and generate D-18506 crude product again, crude product is through silica gel column chromatography, solvent crystallization Methods For Purification, total recovery 70%;
method B--esterification, Trimethylamine 99 ammonium
1, Chemistry and Physics of Lipids, 109 (2), 203-207; 2001 disclose the method for being prepared as follows: hexadecanol react with 2-bromotrifluoromethane-dichloro phosphide after hexadecyl-2-bromotrifluoromethane phosphoric acid ester, react with Trimethylamine 99 and generate D-18506 crude product, crude product is through post layer, solvent (chloroform-acetone) crystallization, obtain D-18506, yield 44%.
method C--is with choline esterification
1, EP 0521297A1 has reported following method: embodiment 1, hexadecanol reacts with Phosphorus Oxychloride and generates dichloro hexadecanyl phosphate, after phosphoric acid ester and acetylcholine response, generate D-18506, crude product yield is 87%, crude product processes with ion-exchange resin and solvent crystallization is purified, obtain D-18506, yield is that 53%(is by cetyl alcohol).
2, Chinese patent CN1068331(applying date 1992.7.3, authorize a day 1997.3.6) claimed following method: the product that alphanol obtains with phosphorus oxychloride reaction reacts with choline salt under inert solvent, alkaline matter existence condition, form phosphodiester muriate, hydrolysis discharges phosphocholine alkyl ester; For obtaining purified, also need ion exchange resin to purify.
Above three kinds of preparation method's final steps reaction, except generating product, also can generate other organic salt by products, and this can cause product purification difficulty, need to be refining by column chromatography, be therefore not suitable for suitability for industrialized production.These methods, necessary separated and purification midbody product and use alkylating reagent; Or by chromatographic process, come work and purifying crude product, or use during recrystallization the ion exchange resin of acid, alkalescence or both sexes to purify.
In addition, D-18506 can also be prepared by method D shown in following reaction formula (Bull. Chem. Soc. Jpn., 78 (8), 1558-1564; 2005):
Aforesaid method need to be prepared chloro-cyclic phosphoric acid ester formula (D-I), has a lot of unfavorable factors here, unstable, the purity difference of this intermediate first, and preparation manipulation is difficult for.Secondly, the preparation the first step (D-I) need to be used severe toxicity, dangerous large phosphorus trichloride, is difficult for industrialization operation; Second step oxidizing reaction is dangerous large, and yield is low.In addition, we find in repeating above-mentioned operational process of craft: intermediate (D-II) purity difference; Intermediate (D-I) is not refining, directly carries out next step reaction, causes final product of poor quality, is difficult to refine; The finished product are done recrystallization after need to processing by column chromatography again.
R.L.Magolda was once used the route shown in following reaction formula to prepare alkyl phosphate choline (alkyl phoshorylcholines, this is invented referred to as Cn-PC) (Tetrahedron Letters, 26 (9), 1167-70; 1985),
, this route does not relate to R=C
16h
33time, i.e. C
16the preparation of-PC; According to the document, intermediate annular phosphate purification yield 65%-75%; Intermediate annular phosphate can, for the preparation of Cn-PC (n=6,8,12,18), also can first re-use after chromatography purity; Gained Cn-PC (n=6,8,12,18) crude product can be used acetonitrile, tetrahydrofuran (THF), and acetone recrystallization, also can chromatogram (chloroform/methanol/water=65:25:4) purify; With ROH(R=C
6h
13, C
8h
17, C
12h
25, C
18h
37) meter, overall yield of reaction 35%-50%; The finished product identify with HNMR and IR, but concrete data are not provided, and only have fusing point data.
