CN101475585A - New compound alkyl bilineurine phosphodiester (miltefosine)and preparation - Google Patents

New compound alkyl bilineurine phosphodiester (miltefosine)and preparation Download PDF

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CN101475585A
CN101475585A CNA2009103001005A CN200910300100A CN101475585A CN 101475585 A CN101475585 A CN 101475585A CN A2009103001005 A CNA2009103001005 A CN A2009103001005A CN 200910300100 A CN200910300100 A CN 200910300100A CN 101475585 A CN101475585 A CN 101475585A
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formula
carbonate
preparation process
miltefosine
acid
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卫永刚
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Abstract

The invention relates to a novel compound of alkyl choline phosphodiester (miltefosine) salts and a method for preparing the same. The method comprises that: choline chloride, (hexadecyl) alcohol and phosphorus oxychloride are reacted in a hydrochloric ether or a nonpolar solvent and then alkyl choline phosphodiester (miltefosine) hydrochloride is obtained directly through hydrolization; the alkyl choline phosphodiester (miltefosine) hydrochloride is treated with different alkalis to form different alkali metal ion salts such as miltefosine sodium; and the sodium salt or other alkali metal ion salts are treated with different acids and thus alkyl choline phosphodiester (miltefosine) salts of different acid groups are obtained. The preparation method has the advantages of easily available reaction raw material, mild conditions, simple operation, low cost and more than 50 percent yield.

