GB1581810A - Process for the preparation of phospholipids - Google Patents
Process for the preparation of phospholipids Download PDFInfo
- Publication number
- GB1581810A GB1581810A GB15174/78A GB1517478A GB1581810A GB 1581810 A GB1581810 A GB 1581810A GB 15174/78 A GB15174/78 A GB 15174/78A GB 1517478 A GB1517478 A GB 1517478A GB 1581810 A GB1581810 A GB 1581810A
- Authority
- GB
- United Kingdom
- Prior art keywords
- phosphoric acid
- diol
- glycerol
- propane
- ester
- 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
- 150000003904 phospholipids Chemical class 0.000 title claims description 25
- 238000000034 method Methods 0.000 title claims description 20
- 230000008569 process Effects 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 13
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 43
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 43
- -1 stearoyl-propane-1,3-diol-phosphoric acid allyl ester sodium salt Chemical class 0.000 claims description 30
- 238000004809 thin layer chromatography Methods 0.000 claims description 24
- 238000001514 detection method Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 13
- YPFDHNVEDLHUCE-UHFFFAOYSA-N Trimethylene glycol Natural products OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 13
- 102000011420 Phospholipase D Human genes 0.000 claims description 12
- 108090000553 Phospholipase D Proteins 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 6
- 150000003138 primary alcohols Chemical class 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims description 2
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 claims description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims description 2
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 claims 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims 1
- 150000002169 ethanolamines Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 7
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 6
- 244000178937 Brassica oleracea var. capitata Species 0.000 description 6
- 238000005809 transesterification reaction Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JFBCSFJKETUREV-LJAQVGFWSA-N 1,2-ditetradecanoyl-sn-glycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCCCCCCCC JFBCSFJKETUREV-LJAQVGFWSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 125000003158 alcohol group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical class CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000008570 general process Effects 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000001312 palmitoyl group Chemical group O=C([*])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 2
- 150000008103 phosphatidic acids Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 125000002948 undecyl 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])[H] 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000004146 Propane-1,2-diol Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000002511 behenyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- BMRWNKZVCUKKSR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO BMRWNKZVCUKKSR-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000003074 decanoyl 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(*)=O 0.000 description 1
- 125000002704 decyl 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])* 0.000 description 1
- OIWXVEYCQPUVKB-UHFFFAOYSA-N di(cyclopentadecyl)methanone 2,3-dihydroxypropyl dihydrogen phosphate Chemical compound P(=O)(O)(O)OCC(CO)O.C1(CCCCCCCCCCCCCC1)C(=O)C1CCCCCCCCCCCCCC1 OIWXVEYCQPUVKB-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ANLFRXGAWNYDEJ-UHFFFAOYSA-L disodium;ethyl phosphate Chemical compound [Na+].[Na+].CCOP([O-])([O-])=O ANLFRXGAWNYDEJ-UHFFFAOYSA-L 0.000 description 1
- MBTOOKBKBYXTCE-UHFFFAOYSA-L disodium;methyl phosphate Chemical compound [Na+].[Na+].COP([O-])([O-])=O MBTOOKBKBYXTCE-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 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
- 230000000694 effects Effects 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N glycerophosphatidylethanolamine Chemical compound NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 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
- 125000001400 nonyl 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])[H] 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([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])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000913 palmityl 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])[H] 0.000 description 1
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical class CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- XGRLSUFHELJJAB-JGSYTFBMSA-M sodium;[(2r)-2-hydroxy-3-[(z)-octadec-9-enoyl]oxypropyl] hydrogen phosphate Chemical class [Na+].CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)([O-])=O XGRLSUFHELJJAB-JGSYTFBMSA-M 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
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000010792 warming 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
- C07F9/10—Phosphatides, e.g. lecithin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
- C12P7/6436—Fatty acid esters
- C12P7/6445—Glycerides
- C12P7/6458—Glycerides by transesterification, e.g. interesterification, ester interchange, alcoholysis or acidolysis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
- C12P7/6436—Fatty acid esters
- C12P7/6445—Glycerides
- C12P7/6481—Phosphoglycerides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P9/00—Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
Description
(54) PROCESS FOR THE PREPARATION OF PHOSPHOLIPIDS
(71) We, MAX-PLANCK-GESELLSCHAFT ZUR FdRDERUNG DER
WISSENSCHAFTEN e.V., of 10 Bunsenstrasse, D-3400 Göttingen, Federal
Republic of Germany, a Company of the Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with a process for the preparation of phospholipids, some of which are new.