Summary of the invention
The technical problem to be solved in the present invention is to provide that a kind of technique 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 preparation method for phosphocholine alkyl ester, the method comprises the following steps:
A, in organic solvent, under alkaline matter effect, in-20 ~ 50 ℃, there are esterifications and obtain substance A in cetyl alcohol and phosphorus oxychloride;
B, in organic solvent, under alkaline matter effect, there are ring-closure reactions to sufficient reacting in-20 ~ 50 ℃ in substance A and ethylene glycol, gained reaction solution carries out solid-liquid separation, after the liquid phase that obtains is concentrated, is dissolved in solvent, through washing, concentrated, obtains intermediate B;
C, under closed environment, in organic solvent, there is open loop substitution reaction in the intermediate B that b step obtains and Trimethylamine 99, to sufficient reacting, gained reaction solution carries out solid-liquid separation, the solid phase obtaining obtains product after solvent treatment.
Substance A is dichloro hexadecanyl phosphate, and intermediate B is hexadecyl annular phosphate.
As preferably, the organic solvent described in step a and step b is selected from one or more in tetrahydrofuran (THF), dioxane, t-butyl methyl ether, sherwood oil, toluene, dimethylbenzene, ethyl acetate, methylene dichloride, acetone, acetonitrile, methyl iso-butyl ketone (MIBK) (MIBK), cyclopentanone or normal hexane independently of one another.One of preferred following: acetone, acetonitrile, tetrahydrofuran (THF), dioxane.
As preferably, the alkaline matter described in step a and 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, sodium carbonate or sodium hydroxide.Alkaline matter described in step a and b is preferably pyridine, triethylamine or salt of wormwood.Alkaline matter described in step a and the molar ratio of cetyl alcohol are 1 ~ 10:1, preferably 1-5:1; Alkaline matter described in step b and the molar ratio of cetyl alcohol are 1 ~ 10:1, preferably 1 ~ 5:1.Select organic bases, mineral alkali conventional, that molecular weight is little, can control reaction volume.Alkali at least 1 equivalent in step a, the hydrogenchloride that absorption reaction generates; Under alkaline condition, reaction is more thorough.Alkali diacidic base at least 1 equivalent in step b, monoatomic base at least 2 equivalents.
As preferably, the temperature of reaction of the esterification described in step a and b and ring-closure reaction is controlled at-10 ~ 10 ℃.Ring-closure reaction is preferably in below 0 ℃.Described cetyl alcohol and the reaction times of phosphorus oxychloride are recommended as 1 ~ 30 hour, preferably 1-8 hour; The reaction times of dichloro hexadecanyl phosphate and ethylene glycol is recommended as 1 ~ 30 hour, preferably 1 ~ 8 hour.Two-step reaction temperature is not high, needs the proper extension reaction times.
The reaction solution that b step obtains can obtain crude product by conventional separation method (as filtration, filtrate concentrate), and gained crude product is dissolved in solvent, washing, concentrated intermediate B, i.e. the hexadecyl annular phosphate of obtaining.As preferably, the solvent described in b step is selected from toluene, ethyl acetate, t-butyl methyl ether, sherwood oil, primary isoamyl alcohol, pimelinketone or methylene dichloride.One of preferred following: toluene, ethyl acetate, methylene dichloride.Gained crude product after preferred solvent is processed, can improve crude product outward appearance, prevents from degenerating in storage process.
As preferably, the molar ratio of the cetyl alcohol described in a step, phosphorus oxychloride, ethylene glycol is 1:0.5 ~ 5:0.5 ~ 5, preferably 1:0.8 ~ 3:0.8 ~ 3.
As preferably, there is open loop substitution reaction in intermediate B and Trimethylamine 99 described in c step in organic solvent, specifically under 0 ~ 150 ℃, the condition of 0.1 ~ 1.0MPa, reacts 1 ~ 12h.Be preferable under 60-100 ℃, the condition of 0.2 ~ 0.5MPa and react 2-4h.Trimethylamine 99 large usage quantity increases confined reaction system pressure and is conducive to speed speed of response, although, because being continues to pass into, without very high pressure, can react completely.
As preferably, the organic solvent described in c step is selected from acetonitrile, acetone, methyl iso-butyl ketone (MIBK) (MIBK), tetrahydrofuran (THF), dioxane, t-butyl methyl ether, toluene or DMF (DMF).One of preferred following: acetonitrile, acetone, tetrahydrofuran (THF), dioxane.Preferred solvent can reduce temperature of reaction and Reaction time shorten well.