Description

A kind of new compound alkyl phosphocholine diester (miltefosine) Salt And Preparation Method
One, new compound general formula:
Figure A200910300100D00051
Formula 1
In the formula: R=C nH 2 (n-1)+3
n＝1～30
M＝H，Na，K，Ca，Zn，Fe，Mg，Al，Cu，Ag，NR 1R 2R 3
R 1，R 2，R 3＝H，CH 3，-CH 2CH 3，-C 6H 5，-C 6H 4NH 3
X＝OH，Cl，SO 4，PO 4，NO 3，CO 3，S，ClO 4，CH 3COO，HCOO，CO 2-CO 2，CH 3CH 2COO，OOCCH 2COO，C 6H 5COO，OOCC 6H 5COO
A special case in the general formula is n=16 in the R, M=H, during X=OH the hydrate of hexadecyl choline base phosphodiester miltefosine, promptly get miltefosine after its hydrate dehydration.
Miltefosine is a kind of medicine for the treatment of mammary cancer and sharp assorted slow disease, and existing many pieces of open the reaching of its compound patent, preparation method's patent and application patent are authorized, and this is not the content of this patent care, therefore seldom does at this and gives unnecessary details.
Miltefosine salt has a variety of, various salt all have different multiple physicochemical property and multiple biological activity, wishing can have more wide application at field of medicaments in the future, makes China can obtain one and has the kind new medicine compound patent, that grasp intellecture property core technology and become possibility.
When the n among the R equaled other numerical value, other special propertys that showed also may find new purposes 0 in other Application Areass.As it stronger surfactivity etc. is arranged.It can dissolve in a lot of inoganic solids salt in the organic solvent.Also non-polar solvents such as trichloromethane can be dissolved in the water by arbitrary proportion.
Two, preparation method: the preparation method of alkyl phosphocholine diester (miltefosine) hydrochloride
With choline chloride 60 and phosphorus oxychloride, direct reaction, temperature of reaction-20～+ 50 ℃, 10～20 ℃ of optimal reaction temperatures; In 1～24 hour reaction times, optimum reacting time is 4～8 hours, obtains intermediate formula 2
Figure A200910300100D00061
Formula 2
Formula 2 and alcohols react in chlorinated hydrocarbon solvent or non-polar solvent, and best hydrochloric ether is trichloromethane and methylene dichloride; Best non-polar solvent is sherwood oil, normal hexane or hexanaphthene; The consumption of solvent is at 5～20mol, and optimum amount is between 10～15mol; Temperature is controlled between 0～60 ℃, and optimum temps is between 5～25 ℃; 1～24 hour reaction times, optimum reacting time 8～10 hours.Reaction obtains formula 3.
Figure A200910300100D00062
Formula 3
Formula 3 adds the water hydrolysis, and amount of water is between 1～4mol, and optimum water is hydrolysis between 2～3mol; Between 0～40 ℃ of the hydrolysis temperature, 10～20 ℃ of optimum hydrolysis temperature; Hydrolysis time 1～4 hour, Best Times are 1～2 hour.Obtain formula 4 crude products behind the hydrolysis reaction.
Figure A200910300100D00063
Formula 4
The crude product acetone recrystallization of formula 4, the consumption of acetone is between 10mol～80mol, and optimum amount is between 30～50; Get the elaboration of formula 4 behind the recrystallization.Formula 4 is exactly one group of special case in the formula 1, i.e. M=H, X=Cl simultaneously.
Formula 4 elaboration obtain corresponding alkali metal salt in the formula 1 with different alkaline purifications in water or alcoholic solvent.PH value is controlled between 8～11 when handling with alkali or subsalt, and optimal PH is controlled between 9～10.
Alcoholic solvent comprises: methyl alcohol, and ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, optimal alcoholic solvent are methyl alcohol or ethanol;
Consumption 10～the 80mol of alcoholic solvent, optimum amount is between 30～60mol;
These alkali comprise: sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood, saleratus, calcium hydroxide, light calcium carbonate, Calcium hydrogen carbonate, magnesium hydroxide, magnesiumcarbonate, Magnesium hydrogen carbonate, magnesium oxide, ironic hydroxide, iron carbonate, hydrogen-carbonate iron, zinc hydroxide, zinc carbonate, hydrogen-carbonate zinc, copper hydroxide, copper carbonate, hydrogen-carbonate copper, silver hydroxide, silver carbonate, silver bicarbonate, hydrated barta, barium carbonate, barium bicarbonate, aluminium hydroxide, aluminium carbonate, hydrogen-carbonate aluminium, ammoniacal liquor, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, aniline, phenylenediamine.
The consumption of alkali is between 1～30mol, and optimum amount is between 2～10mol.
Any an alkali metal salt with in the formula 1 obtains acid salt different in the formula 1 with different acid treatment.When using acid treatment, pH value is controlled between 2～5, and is the most desirable between 3～4.
These acid comprise: hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, sulphur hydracid, formic acid, acetate, propionic acid, propanedioic acid, butyric acid, oxalic acid; Optimal acid is hydrochloric acid, acetate, formic acid.
These sour consumptions are between 1～10mol, and optimum amount is between 2～4mol.
Following preparation example is for the present invention is described, is not restriction the present invention.
Three, preparation example:
1, the preparation method of miltefosine hydrochloride
1), the choline chloride 60 of 1mol is added in the 1000ml reaction flask, adds stirring and dissolving under the phosphorus oxychloride room temperature of 1mol again, obtain formula 2 after the dissolving.
2), 1) in reactant in add the trichloromethane of 12mol, the hexadecanol that under agitation adds 1mol again stirs and spends the night.Get formula 5
Figure A200910300100D00071
Formula 5
Reaction solution after spending the night, the water that the adds 4mol again 1hr that is hydrolyzed, after the hydrolysis, filtering reacting liquid is removed insolubles, and filtrated stock boils off the solvent trichloromethane, obtains the crude product solid of 1mol miltefosine hydrochloride formula 6.
Figure A200910300100D00081
Formula 6
3), with the crude product solid with the dissolving of 50mol anhydrous methanol, filter insolubles, mother liquor revolves steaming, removes methanol solvate, the solid that obtains carries out recrystallization with 30mol acetone, must pure product miltefosine hydrochloride 0.5mol, yield 50%.The PH of its 1% aqueous solution is between 3～4.
2, the preparation method of miltefosine sodium salt
Be dissolved in the 50mol methyl alcohol with miltefosine hydrochloride 1mol, transfer PH between 9～10, filter insolubles, revolve the steaming mother liquor and boil off methyl alcohol, use the 30mol acetone recrystallization with the aqueous solution of 1～10% sodium hydroxide.Get miltefosine sodium salt formula 7, yield is more than 98%, and the PH of its 1% aqueous solution is between 9～10.
Figure A200910300100D00082
Formula 7
3, the preparation method of miltefosine acetate
Be dissolved in the 50mol methyl alcohol with miltefosine sodium salt 1mol, transfer PH between 3～4 with glacial acetic acid, filter insolubles, revolve the steaming mother liquor, boil off methyl alcohol, insolubles is filtered in the useless trichloromethane dissolving of solid, boils off trichloromethane, the residue acetone recrystallization.Get miltefosine acetate formula 8, yield is more than 98%, and the PH of its 1% aqueous solution is between 3～4.
Figure A200910300100D00083
Formula 8
4, the preparation method of miltefosine yellow soda ash double salt
Be dissolved in the 60mol methyl alcohol with miltefosine hydrochloride 1mol, transfer PH between 9～10, filter insolubles, revolve the steaming mother liquor and boil off methyl alcohol, use the 30mol acetone recrystallization with soda ass.Get rice for good fortune sodium bicarbonate double salt formula 9 or formula 10, yield is more than 98%, and the PH of its 1% aqueous solution is between 9～10.
Formula 9
Formula 10
5, the preparation method of miltefosine ammonium salt
Be dissolved in the 60mol methyl alcohol with miltefosine hydrochloride 1mol, transfer PH between 9～10, filter insolubles, revolve the steaming mother liquor and boil off methanol solvate, use the 30mol acetone recrystallization with strong aqua.Get rice for good fortune ammonium salt formula 11, yield is more than 98%, and the PH of its 1% aqueous solution is between 9～10.
Figure A200910300100D00093
Formula 11