According to the present invention, there is provided a process for the preparation of phospholipids of the general formula:
in which R is a straight-chained or branched alkyl radical containing up to 5 carbon atoms which is derived from a primary alcohol and can be substituted by one, two or three hydroxyl groups, halogen atoms, amino groups, C1-C,-monoalkylamino or C1-C3 dialkylamino radicals and/or can contain a double or triple bond, A can be
in which R, or R2 is a hydrogen atom or a hydroxyl group and the other symbol R1 or R, or both symbols R1 and R2 signify a -COR11 radical, a -OR12 radical or together a radical of the general formula:
and in which R1 and R2 can be the same or different, in which R11 and R12, which can be the same or different, signify a saturated or unsaturated, straight-chained or branched aliphatic hydrocarbon radical containing up to 25 carbon atoms, which can be substituted by a cycloalkyl radical containing 4 to 8 carbon atoms or by an aromatic radical or by halogen, y is a whole number of from 5 to 32 or wherein A can be a radical of the general formula:
in which R11 has the same meaning as above and x is 0 or a whole number from 2 to 5, or a radical of the general formula:
wherein R11 has the same meaning as above, m is 0 or a whole number of from 2 to 14, p and q, which may be the same or different, are 0 or a whole riumber of from 1 to 14, the sum of p and q giving m, but with the proviso that p+q is not 0 and p+q is not more than 14, wherein a compound of the general formula:
wherein Z can be a hydrogen atom or a methyl radical and w can have a value of from 1 to 6 and preferably of 2, is allowed to react with phospholipase D in the presence of a compound of the general formula ROH, in which R has the same meaning as above, and possibly in the presence of a solvent, whereafter the phospholipid obtained in isolated in known manner as such or in the form of a salt.
Phospholipids and processes for the preparation thereof have been described by
H. Eibl and 0. Westphal in Chem. Phys. Lipids, 3/1939 as well as in German Patent
Specifications Nos. 2,033,357; 2,033,359; 2,033,360, 2,033,361; 2,009,343; 2,345,057; 2,345,059; 2,345,060; 2,437,832 and 2,437,833. These compounds possess valuable pharmacological properties. The lecithin-analogous compounds are strongly surfaceactive materials which possess a great influence on natural cell membranes and on the permeability behaviour of biomembranes. Because of their.excellent boundary surface activity, in the case of per oral or intraperitoneal administration of the compounds to mammals, they change the properties of cell membranes.
Some of these compounds are only available by means of complicated syntheses.
Surprisingly, however, we have now found that the corresponding phosphatidic acid esters of the general formula (I) can be prepared in a simple manner when the compounds of general formula (VIII), i.e. cephalins and phosphatidic acid alkyl esters, as well as their structural analogues, are reacted with phospholipase D.
The compounds of general formula (VIII) employed as starting materials are known and are the subject of earlier Patent Applications (see above). However, hitherto, transesterification reactions have hitheto only been carried out with lecithins and mostly with natural egg lecithin. Therefore, transesterifications with synthetic cephalins, alkyl esters of phosphatidic acid and of structural analogues are of particular interest because, according to the above-mentioned Patent Applications, alkyl esters of phosphatidic acid but also cephalins are very much easier to obtain than the corresponding lecithins. The transesterifications can be carried out preparatively in a very simple manner. Phospholipase D is a very cheap enzyme and can easily be obtained, for example, from white cabbage. With the enzyme obtained from 1 kg. of white cabbage, for example, it is possible quantitatively to convert 100 g. cephalin or phosphatidic acid ester into phosphatidic acid or the desired phosphatidic acid ester.
Phospholipase D from white cabbage does not possess any stereoselectivity; thus, phospholipids with non-natural configuration from the D series can also be reacted in a corresponding manner (see Example 48 hereinafter). In a correspondingly simple manner, it is possible to prepare marked phospholipids by reaction with deuterated or C14-marked alcohols or aminoalcohols.
For the preparation of compounds of general formula (I), in which R signifies a straight-chained or branched alkyl radical containing up to 5 carbon atoms which is derived from a primary alcohol and can possibly be substituted by hydroxyl groups, halogen atoms, for example fluorine, chlorine or bromine atoms, amino groups or CC,-monoalkylamino groups or C1-C,-dialkylamino groups, the appropriate derivatives of general formula (VIII) are reacted with the alcohol of the general formula ROH, in which R corresponds to the desired radical. As alcohols, there can be used, for example, methanol, ethanol, n-propanol, isobutanol, n-butanol and the corresponding pentanols, as well as allyl alcohol or propargyl alcohol. The reaction can only be carried out with primary alcohols which do not contain more than 5 carbon atoms. If rhe alcohols contain more than 5 carbon atoms, then the corresponding phosphatidic acid is the main product of the reaction. The alcohols used can also be substituted; for example, the reaction can also be carried out with glycol, propane1,3-diol, butane-1,4-diol, butane-1,2-diol and the corresponding pentanediols. Furthermore, the reaction can be carried out with fluoroethanol, chloroethanol, bromoethanol, the correspondingly substituted propanols, butanols and pentanols. In addition, the reaction can also make use of ethanolamine, N-methylethanolamine and N,N-dimethylethanolamine, as well as of homologous alkanolamines. The choice of the alcohol components is in no way limited so long as the above-mentioned requirements are fulfilled, i.e. that it is a primary alcohol.
By means of the process according to the present invention, it is possible to prepare a large number of phosphatidic acid derivatives and of phosphatidic acid ester derivatives from a central intermediate compound.
Since defined synthetic cephalins and alkyl esters of phosphatidic acid can be used as starting materials and the reaction gives high yields, it is possible to synthesise a large number of compounds. The reaction can also be carried out with desoxylysocephalins and with desoxylysophosphatidic acid esters, with lysocephalins and with lysophosphatidic acid esters.