As preferably, solid phase described in c step is successively refining through solvent D, solvent E respectively through solvent-refined process, and described solvent D and solvent E are selected from following a kind of or several combination arbitrarily 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.In c step, gained solid phase is D-18506 crude product, and it is first by the refining final product D-18506 that obtains of solvent D, solvent E.Described solvent D and solvent E can be single solvent, can be also one or more mixed solvents.If refine and can not reach product purity requirement for twice, can increase refining number of times; In the present invention, indication utilizes solvent treatment, includes but not limited to utilize solvent to carry out recrystallization, making beating.
As preferably, Trimethylamine 99 continues to pass into described in c step, maintains reaction system at certain pressure.
The concrete preparation method of described D-18506 that recommends of the present invention carries out in accordance with the following steps:
A, in organic solvent, cetyl alcohol and phosphorus oxychloride under alkaline matter effect in-10 ~ 10 ℃ of resultant of reaction matter A dichloro hexadecanyl phosphates;
B, substance A fully react in-10 ~ 10 ℃ under alkaline matter effect without separation and purification and ethylene glycol, and gained reaction solution after filtration, filtrate is concentrated, and gained enriched material is dissolved in solvent, through washing, the concentrated intermediate B hexadecyl annular phosphate that obtains;
It is one of following that organic solvent in described step a is selected from: acetone, acetonitrile, tetrahydrofuran (THF), dioxane; It is one of following that alkali in described step a, b is independently selected from separately: pyridine, triethylamine, salt of wormwood; It is one of following that solvent in step b is selected from: toluene, ethyl acetate, methylene dichloride;
The hexadecyl annular phosphate that c, step b make and Trimethylamine 99 react 2 ~ 4 h in organic solvent under 60 ~ 100 ℃, the condition of 0.1 ~ 0.5MPa, gained reacting liquid filtering obtains D-18506 crude product, the D-18506 described in gained crude product first obtains by solvent D, solvent E are refining; It is one of following that described organic solvent is selected from: acetonitrile, acetone, tetrahydrofuran (THF), dioxane; Described solvent D and solvent E are independently selected from following a kind of or several combination arbitrarily separately:: acetone, t-butyl methyl ether, sherwood oil, methylene dichloride, ethanol, water.
Compared with the prior art, beneficial effect of the present invention is:
A) with method A, B or C, compare, the synthetic route that the present invention adopts, final step instead would not produce any other by product, therefore, after reaction finishes, only need to simply pull an oar, the method for recrystallization can obtain high purity product, is applicable to suitability for industrialized production.
B) with method D, compare, this route final step synthetic route is consistent with the present invention.The synthetic route that the present invention adopts does not need through intermediate chloro-cyclic phosphoric acid ester formula (D-I), with two-step reaction, directly obtain hexadecyl annular phosphate compound formula (being D-II), and this two-step reaction can complete in one pot, operate very simple; Secondly the raw materials used and reagent hexadecanol of synthetic route of the present invention, phosphorus oxychloride, ethylene glycol, Trimethylamine 99 are safer, and low price; What is more important, the present invention is by the control to step a, step b reaction, improved the purity of intermediate B hexadecyl annular phosphate compound, and can refine to improve its purity to the intermediate B hexadecyl annular phosphate compound formula obtaining, thereby operation is greatly simplified, be suitable for industrialized production.
Embodiment
With specific embodiment, technical scheme of the present invention is described further below, but protection scope of the present invention is not limited to this.
