AU663259B2 - A process for the preparation of alkylphosphocholines and the production thereof in pure form - Google Patents
A process for the preparation of alkylphosphocholines and the production thereof in pure form Download PDFInfo
- Publication number
- AU663259B2 AU663259B2 AU66059/94A AU6605994A AU663259B2 AU 663259 B2 AU663259 B2 AU 663259B2 AU 66059/94 A AU66059/94 A AU 66059/94A AU 6605994 A AU6605994 A AU 6605994A AU 663259 B2 AU663259 B2 AU 663259B2
- Authority
- AU
- Australia
- Prior art keywords
- ion exchanger
- alkylphosphocholines
- prepared
- mixed
- purification process
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 241001132374 Asta Species 0.000 claims 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 1
- 150000002500 ions Chemical class 0.000 abstract description 22
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract 2
- 239000012442 inert solvent Substances 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 239000004381 Choline salt Substances 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract 1
- 235000019417 choline salt Nutrition 0.000 abstract 1
- 150000005690 diesters Chemical class 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 150000003248 quinolines Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- -1 octyl- Chemical group 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229960004592 isopropanol Drugs 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- SBMUNILHNJLMBF-UHFFFAOYSA-N 2-chloro-1,3,2$l^{5}-dioxaphospholane 2-oxide Chemical compound ClP1(=O)OCCO1 SBMUNILHNJLMBF-UHFFFAOYSA-N 0.000 description 2
- ASICVTFPMHAIAV-UHFFFAOYSA-N 2-hexadecyl-1,3,2$l^{5}-dioxaphospholane 2-oxide Chemical compound CCCCCCCCCCCCCCCCP1(=O)OCCO1 ASICVTFPMHAIAV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 2
- 229960003775 miltefosine Drugs 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- VJRYWXNPDKUNNG-UHFFFAOYSA-N 1,3,2lambda5-dioxaphospholane 2-oxide Chemical compound O=P1OCCO1 VJRYWXNPDKUNNG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PYTMBSDYMPHFOQ-UHFFFAOYSA-N 2,2,2-trichloro-n-[4-(trifluoromethyl)phenyl]acetamide Chemical compound FC(F)(F)C1=CC=C(NC(=O)C(Cl)(Cl)Cl)C=C1 PYTMBSDYMPHFOQ-UHFFFAOYSA-N 0.000 description 1
- GGNHQPDMWPBKQF-UHFFFAOYSA-N 2-hexadecyl-1,3,2-dioxaphospholane Chemical compound CCCCCCCCCCCCCCCCP1OCCO1 GGNHQPDMWPBKQF-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Steroid Compounds (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
Abstract
Process for the preparation of C14-C18-alkylphosphocholines in a one-pot process by reaction of an n-alkanol having a chain length of C14-C18 with phosphorus oxychloride in an inert solvent or else without solvent in the presence or absence of a basic substance, and further reaction of the reaction product in an inert solvent with a choline salt in the presence of a basic substance to give the phosphoric acid diester chloride, followed by hydrolysis and isolation of alkylphosphocholine, and, if appropriate, purification by means of a mixed-bed ion exchanger or in succession with an acidic ion exchanger and a basic ion exchanger.
Description
I
A Process For The Production Of Alkylphosphocholines In Pure Form Eibl et al. (EP 225,608) describe the preparation and use of alkylphosphocholines for the treatment of tumours. The starting substances are in the Eibl process of preparation are the n-alcohol and phosphorus oxychloride. They are reacted to phosphoric acid ester dichloride in tetrahydrofuran. In a second step 2-aminoethanol is reacted with the phosphoric acid ester dichloride to 2-hexadecyl-1,3,2-oxaphospholan-2oxide in dioxan. Hydrolysis with 2N hydrochloric acid yields the open-chain amine which is exhaustively methylated to alkylphosphocholine with dimethyl sulphate in 2propanol.
This process has the following disadvantages: it is necessary to isolate and purify the intermediate products. In addition, alkylating reagents are used. The use of potassium carbonate as an auxiliary base in this step of the process leads to the product having a potassium content that is undesirably high for pharmaceutical purposes.