When, in rhe above-given general formula (I), A possesses the meaning according to general formula (II), in a simple manner there can be prepared 1 - acyldesoxylysophospholipids ('IX), 1 - acyllysophospholipids (X), 1,2 - diacylphospholipids (XI) and cycloalkylideoketalglycerol - phospholipids (XII):
In the above-given general formulae, R11 can be a straight-chained or branched, saturated or unsaturated aliphatic hydrocarbon radical. R1l is preferably derived from natural fatty acids and signifies, for example, a stearyl, palmityl, myristyl, undecyl, caprinyl, oleoyl or linolyl radical. However, R11 can, for example, also be a heptyl, octyl, nonyl, decyl, undecyl, lauryl, crotyl, behenyl, or arachidyl radical.
In the compounds of general formula (XI), R,l radicals can be the same or different.
The transesterification of compounds of general formula (VIII) with phospholipase D takes place in known manner. For the preparation of an ester, a corresponding cephalin or phosphatidic acid alkyl ester is dissolved in the appropriate alcohol of the general formula ROH and if desired, a solvent is added to the reaction mixture which does not disturb the reaction. As solvent, there can be used, for example, water or a mixture of water and organic solvent, for example, diethyl ether, diisopropyl ether or a secondary or tertiary alcohols. If desired, a buffer, for example sodium acetate, can be added to the reaction mixture and calcium chloride, followed by the addition of the enzyme phospholipase D. Generally, the reaction is carried out at ambient temperature with stirring or shaking. In this case, the reaction is finished afterabout 12 hours. However, it is also possible to operate at lower or higher temperatures, the reaction time then being correspondingly lengthened or shortened. The course of the reaction can be monitored, for example, by thin layer chromatography.
When the reaction is finished, the reaction mixture can then be worked up in the usual manner. For example, the solvent can be distilled off on a rotary evaporator and the aqueous phase acidified in order to precipitate out the protein. The corresponding phospholipid can be isolated, for example, by extraction.
The following Examples are given for the purpose of illustrating the present invention:
Preparation of phospholipase D from white cabbage.
Leaves of white cabbage are homogenised for 5 minutes (Russel and Stoll homogeniser, U.S.A.; 250 ml. water per 1.6 kg. white cabbage at OOC.). The homogenisate is suction filtered at 0 to 50C. and the green-yellow filtrate centrifuged for 20 minutes at 25,000 g and at 0 to 5"C. The clear supernatant contains about 3 mg. protein/ml.
of solution and is used directly for the transesterification reaction. The enzyme is stored at -200C. and is stable for several months.
Example 1.
General process for the preparation of phosphatidic acid or analogous compounds by
hydrolysis with phospholipase D.
In a 500 ml. Erlenmeyer flask, 1 mMol of the corresponding phospholipid (for example, 636 mg SN - 1,2 - dimyristoyl - glycerol - 3 - phosphoric - ethanolamine, 445 mg. palmitoylpropane - 1,3 - diol - phosphoric acid ethyl ester or 472 mg. cyclopentadecylideneketal of glycerol - 3 - phosphoryl - N - N - dimethyl - ethanolamine) is dissolved in 5 ml. sec.-butanol, with gentle warming. The solution is stirred with a magnetic stirrer and the solution is successively mixed with 100 ml. diethyl ether, 50 ml. 0.2M aqueous sodium acetate solution (pH 5.6), 25 ml. distilled water, 5 ml.
1M aqueous calcium chloride solution and 25 ml. phospholipase D (concentration: 3 mg. protein/ml.). As the thin layer chromatogram shews, the reaction has proceeded to completion after about 12 hours shaking at 200C.
The reaction mixture is freed from diethyl ether on a rotary evaporator and the aqueous phase is mixed with 50 ml. 1N sulphuric acid in order to precipitate the protein. By means of the addition of 120 ml. methanol and 100 ml. chloroform, followed by vigorous shaking, the phospholipid is extracted into the chloroform phase. The chloroform phase is separated off and the aqueous phase again extracted with 50 ml.
chloroform. The combined chloroform phases (150 ml.) are mixed with 150 ml.
methanol and with 150 ml. 0.5M aqueous sodium ethylenediaminetetraacetate solution (pH 10) and well shaken in order also to remove traces of calcium ions. The chloroform phase is separated off, briefly dried over anhydrous sodium sulphate and then evaporated on a rotary evaporator. The white residue is pure phosphatidic acid or a corresponding analogue (sn - 1,2 - dimyristoyl - glycerol - 3 - phosphoric acid, palmitoyl - propane - 1,3 - diol - phosphate or cyclopentadecyl - ketone - glycerol - 3phosphate, for example). The residue is treated with acetone in order to remove traces of water. The residue is the chromatographically pure product. In general, the yield is 90 to 95% of theory.
Example 2.
General process for the preparation of alkyl esters of phosphatidic acid or of analogous
compounds by transesterification of phospholipase D.