Claims (6)

  1. [claim 1]
    A kind of new compound
    Figure A200910300100C00021
    Formula 1
    In the formula: R=CnH2n-1+3
    n＝1～30
    M two H, Na, K, Ca, Zn, Fe, Mg, Al, Cu, Ag, NR1R2R3
    R1，R2，R3＝H，CH3，-CH2CH3，-C6H5，-C6H4NH3
    X＝OH，Cl，SO4，PO4，NO3，CO3，S，ClO4，CH3COO，HCOO，CO2-CO2，CH3CH2COO，OOCCH2COO，C6H5COO，OOCC6H5COO
    Comprise in the formula 1 all single compounds, as the formula in the example 5, formula 6, formula 7, formula 8, formula 9, formula 10 etc. by the moiety combinations of above-mentioned R, M and X representative.
  2. [claim 2]
    Related intermediate in realization formula 1 process:
    Figure A200910300100C00022
    Formula 2
    Formula 3
  3. [claim 3]
    Related solvent and reagent in the preparation process of formula 1
    1) chlorinated hydrocarbon solvent: methylene dichloride, trichloromethane, tetracol phenixin it would be desirable trichloromethane.
    2) alcoholic solvent: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, optimal alcoholic solvent are methyl alcohol or ethanol
    3) ketone flux: acetone, methyl ethyl ketone it would be desirable acetone;
    4) alkali reagent: sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood, saleratus, calcium hydroxide, light calcium carbonate, Calcium hydrogen carbonate, magnesium hydroxide, magnesiumcarbonate, Magnesium hydrogen carbonate, magnesium oxide, ironic hydroxide, iron carbonate, hydrogen-carbonate iron, zinc hydroxide, zinc carbonate, hydrogen-carbonate zinc, copper hydroxide, copper carbonate, hydrogen-carbonate copper, silver hydroxide, silver carbonate, silver bicarbonate, hydrated barta, barium carbonate, barium bicarbonate, aluminium hydroxide, aluminium carbonate, hydrogen-carbonate aluminium, ammoniacal liquor, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, aniline, phenylenediamine.Optimal alkali reagent has sodium hydroxide, yellow soda ash, sodium bicarbonate, ammoniacal liquor;
    5) sour reagent: hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, sulphur hydracid, formic acid, acetate, propionic acid, propanedioic acid, butyric acid, oxalic acid.Optimal reagent has hydrochloric acid, acetate, formic acid.
  4. [claim 4]
    Related reaction times in the preparation process of formula 1
    1) in the preparation process of formula 2, reacted 1～24 hour, optimum reacting time is 4～8 hours;
    2) in the preparation process of formula 3,1～24 hour reaction times, optimum reacting time 8～10 hours;
    3) in the preparation process of formula 3, in 0.5～4 hour reaction times, Best Times is 1～2 hour.
  5. [claim 5]
    Related temperature of reaction in the preparation process of formula 1
    1) in the preparation process of formula 2, temperature of reaction is-20～+ 50 ℃, 10～20 ℃ of optimal reaction temperatures;
    2) in the preparation process of formula 3, temperature of reaction is 0～60 ℃, 5～25 ℃ of optimal reaction temperatures; 3) in the preparation process of formula 4, hydrolysis temperature is 0～40 ℃, 10～20 ℃ of optimum hydrolysis temperature
  6. [claim 6]
    Related pH value in the preparation process of formula 1
    1), pH value is controlled between 1～5 in the acid salt preparation process of miltefosine, and is the most desirable between 3～4.
    2), pH value is controlled between 8～11 in the subsalt preparation process of miltefosine, and is the most desirable between 9～10.
CNA2009103001005A 2009-01-07 2009-01-07 New compound alkyl bilineurine phosphodiester (miltefosine)and preparation Pending CN101475585A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102491994A (en) * 2011-12-07 2012-06-13 宁波九胜创新医药科技有限公司 Preparation method of phosphocholine alkyl ester
CN109354594A (en) * 2018-11-11 2019-02-19 苏州怡彼得生物技术有限公司 A kind of synthetic method of the phosphoryl choline derivative of cosmetics antioxidant Idebenone

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102491994A (en) * 2011-12-07 2012-06-13 宁波九胜创新医药科技有限公司 Preparation method of phosphocholine alkyl ester
CN102491994B (en) * 2011-12-07 2014-10-15 宁波九胜创新医药科技有限公司 Preparation method of phosphocholine alkyl ester
CN109354594A (en) * 2018-11-11 2019-02-19 苏州怡彼得生物技术有限公司 A kind of synthetic method of the phosphoryl choline derivative of cosmetics antioxidant Idebenone
CN109354594B (en) * 2018-11-11 2020-10-30 苏州怡彼得生物技术有限公司 Synthetic method of cosmetic antioxidant idebenone phosphorylcholine

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