Long-chain alkylphosphocholines having an antimicrobial effect are described by Kanetani et al., Nippon Kayaku Kaushi, 2, 1452 (1984).
i. They are prepared using the following process: ethylene glycol and phosphorus trichloridc are reacted to form 2-ch!oro-l,3,2dioxaphospholane, the product purified by distillation is oxidized with oxygen to 2-chloro- 20 1,3,2-dioxaphospholane-2oxide and then distilled again. The 2-chloro-1,3,2dioxaphospholane-2-oxide is then reacted with 1-hexadecanol to 2-hexadecyl-1,3,2dioxaphospholane-2-oxide. The 2-hexadecyl-1,3,2-dioxaphospholane-2-oxide is re'ctd with trimethylamine in the autoclave to hexadecylphosphocholine, the raw product is purified both with alkaline and with acid ion exchangers and recrystallized from acetone/chloroform. The analogous process is also used to prepare the octyl-, decyl-, dodecyl, tetradecyl and octadecyl derivatives.
The disadvantage of this process is that it is necessary to work with increased pressure in the last step ol the process and that the use of trimethylamine constitutes an industrial hygiene problem in the technical plpara:o 'i of the substance. It is also a 30 disadvantage that the hydrolysis-sensitive intermediate products 2-chloro-1,3,2dioxaphrspholane, 2-chloro-1,3 ,2-dioxaphospholane-2-oxide and 2-hexadecyl-2-oxa- 1,3,2-dioxaphospholane need to be isolated and purified. In addition, environmentallyunfriendly solvents such as benzene are used, the solvents being changed from step to step.
All known processes use chromatographic methods for working up and purifying the raw products.
However, chromatographic working up processes of this kind have the following disadvantages: their conversion to a technical scale causes difficulties since the dimensions of the stationary phase cannot be increased at will, IG:\WPUSER\LIUBVV0270:CE ;hromatographic processes are time-consuming.
The invention relates to a new, advantageous method of purifying alkylphosphocholines.
The process of preparing alkylphosphocholines is the subject of Australian Patent Application No. 19441/92.
The process of the invention avoids the time-consuming chromatographic step during working up.
The product purity achieved in the process claimed is greater than in the known processes.
According to a broad form of the invention there is provided a purification process for alkylphosphocholines characterized in that a solution of alkylphosphocholines, prepared using conventional processes is prepared and treated in an organic agent with a mixed-bed ion exchanger or successively with an acid ion exchanger and a basic ion exchanger.
The product prepurified in the manner described in Australian Patent Application No. 19441/92 may be taken up in anhydrous alcohols (C 1 to C4) or in alcohols which contain no mo,'e than up to 5 percent by weight of water at 20 0 C to 60 0 C, preferably 40 0 C and insoluble constituents filtered off. Alcohols that may for example be used are methanol, ethanol, isopropanol, butanol, isobutanol.
20 The prepurified product may also be dissolved in water. The filtrate obtained is then stirred with a mixed-bed ion exchanger, for example AmberliteR MB3, for example for 1 to 5 hours, preferably 2 hours at 10 0 C to 50 0 C, preferably 20°C. Instead of a mixed-bed ion exchanger the purification may also be effected simultaneously or successively with an acid ion exchanger and a basic ion exchanger.
Ion exchangers which may also be used are all insoluble solids which contain ion exchanging groups.
Acid ion exchangers are those which contain for example acid groups such as sulphonic a -d groups, carboxyl groups. Examples are ion exchangers with sulphonic acid groups in a polystyrene matrix such as Amberlite R IR 120, DowexR HCR, DuoliteR 30 C 20 or LewatitR S 100.
Weakly acid ion exchangers are for example those which carry carboxylic acid groups on the basis of a polyacrylic acid matrix, such as AmberliteR IRC 76, DuoliteR C 433 or ReliteR CC.
Basic ion exchangers that may for example be considered are those carrying on a polymer matrix polystyrene matrix) primary, secondary, tertiary or quaternary amino groups such as DuoliteR A 101, DuoliteR A 102, DuoliteR15 A 348, DuoliteR A 365, DuoliteR A 375, AmberliteR IRA 67, DuoliteR A 375, AmberliteR IRA 458 and DuoliteR A 132.