In a 500 ml. Erlenmeyer flask, 1 mMol of the corresponding phosphoryl - Nmethylethanolamine (for example 636 mg. SN - 1,2 - dimyristoyl - glycerol - 3phosphoryl - ethanolamine, 445 mg. palmitoyl - propane - 1,3 - diol - phosphoric acid ethyl ester or 472 mg. cyclopentadecylideneketal of glycerol - 3 - phosphoryl - N,Ndimethylethanolamine) is dissolved in 25 ml. methanol. While stirring, there are successively added 100 ml. diethyl ether, 50 ml. 0.2M aqueous sodium acetate solution (pH 5.6), 5 ml. 1M aqueous calcium chloride solution and 25 ml. phospholipase D (concentration 3 .mg. protein/ml.). The thin layer chromatogram shews that the reaction has proceeded to completion after 8 to 12 hours.
The reaction mixture is transferred to a separating funnel and mixed with 25 ml.
1N hydrochloric acid, 100 ml. diisopropyl ether and 50 ml. methanol. It is well shaken up and the ethereal phase then filtered through a fluted filter paper. The filtrate contains the methyl ester of the phosphatidic acid or of the analogous starting compound. -For the removal of traces of calcium ions and for the complete conversion into the sodium salt, the ethereal phases are treated with 100 ml. 0.5M aqueous sodium ethylenediamine - tetraacetate solution (pH 10). After phase separation, the ethereal phase is removed, briefly dried with anhydrous sodium sulphate and evaporated on a rotary evaporator. The The~-residue is recrysillised from acetone or methyl eiliyl ketone and consists of pure methyl ester of the corresponding starting compound. The yields amount to 90 to 95% of theory.
Examples 3 to 52.
The following compounds are prepared in a manner aanlogous to that described in Examples 1 and 2. In the following Examples, SN indicates the stereospecific numbering according to the IUPAC IUB sales for the nomenclature of lipids (see
Arch. Biochem. Biophys., 123, 409--415/1968).
Example 3.
S.N-1,2-dimyristoyl-glycerol-3-phosphoric acid methyl ester sodium salt
M.W. 628.81 C,2H62OPNa calculated: C 61.12%; H 9.94%; P 4.92%
found: 60.98%; 9.87%; 4.50%
Example 4.
SN-1,2-dimyristoyl-glycerol-3-phosphoric acid ethyl ester sodium salt
M.W. 642.84 C33H64O8PNa calculated: C 61.66%; H-10.03%; P 4.82%
found: 61.47%; 10.100/c; 4.71%
Example 5.
SN-1,2-dimyristoyl-glycerol-3-phosphoric acid propyl ester sodium salt
M.W. 656.87 C34H66O3PNa calculated: C 62.12%; H 10.13%; P 4.71% found: 62.29%; 10.01%; 4.69%
Example 6.
SN- 1 ,2-dimyristoyl-glycerol-3 -phosphoric acid butyl ester sodium salt
M.W. 670.59% C3UHG808PNa calculated: C 62.66%; H 10.22%; P 4.62% found: 62.64%; 10.21%; 4.55%
Example 7.
SN-1,2-dimyristoyl-glycerol-3-phosphoric acid glycol ester sodium salt
M.W. 658.84 C,,He.O9PNa calculated: C 60.16%; H 9.79%; P 4.70%
found: 59.89%; 9.69%; 4.65% Example 8.
SN- 1,2-dimyristoyl-glycerol-3 -phosphoric acid propane-1,3-diol ester sodium salt
M.W. 672.87 C3,H6609PNa calculated: C 60.69%; H 9.89%; P 4.60% found: 60.53%; 9.79%; 4.50%
Example 9.
SN- 1,2-dimyristoyl-glycerol-3 -phosphoric acid butane 1,4-diol ester sodium salt
M.W. 683.90 C85H68O9PNa calculated: C 61.45%; H 9.58%; P 4.53% found: 61.34%; 9.57%; 4.51%
Example 10.
SN- 1,2-dimyristoyl-glycerol-3-phosphoric acid fluoroethyl ester sodium salt
M.W. 660.83 C,,H6,OPFNa calculated: C 59.98%; H 9.61%; P 4.67%; F 2.87% found: 59.83%; 9.55%; 4.50%; 2.31%
Example 11.
SN-1,2-dimyristoyl-glycerol-3-phosphoric acid 2-chloro-ethyl ester sodium salt
M.W. 677.29 C33H63O8PCINa calculated: C 58.51%; H 9.38%; P 4.57%; Cl 5.23% found: 58.10%; 9.28%; 4.40%; 5.10%
Example 12.
SN-1,2-dimyristoyl-glycerol-3-phosphoryl-ethanolamine
M.W. 635.87 C,,Hc6O8PN calculated: C 62.33%; H 10.46%; P 4.87%; N 2.20% found: - - 4.61%; 2.04%
Example 13.
SN-1,2-dimyristoyl-glycerol-3-phosphoryl-N-methyl-ethanolamine
M.W. 649.90 C84H6608ZPN calculated: C 62.84%; H 10.55%; P 4.77%; N 2.16% found: - - 4.59%; 2.04%
Example 14.