Embodiment 1
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 500ml four-hole bottle, drop into phosphorus oxychloride 27.9g (1.1eq), dry tetrahydrofuran (THF) 100ml, stir, cryosel is bathed cooling reaction to below-5 ℃, drips hexadecanol 40g (1eq)-triethylamine 25g (1.5eq)-tetrahydrofuran (THF) 100ml solution simultaneously, about 2h dropwises, then continue at-5 ℃ of left and right insulation reaction 0.5h, filter, 20ml tetrahydrofuran (THF) washing for filter cake;
Filtrate and washing lotion go back in four-hole bottle, stir, be cooled to-5 ℃ of left and right, the solution that starts to drip ethylene glycol 10.3g (1eq) and triethylamine 40 g (2.4eq)-tetrahydrofuran (THF) 40ml, about 1h dropwises, and reaction is spent the night, primitive reaction is complete, filter, the washing of filter cake 40ml tetrahydrofuran (THF), filtrate decompression is revolved evaporate to dryness;
In gained residue, add methylene dichloride 250ml, dissolve, 50ml water washing 2-3 time, anhydrous magnesium sulfate drying, decompression is spin-dried for, and gained residue is intermediate B hexadecyl annular phosphate compound, is directly used in next step reaction.
Step 2: by formula intermediate B hexadecyl annular phosphate compound preparation formula D-18506
By step 1 products obtained therefrom formula intermediate B hexadecyl annular phosphate compound 42g, drop in 500ml autoclave, add 15ml acetonitrile, sealing autoclave, pass into Trimethylamine 99 gas, stir, be warmed up to 78-82 ℃, interior pressure is about 0.2Mpa, reaction 3.5h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, obtain D-18506 crude product;
Gained D-18506 crude product 40ml*2 washing with acetone, then drops in a 500ml four-hole bottle, adds acetone 300ml, in 20-30 ℃ of stirring to pulp 3h left and right, filters, and obtains filter cake, weight in wet base 37.5g;
Filter cake 40ml*2 washed with dichloromethane, drops into gained filter cake in one 500ml four-hole bottle, adds methylene dichloride 300ml recrystallization; Repeat above-mentioned acetone making beating and methylene dichloride recrystallization two step 2 times; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 30g, and yield 44.6%(equivalence ratio, yield, all in hexadecanol).
Embodiment 2
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 500L reactor, drop into phosphorus oxychloride 11.5kg (1.5eq), dry 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, then continue at-10 ℃ of left and right insulation reaction 0.5h, filter, 3L dioxane washing for filter cake;
Filtrate and washing lotion go back in four-hole bottle, stir, be cooled to-10 ℃ of left and right, start to drip ethylene glycol 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;
In gained residue, add toluene 200L, dissolve, water washing 2-3 time, decompression is spin-dried for, and obtains 15.4kg solid, and gained residue is intermediate B hexadecyl annular phosphate compound, is directly used in next step reaction.
Step 2: prepare D-18506 by formula intermediate B hexadecyl annular phosphate compound
By step 1 gained intermediate B hexadecyl annular phosphate compound 2.2kg, drop in 10L autoclave, add 3L acetone, sealing autoclave, stir, pass into containing Trimethylamine 99 gas, be warmed up to 56-62 ℃, interior pressure is about 0.4MPa, reaction 2h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, obtain D-18506 crude product;
By D-18506 crude product 0.5L*2 washing with alcohol, then drop in a 10L reactor, add ethanol 3L, in 20-30 ℃ of stirring to pulp 3h left and right, filter; Filter cake 0.5L*2 washed with dichloromethane, drops into gained filter cake in one 10L reactor, adds methylene dichloride 5L recrystallization; Repeat above-mentioned ethanol making beating and methylene dichloride recrystallization two step 1 time; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 1.9kg, and yield 65.9%(equivalence ratio, yield, all in hexadecanol).
Step 2 ': by formula intermediate B hexadecyl annular phosphate compound, prepare D-18506
By step 1 gained intermediate B hexadecyl annular phosphate compound 2.2kg, drop in 10L autoclave, add 4L cyclopentanone, sealing autoclave, stir, pass into containing Trimethylamine 99 gas, be warmed up to 90 ℃, interior pressure is about 0.6MPa, reaction 2h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, obtain D-18506 crude product;
By D-18506 crude product 0.5L*2 washing with acetone, then drop in a 10L reactor, add acetone 5L, in 20-30 ℃ of stirring to pulp 2h left and right, filter; Filter cake 0.5L*2 washing with alcohol, drops into gained filter cake in one 20L reactor, adds ethanol 12L recrystallization; Repeat above-mentioned acetone making beating and ethyl alcohol recrystallization two step 1 time; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 1.7kg, and yield 59%(yield is in hexadecanol).