Mixed-bed ion exchangers are mixtures of acid and alkaline ion exchanger resins, such as AmberliteR MBI, AmberliteR MB2, AmberliteR MB3 and AmberliteR MB6.
G:\WPUSER\LUBVV00270:CE _L It is also possible to use all conventional ion exchangers in the process.
Reference is also made to Ullmann's Encyclopedia of Industrial Chemistry, Edition (1989), Volume A14, p. 450.
Following vacuum suctioning of the ion exchanger resin the mixture is evaporated under reduced pressure (for example 20 Torr to 200 Torr) at 40°C to 70 0 C and the mixture is then recrystallized from halogenated hydrocarbons or from alcohol/ketone mixtures.
Halogenated hydrocarbons that may for example be considered for the recrystallization are hydrocarbons containing 1 to 6 carbon atoms where one or several or all carbon atoms are replaced by chlorine atoms.
It is for example possible to use methylene chloride, chloroform, ethylene chloride, chlorobenzene.
Alcohols that may be considered are saturated aliphatic alcohols with 1 to 6 carbon atoms and 1 to 2 hydroxyl groups. Ketones that may be considered are saturated, aliphatic ketones with 3 to 8 carbon atoms, The mixing ratio alcohol:ketone is 1 to 1-5 (volume/volume). An ethanol/acetone mixture in the ratio of 1:1 is particularly preferred.
The crystals of alkylphosphocholine obtained are suction filtered and if necessary washed for example with saturated hydrocarbons containing 1 to 6 carbon atoms.
20 (Temperature of the washing liquid for example 15 to 30 0
C),
Drying is effected for example in a vacuum at 40 0 C to 80 0 C over conventional drying agents, for example phosphorus pentoxide or silica gel.
Example 1 Preparation of hexadecyl phosphocholine 25 1.0 Mol (92ml) POC13 in 1.5L chloroform are added to a 6 litre stirring apparatus under nitrogen and cooled in an ice bath to 5°C. 0.90Mol (218g) hexadecanol are dissolved in 700ml chloroform and added dropwise together with 4.00Mol (320ml) pyridine at a temperature of 5-12 0 C. Dropping time: 1.25 hours. The dropping funnel is then flushed with the remaining 300ml chloroform. After one and a half hours poststirring at 0-5 0 C, 1.35Mol (372g) Folid choline tosylate are added and then 400ml pyridine added dropwise over 15 minutes. This causes the temperature to rise to 20 0
C.
The ice bath is removed and the reaction mixture is stirred at room temperature for 3 hours. For purposes of hydrolysis 150ml water are added dropwise over 20 minutes, the temperature rising from 25°C to 36°C. After stirring for half an hour, the reaction solution is washed in each case once with 1,50 litres water/methanol 1.50 litres 3% sodium carbonate/methanol and 1.50 litres water/methanol The chloroform phase washed in this manner is dried over sodium sulphate and evaporated in a rotary evaporator in a vacuum after addition of 50ml iso-propanol. n-butanol is added for drying and the mixture is evaporated in a rotary evaporator again.
IG:\WPUSER\LIBVV00270:CE
L
Purification is carried out as follows: The residue is suspended in 2.0 litres acetone, stirred for approx. 2 hours, suction filtered and dried at 30 0 C in a vacuum. Raw yield: 325g The raw product is taken up in 3.0 litres absolute ethanol and insoluble portions filtered off. The filtrate is a stirred for two hours with 1.0 litre mixed-bed ion exchanger Amberlite MB 3R(FLTUKA).
After suction filtration of the ion exchanger resin the mixture is evaporated in a rotary evaporator in a vacuum and then recrystallized once from 0.70 litres methylene chloride.
Complete crystallization is achieved in the refrigerator. The crystals are suction filtered and washed with pentane. The mixture is then dried in a vacuum at 30 0 C over phosphorus pentoxide.
Yield 193g (0.47Mol, 53%) The reaction product has a mclting point of 241-245 C.
Examples 2-5 are prepared according to the same procedure.