SN-1,2-dimyristoyl-glycerol-3-phosphoryl-N,N-dimethyl-ethanolamine
M.W. 663.93 C3bH7o08PN calculated: C 63.32%; H 10.62%; P 4.67%; N 2.11% found: - - 4.40%; 1.97%
Example 15.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid methyl ester sodium salt
M.W. 414.46 C19H36O6PNa calculated: C 55.06%; H 8.76%; P 7.47% found: 54.87%; 8.69%; 7.30%
Example 16.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid ethyl ester sodium salt
M.W. 428.49 C20H,O6PNa detection by thin layer chromatography.
Example 17.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid propyl ester sodium salt
M.W. 442.52 C21H40OPNa detection by thin layer chromatography.
Example 18.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid butyl ester sodium salt
M.W. 456.55 CppH,2OPNa detection by thin layer chromatography.
Example 19.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid glycol ester sodium salt
M.W. 444.49 C20H3807PNa detection by thin layer chromatography.
Example 20.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid propane-1,3-diol ester
sodium salt
M.W. 458.51 C21H40O 7PNa detection by thin layer chromatography.
Example 21.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid butane-1,4-diol ester
sodium salt
M.W. 472.55 C22H42O,PNa detection by thin layer chromatography.
Example 22.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid fluoroethyl ester sodium
salt
M.W. 446.68 C20HsrOePFNa detection by thin layer chromatography.
Example 23.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid chloroethyl ester sodium
salt
M.W. 462.94 C20H,7OOClNa detection by thin layer chromatography.
Example 24.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoryl-ethanolamine
M.W. 421.52 C20H3sOePN detection by thin layer chromatography.
Example 25.
1,2-Cyclopentadecylidene ketal of-glycerol-3 -phosphoryl-N-methyl-ethanolamine M.W. 435.54 C21H41O6PN detection by thin layer chromatography.
EXAMPLE 26.
1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoryl-N,N-dimethyl-ethanolamine
M.W. 449.56 C22H43OePN detection by thin layer chromatography.
Example 27.
palmitoyl-propane-1,2-diol phosphoric acid methyl ester sodium salt
M.W. 430.51 C20H40OfiPNa calculated: C 55.79%; H 9.36%; P 7.19%
found: 55.52%; 9.31%; 7.10%
Example 28.
palmitoyl-propane-1,3-diol phosphoric acid ethyl ester sodium salt
M.W. 444.53 C21H42OePNa calculated: C 56.74%; H 9.32%; P 6.97%
found: 56.45%; 9.22%; 6.81%; Example 29.
palmitoyl-propane-1,3-diol-phosphoric acid propyl ester sodium salt
M.W. 458.56 C22H44OePNa calculated: C 57.62%; H 9.67%; P 6.75%
found: 57.61%; 9.45%; 6.88%
Example 30.
palmitoyl-propane-1,3-diol-phosphoric acid butyl ester sodium salt
M.W. 472.58 C23H46O6PNa calculated: C 58.49%; H 9.81%; P 6.55% found: 58.24%; 9.65%; 6.69%
Example 31.
palmitoyl-propane-1,3-diol-phosphoric acid glycol ester sodium salt
M.W. 460.53 C2lH4207PNa detection by thin layer chromatography.
Example 32.
palmitoyl-propane-1,3-diol-phosphoric acid propane-1,3-diol ester sodium salt
M.W. 474.56 C22H44O7PNa Example 33.
palmitoyl-propane-1,3-diol-phosphoric acid butane- 1 ,4-diol ester sodium salt
M.W. 488.58 C23H4fiO7PNa detection by thin layer chromatography.
Example 34.
palmitoyl-propane-1,3-diol-phosphoric acid 2-fluoroethyl ester sodium salt
M.W. 462.56 C21H41OePFNa detection by thin layer chromatography.
Example 35.
palmitoyl-propane-1,3-diol-phosphoric acid chloroethyl ester sodium salt
M.W. 478.98 C21H41O6PClNa detection by thin layer chromatography.
Example 36.
palmitoyl-propane-1,3-diol-phosphoryl-ethanolamine
M.W. 437.6 C21H44OfiPN calculated: C 57.64%; H 10.14%; P 7.08%; N 3.20% found: 57.32%; 10.01% 6.71%; 3.28%
Example 37.
palmitoyl-propane-1,3-diol-phosphoryl-N-methylethanolamine
M.W. 451.6 C22H46O6PN calculated: C 58.51%; H 10.27%; P 6.86%; N 3.10% found: 58.41%; 10.15%; 6.82%; 3.12%
Example 38.
palmitoyl-propane-1,3-diol-phosphoryl-N,N-dimethylethanolamine
M.W. 465.6 C23H43O6PN calculated: C 59.33%; H 10.39%; P 6.65%; N 3.01% found: 58.91%; 10.41%; 6.57%; 3.05%
Example 39.
stearoyl-propane-1,3 -diol-phosphoric acid glycerol ester sodium salt
M.W. 518.61 C24H,808PNa calculated: C 55.58%; H 9.33%; P 5.97% found: 55.11%; 9.27%; 6.05% Example 40.