Embodiment 3
Step 1: preparation formula intermediate B hexadecyl annular phosphate compound
In a 20L reactor, drop into phosphorus oxychloride 0.75kg(0.8eq), dry acetone 2L, stir, cryosel is bathed cooling reaction to below-8 ℃, drips hexadecanol 1.5kg(1eq simultaneously)-pyridine 0.7kg(1.4eq)-acetone 6L solution, about 1h dropwises, then continue at-8 ℃ of left and right insulation reaction 0.5h, filter filter cake 3L washing with acetone;
Filtrate and washing lotion go back in four-hole bottle, stir, and are cooled to-8 ℃ of left and right, start to drip ethylene glycol 0.8kg(2eq) and pyridine 1kg(2eq) be dissolved in the solution of 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;
In gained residue, add pimelinketone 1L, dissolve, water washing 2-3 time, decompression is spin-dried for, and obtains 1.86kg solid, and gained residue is intermediate B hexadecyl annular phosphate compound, is directly used in next step reaction.
Step 2: prepare D-18506 by formula intermediate B hexadecyl annular phosphate compound
By step 1 gained intermediate B hexadecyl annular phosphate compound 1.86kg, drop in 10L autoclave, add 3L tetrahydrofuran (THF), sealing autoclave, stir, pass into containing Trimethylamine 99 gas, be warmed up to 75 ℃, interior pressure is about 0.3MPa, reaction 3h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, obtain D-18506 crude product;
By 0.2L*2 t-butyl methyl ether washing for D-18506 crude product, then drop in a 10L reactor, add t-butyl methyl ether 5L, in 20-30 ℃ of stirring to pulp 1h, filter, gained filter cake is dropped in a 20L reactor, add ethanol 10L recrystallization; Repeat above-mentioned t-butyl methyl ether making beating and ethyl alcohol recrystallization two step 1 time; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 1.25kg, and 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 reactor, drop into phosphorus oxychloride 1.9kg(2.0eq), dry toluene 10L, stir, cryosel is bathed below cooling reaction to 0 ℃, drips hexadecanol 1.5kg(1eq simultaneously)-triethylamine 1.25(3.0eq)-toluene 3L solution, about 0.5h dropwises, then continue at 0 ℃ of left and right insulation reaction 0.5h, filter filter cake 2L toluene wash;
Filtrate and washing lotion go back in four-hole bottle, stir, and are cooled to 0 ℃ of left and right, start to drip ethylene glycol 0.77kg(5eq)-triethylamine 1.25kg(4eq) solution of-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;
In gained residue, add ethyl acetate 500ml, dissolve, water washing 2-3 time, decompression is spin-dried for, and obtains 1.83kg solid, and gained residue is intermediate B hexadecyl annular phosphate compound, is directly used in next step reaction.
Step 2: prepare D-18506 by formula intermediate B hexadecyl annular phosphate compound
By step 1 gained intermediate B hexadecyl annular phosphate compound 1.83kg, drop in 10L autoclave, add 3L toluene, sealing autoclave, stir, pass into containing Trimethylamine 99 gas, be warmed up to 100 ℃, interior pressure is about 0.8MPa, reaction 5h, and reaction solution cools to room temperature;
Open autoclave, take out reacting liquid filtering, obtain D-18506 crude product;
By D-18506 crude product 0.2L*2 petroleum ether, then drop in a 10L reactor, add sherwood oil 5L, in 20-30 ℃ of stirring to pulp 1h, filter, gained filter cake is dropped in a 20L reactor, add ethanol 10L recrystallization; Repeat above-mentioned sherwood oil making beating and ethyl alcohol recrystallization two step 1 time; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 1.3kg, and 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 reactor, drop into phosphorus oxychloride 2.37kg(2.5eq), dry methylene dichloride 10L, stir, cryosel is bathed below cooling reaction to 5 ℃, drips hexadecanol 1.5kg(1eq simultaneously)-pyridine 3.1kg(5.0eq)-toluene 3L solution, about 0.5h dropwises, then continue at 0 ℃ of left and right insulation reaction 0.5h, filter filter cake 2L washed with dichloromethane;
Filtrate and washing lotion go back in four-hole bottle, stir, and are cooled to 0 ℃ of left and right, start to drip ethylene glycol 1.54kg(4eq)-pyridine 3.1kg(5eq) solution of-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;
In gained residue, add primary isoamyl alcohol 500ml, dissolve, water washing 2-3 time, decompression is spin-dried for, and obtains 1.8kg solid, and gained residue is intermediate B hexadecyl annular phosphate compound, is directly used in next step reaction.