Example 2:
.O
.II D-19390: H 3
C-(CH
2 13
-O-P-O-(CH
2 2 -N(CH3)3 0© Mp: 260 0 C (disintegration)
C
19
H
42
NO
4 P (379.52) TL: 89 a (chloroform/methanol/ammonia 25% 70:20:10) Rf: 0.27 EA: calc. C 60.13% H 11.16% N 3.69% H20 57.41% 11.16% 3.52% found C 57.40% H 11.42% N 3.61% 57.43% 11.47% 3.65% 20 'H-NMR: (250 MHz, CDC1 3 5 0.90 ppm 3H) 3.80 2H) 1.25 22H) 3.85 2H) 1.55 2H) 4.25 2H) 3.40 9H) Example 3:
O
II
G
D-20403: H 3
C-(CH
2
(CH
2 2 -N(CH3)3 6o IG:\WPUSER\LIBVVI00270;CE Mp: 244'C (disintegration)
C
20 11 44 N0C 4 P (393.555) -TL: 89 a (chloroform/methanol/amimonia 25
EA:
Rf: 0.49 cal'z.
*21120 found C 61 .04% 55.92% C 56. 14% 55.74% -70:40:10) 11.27% 11.26% 10.99% 10.85% N 3.56% 3.26% N 3.67% 3.59% TT.-NMR: (250 MHz, CDCl 3 8 0.90 ppm 3H1) 3.80 211) 1.30 (in, 24H1) 3.85 (in, 211) 1.55 2H1) 4.25 (in, 211) 3.40 9H1) 0 0.
Example 4: 0 D-19767: H 3 0-(0H 2 16 0--(H 2 2
-N(CH
3 3 Mp: 254-256'C
C
22 11 48 N0 4 P (421.61) ITL: 127 c (I-butanol/glacial acetic acid/water Rf: 0.34 caic.
*1120 found C 62.68% 60.11 C 60.2% 60.5'% -60:20:20) 11 11.48% 11.46% 1111.7% 11.7% N 3.32% 3.19% N 3.1% 'H-NMR: (250 MHz, CDC1 3 5 0.90 ppm 311) 3.80 211) 1.25 (in, 2811) 3.85 (in, 211) 1.60 211) 4.25 (in, 211) 3.40 911) Example 0 D-19391: H 3
C-(CH
2 )17r-O-P H 2 2 -N(CH)3 Mp: 258 0 C (disintegration) jG:%WPUSER\UBVVOO270:CE
C
2 3
H
50 N0 4 P (435.62) TL: 126 (1-butanol/glacial acetic acid/water =40: 10: Rf: 0, 3 EA: caic. C 63.41 H111.57% N 3.22 *1120 60.90% 11.55% 3.09% found C 60.80% H 11.93% N 3.15 60.83% 12.02% 3.15% 'H-NMR: (250 MHz, CDC1 3 8= 0.90 ppm 3H) 3.80 211) 1.25 (in, 3011) 3.85 (mn, 2H) 1.60 211) 4.30 (in, 211) 3.40 911) too.* IGAWPUSEVAWIDVVIO027O:CE
Claims (4)
1. A purification process for alkylphosphocholines characterized in that a solution of alkylphosphocholines, prepared using conventional processes is prepared and treated in an organic agent with a mixed-bed ion exchanger or successively with an acid ion exchanger and a basic ion exchanger.
2. A purification process for alkylphosphocholines substantially as hereinbefore described with reference to any one of the Examples.