1-stearoyl-SN-glycerol-3-phosphoric acid glycerol ester sodium salt
M.W. 518.61 C24H,808PNa calculated: C 55.58%; H 9.33%; P 5.97% found: 55.01%; 9.27%; 6.01% Example 41.
oleoyl-propane-1,3-diol-phosphoric acid propane-1,3-diol ester sodium salt
M.W. 500.60 C,4H46O,PNa calculated: C 57.58%; H 9,26%; P 6.19% found: 57.37%; 9.16%; 6.18%
Example 42.
1 -palmitoyl-2-oleoyl-SN-glycerol-3 -phosphoryl-ethanolamine
M.W. 718.02 G39H7fiO8PN calculated: C 65.24%; H 10.67%; P 4.31%; .N 1.95% found: 64.98%; 10.49%; 4.27%; 1.93%
Example 43.
1,2-dilauroyl-SN-glycerol-3-phosphoric acid methyl ester sodium salt
M.W. 563.72 C28H54O8PNa detection by thin layer chromatography.
Example 44.
1,2-dimyristoyl-SN-glycerol-3-phosphoric acid allyl ester sodium salt
M.W. 654.85 C34H64OPNa detection by thin layer chromatography.
Example 45.
1,2-dimyristoyl-SN-glycerol-3-phosphoric acid propargyl ester sodium salt
M.W. 652.84 Cs4He2O8PNa detection by thin layer chromatography.
Example 46.
stearoyl-propane-1,3-diol-phosphoric acid allyl ester sodium salt
M.W. 584.60 C24H4fiO^PNa Example 47.
stearoyl-propane-1,3-diol-phosphoric acid propargyl ester sodium salt
M.W. 582.58 C24H4408PNa detection by thin layer chromatography.
WHAT WE CLAIM IS:- 1. Process for the preparation of phospholipids of the general formula:
in which R is a straight-chained or branched alkyl radical containing up to 5 carbon atoms which is derived from a primary alcohol and is optionally substituted by one, two or three hydroxyl groups, halogen atoms, amino groups, C1-C,-monoalkylamino or C1-C3-dialkylamino radicals and/or can contain a double or triple bond, A can be a radical of the general formula:
in which the symbols R1" or R2 signify a hydrogen atom or a hydroxyl group and the other group R1 or R2 or both groups R1 and R2 signify an -0-COR11, an -O-R12 group or together a group of the general formula:
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (28)
1,2-dimyristoyl-SN-glycerol-3-phosphoric acid propargyl ester sodium salt
M.W. 652.84 Cs4He2O8PNa detection by thin layer chromatography.
Example 46.
stearoyl-propane-1,3-diol-phosphoric acid allyl ester sodium salt
M.W. 584.60 C24H4fiO^PNa Example 47.
stearoyl-propane-1,3-diol-phosphoric acid propargyl ester sodium salt
M.W. 582.58 C24H4408PNa detection by thin layer chromatography.
WHAT WE CLAIM IS:- 1. Process for the preparation of phospholipids of the general formula:
in which R is a straight-chained or branched alkyl radical containing up to 5 carbon atoms which is derived from a primary alcohol and is optionally substituted by one, two or three hydroxyl groups, halogen atoms, amino groups, C1-C,-monoalkylamino or C1-C3-dialkylamino radicals and/or can contain a double or triple bond, A can be a radical of the general formula:
in which the symbols R1" or R2 signify a hydrogen atom or a hydroxyl group and the other group R1 or R2 or both groups R1 and R2 signify an -0-COR11, an -O-R12 group or together a group of the general formula:
and wherein R1 and R2 can be the same or different, in which R11 and R12, which can be the same or different, are saturated or unsaturated, straight-chained or branched aliphatic hydrocarbon radicals containing up to 25 carbon atoms which can possibly be substituted by a cycloalkyl radical containing 4 to 8 carbon atoms or an aromatic radical or by halogen, y is a whole number of from 5 to 32 or wherein A can be a radical of the general formula:
in which R1l has the same meaning as above and x is 0 or a whole number of from 2 to 5, or a radical of the general formula:
in which R11 has the same meaning as above, m is 0 or a whqle number of from 2 to 14, p and q, which may be the same or different, are 0 or a whole number of from 1 to 14, the sum of p and q giving m, but with the proviso that p + q is not 0 and p + q is not more than 14, wherein a compound of the general formula:
in which Z can be a hydrogen atom or a methyl radical and w can have a value of from 1 to 6, is allowed to react with phospholipase D in the presence of a compound of the general formula ROH, in which R has the same meaning as above, optionally in the presence of a solvent, whereafter the phospholipid obtained is isolated in known manner as such or in the form of a salt.
2. Process according to claim 1, wherein the compound of general formula ROH is methanol, ethanol, propanol, butanol, glycol, propane-1,3-diol, butane-1,4-diol, pentane-1,5-diol, propargyl alcohol, allyl alcohol, 2-fluoroethanol, 2-chloroethanol, ethanolamine, N-methylethanolamine, N,N-dimethylethanolamine or glycerol.