Step 2: prepare D-18506 by formula intermediate B hexadecyl annular phosphate compound
By step 1 gained intermediate B hexadecyl annular phosphate compound 1.8kg, drop in 10L autoclave, add 3L acetonitrile, sealing autoclave, stirs, and passes into containing 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, obtain D-18506 crude product;
By the 0.2L*2 water washing of D-18506 crude product, then drop in a 10L reactor, add water 5L, in 20-30 ℃ of stirring to pulp 1h, filter, gained filter cake is dropped in a 20L reactor, add methylene dichloride 10L recrystallization; Repeat above-mentioned water making beating and methylene dichloride recrystallization two step 1 time; Be filtered dry, 50 ℃ of oven dry of filter cake vacuum, obtain white solid 1.51kg, and yield 60.0%(equivalence ratio, yield are all in hexadecanol).
Claims (9)
1. a preparation method for phosphocholine alkyl ester, is characterized in that comprising the following steps:
A, in organic solvent, under alkaline matter effect, in-20 ~ 50 ℃, there are esterifications and obtain substance A in cetyl alcohol and phosphorus oxychloride;
B, in organic solvent, under alkaline matter effect, there are ring-closure reactions to sufficient reacting in-20 ~ 50 ℃ in substance A and ethylene glycol, gained reaction solution carries out solid-liquid separation, after the liquid phase that obtains is concentrated, is dissolved in solvent, through washing, concentrated, obtains intermediate B;
C, under closed environment, in organic solvent, there is open loop substitution reaction in the intermediate B that b step obtains and Trimethylamine 99, to sufficient reacting, gained reaction solution carries out solid-liquid separation, the solid phase obtaining 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 step b is selected from one or more in tetrahydrofuran (THF), dioxane, t-butyl methyl ether, sherwood oil, toluene, dimethylbenzene, ethyl acetate, methylene dichloride, acetone, acetonitrile, methyl iso-butyl ketone (MIBK) (MIBK), cyclopentanone or normal hexane 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 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, sodium carbonate 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 the esterification described in step a and 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 b step is selected from toluene, ethyl 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 described cetyl alcohol, phosphorus oxychloride, ethylene glycol 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: open loop substitution reaction occurs in organic solvent for the intermediate B described in c step and Trimethylamine 99, specifically under 0 ~ 150 ℃, the condition of 0.1 ~ 1.0MPa, reacts 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 c step is selected from acetonitrile, acetone, methyl iso-butyl ketone (MIBK), tetrahydrofuran (THF), dioxane, t-butyl methyl ether, toluene or DMF.
9. the preparation method of phosphocholine alkyl ester as claimed in claim 1, it is characterized in that: the solid phase described in c step is through solvent-refined process for successively refining through solvent D, solvent E respectively, and described solvent D and solvent E are selected from following a kind of or several combination arbitrarily independently of one another: water, chloroform, methylene dichloride, acetonitrile, methyl alcohol, ethanol, Virahol, acetone, t-butyl methyl ether, sherwood oil.
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| CN201110402434.0A Active CN102491994B (en) | 2011-12-07 | 2011-12-07 | Preparation method of phosphocholine alkyl ester |
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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 |
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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 |
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