3. A C 14 -C 18 -alkylphosphocholine derivative whenever purified by a process according to claim 1 or 2.
4. A method of treating a tumour in a patient requiring such treatment comprising administering to said patient an effective amount of a derivative as defined in claim 3. Dated 28 June, 1994 ASTA Medica Aktiengsellschaft 15 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON *o o*o* IG:\WPU' ER\LIBW100270;CE I a A Process For The Production Of Alkyiphosphocholines In Pure Form Abstract A purification process for alkylphosphor-hnlines charL. .,ised in that a solution of alkyiphosphocholines, prepared using conventional pik sses, is prepared and treated in an organic agent with a mixed-bed ion exchanger or successively wvith an acid ion exchanger and a basic ion exchanger. *a sees a. a a a. a. a. a a. INMABTIMM.CE I of I
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4122127 | 1991-07-04 | ||
| DE4122127 | 1991-07-04 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU19441/92A Division AU652646B2 (en) | 1991-07-04 | 1992-07-03 | A process for the preparation of alkylphosphocholines and the production thereof in pure form |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6605994A AU6605994A (en) | 1994-09-22 |
| AU663259B2 true AU663259B2 (en) | 1995-09-28 |
Family
ID=6435410
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU19441/92A Expired AU652646B2 (en) | 1991-07-04 | 1992-07-03 | A process for the preparation of alkylphosphocholines and the production thereof in pure form |
| AU66059/94A Expired AU663259B2 (en) | 1991-07-04 | 1994-06-29 | A process for the preparation of alkylphosphocholines and the production thereof in pure form |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU19441/92A Expired AU652646B2 (en) | 1991-07-04 | 1992-07-03 | A process for the preparation of alkylphosphocholines and the production thereof in pure form |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0521297B1 (en) |
| JP (1) | JP3171279B2 (en) |
| CN (1) | CN1034941C (en) |
| AT (1) | ATE158295T1 (en) |
| AU (2) | AU652646B2 (en) |
| CA (1) | CA2073126C (en) |
| DE (2) | DE59208905D1 (en) |
| DK (1) | DK0521297T3 (en) |
| EG (1) | EG20551A (en) |
| ES (1) | ES2108715T3 (en) |
| FI (1) | FI107260B (en) |
| GR (1) | GR3025490T3 (en) |
| HU (1) | HU219243B (en) |
| IE (1) | IE80555B1 (en) |
| IL (1) | IL102379A (en) |
| NO (2) | NO304232B1 (en) |
| PL (1) | PL169571B1 (en) |
| SG (1) | SG47844A1 (en) |
| ZA (1) | ZA924980B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0521353T3 (en) * | 1991-07-04 | 1996-05-13 | Asta Medica Ag | Antineoplastic drug containing octadecyl (2- (N-methylpiperidino) ethyl) phosphate as an active ingredient and process for its preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3239489A (en) * | 1988-04-04 | 1989-10-05 | American Cyanamid Company | Novel antagonists of platelet activating factor |
| WO1990013552A1 (en) * | 1989-05-08 | 1990-11-15 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | PROCESS FOR THE PREPARATION OF L-α-GLYCERYLPHOSPHORYLCHOLINE AND OF L-α-GLYCERYLPHOSPHORYLETHANOLAMINE |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3164332D1 (en) * | 1980-10-21 | 1984-07-26 | Boehringer Mannheim Gmbh | Phospholipids that contain sulphur, process for their preparation and medicines containing these compounds |
| JPS60184092A (en) * | 1984-03-01 | 1985-09-19 | Kao Corp | Phosphoric ester and its preparation |
| IE59778B1 (en) * | 1985-12-04 | 1994-04-06 | Max Planck Gesellschaft | Medicament with anti-tumour action containing hexadecylphosphocholine |
-
1992
- 1992-05-26 ES ES92108826T patent/ES2108715T3/en not_active Expired - Lifetime
- 1992-05-26 DE DE59208905T patent/DE59208905D1/en not_active Expired - Lifetime
- 1992-05-26 EP EP92108826A patent/EP0521297B1/en not_active Expired - Lifetime
- 1992-05-26 SG SG1996004669A patent/SG47844A1/en unknown
- 1992-05-26 AT AT92108826T patent/ATE158295T1/en active