3. Process according to claim 1 or 2, wherein the phospholipids used are diacylglycerol phosphoric acid ethanolamine esters (cephalins).
4. Process according to claim 1 or 2, wherein the phospholipids used are diacylglycerol phosphoric acid alkyl esters.
5. Process according to claim 1 or 2, wherein the phospholipids used are monoacyl-glycerol-phosphoric acid ethanolamine esters (lysocephalins).
6. Process according to claim 1 or 2, wherein the phospholipids used are monoacyl-glycerol-phosphoric acid alkyl esters (lysophosphatidic acid alkyl esters).
7. Process according to claim 1 or 2, wherein the phospholipids used are monoacyl-alkanediol-phosphoric acid ethanolamine esters (desoxylysocephalins).
8. Process according to claim 1 or 2, wherein the phospholipids used are monoacyl-alkanediol-phosphoric acid alkyl esters (desoxylysophosphatidic acid alkyl esters).
9. Process according to claim 1 or 2, wherein the phospholipids used are cycloalkylideneketalglycerolphosphoric acid ethanolamine esters.
10. Process according to claim 1 or 2, wherein the phospholipids used are cycloalkylideneketalglycerolphosphoric acid alkyl esters.
11. Process according to claim 1 for the preparation of phospholipids, substantially as hereinbefore described and exemplified.
12. Phospholipids, whenever prepared by the process according to any of claims 1 to 11.
13. SN-1,2-dimyristoyl-glycerol-3-phosphoric acid glycol ester.
14. SN-1,2-dimyristoyl-glycerol-3-phosphoric acid propane-1,3-diol ester.
15. SN-1,2-dimyristoyl-glycerol-3-phosphoric acid butane-1,4-diol ester.
16. 1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid glycol ester.
17. 1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid propane-1,3-diol ester.
18. 1,2-Cyclopentadecylidene ketal of glycerol-3-phosphoric acid butane-1,4-diol ester.
19. Palmitoyl-propane-1,3-diol-phosphoric acid glycol ester.
20. Palmitoyl-propane- 1,3-diol-phosphoric acid propane- 1 ,3-diol ester.
21. Palmitoyl-propane- 1,3 -diol-phosphoric acid butane- 1 ,4-diol ester.
22. Stearoyl-propane-1,3-diol-phosphoric acid glycerol ester.
23. 1-Stearoyl-SN-glycerol-3-phosphoric acid glycerol ester.
24. Oleovl-propane-13-diol-phosDhoric acid propane-1,3 -diol ester.
25. 1,2-Dimyristoyl-SN-glycerol-3-phosphoric acid allyl ester.
26. 1,2-dimyristoyl-SN-glycerol-3-phosphoric acid propargyl ester.
27. Stearoyl-propane-1,3-diol-phosphoric acid allyl ester.
28. Stearoyl-propane-1,3-diol-phosphoric acid propargyl ester.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772717547 DE2717547A1 (en) | 1977-04-20 | 1977-04-20 | PROCESS FOR REESTERIFICATION OF PHOSPHOLIPIDS WITH PHOSPHOLIPASE D. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1581810A true GB1581810A (en) | 1980-12-17 |
Family
ID=6006824
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB15174/78A Expired GB1581810A (en) | 1977-04-20 | 1978-04-18 | Process for the preparation of phospholipids |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE2717547A1 (en) |
| GB (1) | GB1581810A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0122151A2 (en) * | 1983-04-11 | 1984-10-17 | Meito Sangyo Kabushiki Kaisha | Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique |
| EP0122152A2 (en) * | 1983-04-11 | 1984-10-17 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of sphingophospholipid derivatives |
| EP0125039A2 (en) * | 1983-04-11 | 1984-11-14 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of phospholipid-saccharide derivatives |
| GB2172889A (en) * | 1985-03-20 | 1986-10-01 | Kao Corp | Phosphoric esters |
| US5441876A (en) * | 1993-07-30 | 1995-08-15 | The United States Of America As Represented By The Secretary Of The Navy | Process for the preparation of headgroup-modified phospholipids using phosphatidylhydroxyalkanols as intermediates |
| WO2003020941A1 (en) * | 2001-08-28 | 2003-03-13 | Degussa Food Ingredients Gmbh | Method for the production of phospholipids |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE452466B (en) * | 1983-03-24 | 1987-11-30 | Paul Gunnar Embring | MIXTURE OF WATER-SOLUBLE 3-PHOSPHATIDYL ESTERS AND CHOLINE, SET TO MAKE THIS AND A RECTALLY ADMINISTRATIVE PREPARATION FOR EMPTYING |
| JP2657274B2 (en) * | 1987-04-21 | 1997-09-24 | 株式会社ヤクルト本社 | Method for producing phospholipid |
| GB9102812D0 (en) * | 1991-02-11 | 1991-03-27 | Enzymatix Ltd | Compounds |
| WO2021195555A1 (en) * | 2020-03-27 | 2021-09-30 | Travecta Therapeutics, Pte. Ltd. | Palmitoylethanolamide compounds |
-
1977
- 1977-04-20 DE DE19772717547 patent/DE2717547A1/en not_active Ceased
-
1978
- 1978-04-18 GB GB15174/78A patent/GB1581810A/en not_active Expired