- 1992-05-26 DK DK92108826.6T patent/DK0521297T3/en active
- 1992-06-25 DE DE4220852A patent/DE4220852C2/en not_active Expired - Lifetime
- 1992-07-01 EG EG34492A patent/EG20551A/en active
- 1992-07-02 IL IL10237992A patent/IL102379A/en not_active IP Right Cessation
- 1992-07-02 PL PL92295129A patent/PL169571B1/en unknown
- 1992-07-02 NO NO922612A patent/NO304232B1/en not_active IP Right Cessation
- 1992-07-03 IE IE922182A patent/IE80555B1/en not_active IP Right Cessation
- 1992-07-03 FI FI923087A patent/FI107260B/en not_active IP Right Cessation
- 1992-07-03 ZA ZA924980A patent/ZA924980B/en unknown
- 1992-07-03 CN CN92105432A patent/CN1034941C/en not_active Expired - Lifetime
- 1992-07-03 JP JP17691392A patent/JP3171279B2/en not_active Expired - Lifetime
- 1992-07-03 AU AU19441/92A patent/AU652646B2/en not_active Expired
- 1992-07-03 HU HU9202233A patent/HU219243B/en unknown
- 1992-07-03 CA CA002073126A patent/CA2073126C/en not_active Expired - Lifetime
-
1994
- 1994-06-29 AU AU66059/94A patent/AU663259B2/en not_active Expired
-
1997
- 1997-11-26 GR GR970403139T patent/GR3025490T3/en unknown
-
1998
- 1998-04-17 NO NO981742A patent/NO304316B1/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3239489A (en) * | 1988-04-04 | 1989-10-05 | American Cyanamid Company | Novel antagonists of platelet activating factor |
| EP0336142A2 (en) * | 1988-04-04 | 1989-10-11 | American Cyanamid Company | Novel antagonists of platelet activating factor |
| WO1990013552A1 (en) * | 1989-05-08 | 1990-11-15 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | PROCESS FOR THE PREPARATION OF L-α-GLYCERYLPHOSPHORYLCHOLINE AND OF L-α-GLYCERYLPHOSPHORYLETHANOLAMINE |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU663259B2 (en) | A process for the preparation of alkylphosphocholines and the production thereof in pure form | |
| US6028209A (en) | Process for the preparation of alkylphosphocholines and the production thereof in pure form | |
| IE48781B1 (en) | Fosfomycin derivatives | |
| JP3115489B2 (en) | Method for producing phosphate monoester | |
| JP3688304B2 (en) | Phospholipid derivative, method for producing the derivative, purification method for the derivative, pharmaceutical product containing the derivative, and method for producing the pharmaceutical product | |
| Chasar et al. | 2, 4, 6-Tris (2, 6-di-tert-butyl-4-substituted-phenoxy)-1, 3, 5, 2, 4, 6-trioxatriphosphorinanes. Synthesis, characterization, x-ray structure, and solid-state phosphorus-31 NMR of a novel family of phosphorus (III)-oxygen heterocycles | |
| US4386079A (en) | Method of treating depression | |
| EP0021391B1 (en) | Phosphonoformic acid hydrazides, process for their preparation and their use as medicines | |
| DE4219972A1 (en) | MEDICINE WITH ANTINEOPLASTIC EFFECT CONTAINING OCTADECYL- (2- (N-METHYLPIPERIDINO) -ETHYL) -PHOSPHATE AS AN ACTIVE SUBSTANCE AND METHOD FOR THE PRODUCTION THEREOF | |
| EP1370565A2 (en) | Method of producing 1-hydroxy-1,1-diphosphonic acid compounds | |
| JPS62123191A (en) | Phosphoric acid ester and production thereof | |
| US4179464A (en) | Preparation of N-(phosphonoacetyl)-L-aspartic acid | |
| US5958906A (en) | Phospholipid derivatives containing higher elements of the fifth main group | |
| US2361286A (en) | Phosphoric acid esters of glycerol ethers and their manufacture | |
| FI65261C (en) | FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT ANVAENDBART DINATRIUMSALT AV N- (FOSFONOACETYL) -L-ASPARAGINSYRA | |
| EP2671886B1 (en) | Method for producing polyprenyl phosphates | |
| RU2471804C2 (en) | Method of producing polyprenyl phosphates | |
| US7273945B2 (en) | Preparation of phosphorus-containing alkoxylation products | |
| JP2649343B2 (en) | Method for producing phosphate ester | |
| JPH04282390A (en) | Production of phosphoric diester | |
| KR20030046269A (en) | Process for preparation of Magnesium L-ascorbyl-2-phosphate |