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4783402A (en) * | 1983-04-11 | 1988-11-08 | Meito Sangyo Kabushiki Kaisha | Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique |
| EP0125039A2 (en) * | 1983-04-11 | 1984-11-14 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of phospholipid-saccharide derivatives |
| EP0122152A3 (en) * | 1983-04-11 | 1986-03-12 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of sphingophospholipid derivatives |
| EP0122151A3 (en) * | 1983-04-11 | 1986-03-26 | Meito Sangyo Kabushiki Kaisha | Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique |
| EP0125039A3 (en) * | 1983-04-11 | 1986-03-26 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of phospholipid-saccharide derivatives |
| US4782019A (en) * | 1983-04-11 | 1988-11-01 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of sphingophospholipid derivatives |
| US4624919A (en) * | 1983-04-11 | 1986-11-25 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of phospholipid-saccharide derivatives |
| EP0122152A2 (en) * | 1983-04-11 | 1984-10-17 | Meito Sangyo Kabushiki Kaisha | Enzymatic production of sphingophospholipid derivatives |
| EP0122151A2 (en) * | 1983-04-11 | 1984-10-17 | Meito Sangyo Kabushiki Kaisha | Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique |
| GB2172889A (en) * | 1985-03-20 | 1986-10-01 | Kao Corp | Phosphoric esters |
| US5441876A (en) * | 1993-07-30 | 1995-08-15 | The United States Of America As Represented By The Secretary Of The Navy | Process for the preparation of headgroup-modified phospholipids using phosphatidylhydroxyalkanols as intermediates |
| US5516662A (en) * | 1993-07-30 | 1996-05-14 | The United States Of America As Represented By The Secretary Of The Navy | Process for the preparation of headgroup-modified phospholipids using phosphatidylhydroxyalkanols as intermediates |
| WO2003020941A1 (en) * | 2001-08-28 | 2003-03-13 | Degussa Food Ingredients Gmbh | Method for the production of phospholipids |
| US7067292B2 (en) | 2001-08-28 | 2006-06-27 | Bioghurt Biogarde Gmbh & Co. Kg | Method for the production of phospholipids |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2717547A1 (en) | 1978-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Eibl et al. | The synthesis of phospholipids by direct amination | |
| Baer et al. | L-α-Glycerylphosphorylcholine | |
| ES2165115T5 (en) | A PROCEDURE FOR THE PURIFICATION OF PHOSFATIDINILSERINE. | |
| GB1581810A (en) | Process for the preparation of phospholipids | |
| EP0121088B1 (en) | New o-acyl-alkanediol-phospholipids, processes for their preparation and pharmaceutical preparations containing them | |
| EP0486100A1 (en) | Process for preparing alpha-glycerophosphorylcholine | |
| CA2092005A1 (en) | A process for the preparation of glycerophospholipids | |
| US4163748A (en) | Propane-1,3-diol phosphatides and method of preparing the same | |
| Baer et al. | The Synthesis of O-(L-α-Glycerylphosphoryl)-ethanolamine and Some Comments on the Stereochemical Aspects of the Biosynthesis of Glycerolphosphatides from Carbohydrates | |
| Baer et al. | Synthesis of L-α-lecithins containing shorter chain fatty acids. Water-soluble glycerolphosphatides. I | |
| Eibl | An efficient synthesis of mixed acid phospholipids using 1-palmitoyl-sn-glycerol-3-phosphoric acid bromoalkyl esters | |
| Woolley et al. | Synthesis of enantiomerically pure phospholipids including phosphatidylserine and phosphatidylglycerol | |
| FI91966B (en) | Methods for preparing pharmacologically valuable alkylphosphonoserines | |
| Baer | The synthesis of glycerolphosphatides | |
| Baer | Phosphatide Analogs. The Synthesis of Glycollecithins and Bis-(glycol)-phosphatidic Acids1 | |
| US4751320A (en) | Phosphoric ester and process for producing same | |
| CA1063615A (en) | Synthetic phospholipids, a process for their manufacture and their use | |
| HU210285B (en) | Process for preparing l-alpha-glyceryl phosphoryl-d-myoinositol and its salts | |
| Bittman | Chemical Preparation of Glycerolipids: A | |
| Baer et al. | Phosphonolipids. XX. Total synthesis of a naturally occurring ceramide aminoethylphosphonate and of its enantiomer | |
| EP0229128B1 (en) | Derivatives of glycero-3(2)-phospho-l-serine and pharmaceutical preparations containing them | |
| Witzke et al. | Synthesis of phosphatidylcholine analogs with an alkyl group at C1 or C3 of the glycerol moiety. | |
| Baer et al. | PHOSPHONOLIPIDS: VI. CHEMICAL AND ENZYMATIC DEGRADATION FOR STUDY OF STRUCTURE | |
| US20060079703A1 (en) | Process for preparing lysophosphatidylcholine | |
| US4160773A (en) | Synthetic alkyl esters of phospholipid acid, structural analogs thereof and a process for their manufacture and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |
