US2009988A - Substituted glycerols and process of producing same - Google Patents
Substituted glycerols and process of producing same Download PDFInfo
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- US2009988A US2009988A US730461A US73046134A US2009988A US 2009988 A US2009988 A US 2009988A US 730461 A US730461 A US 730461A US 73046134 A US73046134 A US 73046134A US 2009988 A US2009988 A US 2009988A
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- acid
- radical
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- hydrogen
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- 238000000034 method Methods 0.000 title description 29
- 150000002314 glycerols Chemical class 0.000 title description 8
- 235000011187 glycerol Nutrition 0.000 title 1
- -1 fatty-acid radical Chemical class 0.000 description 46
- 239000000194 fatty acid Substances 0.000 description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 39
- 235000014113 dietary fatty acids Nutrition 0.000 description 36
- 229930195729 fatty acid Natural products 0.000 description 36
- 150000003839 salts Chemical class 0.000 description 33
- 229910052739 hydrogen Inorganic materials 0.000 description 32
- 239000001257 hydrogen Substances 0.000 description 32
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 30
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 24
- 229960004838 phosphoric acid Drugs 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
- 235000011007 phosphoric acid Nutrition 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 229910052783 alkali metal Inorganic materials 0.000 description 13
- 150000004665 fatty acids Chemical class 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 150000003863 ammonium salts Chemical class 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- XMVQWNRDPAAMJB-UHFFFAOYSA-N (+)-13-Cyclopent-2-enyl-tridecansaeure Natural products OC(=O)CCCCCCCCCCCCC1CCC=C1 XMVQWNRDPAAMJB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000001931 aliphatic group Chemical group 0.000 description 9
- 150000001340 alkali metals Chemical class 0.000 description 9
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 9
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 9
- XMVQWNRDPAAMJB-QGZVFWFLSA-N (S)-chaulmoogric acid Chemical compound OC(=O)CCCCCCCCCCCC[C@H]1CCC=C1 XMVQWNRDPAAMJB-QGZVFWFLSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 7
- 239000005977 Ethylene Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 125000005456 glyceride group Chemical group 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- 150000001342 alkaline earth metals Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010024229 Leprosy Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 229940093476 ethylene glycol Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 3
- 229960002901 sodium glycerophosphate Drugs 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- ASCFNMCAHFUBCO-UHFFFAOYSA-N 2-phosphoglycolic acid Chemical compound OC(=O)COP(O)(O)=O ASCFNMCAHFUBCO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- REULQIKBNNDNDX-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl hydrogen phosphate Chemical compound [Na+].OCC(O)COP(O)([O-])=O REULQIKBNNDNDX-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SRELFLQJDOTNLJ-HNNXBMFYSA-N (R)-hydnocarpic acid Chemical compound OC(=O)CCCCCCCCCC[C@@H]1CCC=C1 SRELFLQJDOTNLJ-HNNXBMFYSA-N 0.000 description 1
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 description 1
- KIHQZLPHVZKELA-UHFFFAOYSA-N 1,3-dibromopropan-2-ol Chemical compound BrCC(O)CBr KIHQZLPHVZKELA-UHFFFAOYSA-N 0.000 description 1
- DEWLEGDTCGBNGU-UHFFFAOYSA-N 1,3-dichloropropan-2-ol Chemical compound ClCC(O)CCl DEWLEGDTCGBNGU-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- QMTHILFALDMACK-UHFFFAOYSA-N 2-heptyl-nonanoic acid Chemical compound CCCCCCCC(C(O)=O)CCCCCCC QMTHILFALDMACK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000870800 Carpotroche Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- SRELFLQJDOTNLJ-UHFFFAOYSA-N Hydnocarpic acid Natural products OC(=O)CCCCCCCCCCC1CCC=C1 SRELFLQJDOTNLJ-UHFFFAOYSA-N 0.000 description 1
- 241001671327 Hydnocarpus Species 0.000 description 1
- 241001179022 Hydnocarpus anthelminthicus Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- FDGHZUQYDACRTA-LJQANCHMSA-N ethyl 13-[(1s)-cyclopent-2-en-1-yl]tridecanoate Chemical compound CCOC(=O)CCCCCCCCCCCC[C@H]1CCC=C1 FDGHZUQYDACRTA-LJQANCHMSA-N 0.000 description 1
- FDGHZUQYDACRTA-IBGZPJMESA-N ethyl chaulmoograte Natural products CCOC(=O)CCCCCCCCCCCC[C@@H]1CCC=C1 FDGHZUQYDACRTA-IBGZPJMESA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 125000005639 glycero group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/02—Anionic compounds
- C11D1/34—Derivatives of acids of phosphorus
- C11D1/347—Other P-containing anionic compounds
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- 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
-
- 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
-
- 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
Definitions
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of R and R in any Z is hydrogen
- the total number of carbon atoms in any Z which has carbon atoms is between 12 and 18 inclusive
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that Z
- T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
- leprae may be represented by the following formula:
- Procedure A First I form a glycerol or ethylene-glycol ester of the initial fatty acid, by reacting the desired dichloro-hydrin or chlorohydrin, or other halogen hydrin, with the sodium, potassium, ammonium, calcium, or other soluble salt of the desired fatty acid; or by reacting the free fatty acid with the desired glycol or glycerol, with heat.
- the glyceride or ethylene glycolide thus obtained is caused to react with phosphoric anhydride, to introduce a phosphoricacid radical at one or each of the hydroxyl groups of the glyceride or ethylene glycolide.
- the metaphosphoric ester of the glyceride or ethylene glycolide is first formed; and this may be converted into the phosphoric-acid ester by reaction with aqueous alcohol, and into a phosphate thereof by reaction with a suitable base, such as sodium carbonate or bicarbonate or hydroxide.
- Procedure B First a suitable glycero-phosphoric acid or glyco-phosphoric acid, or conveniently its sodium salt, is suitablyprepared; and in the presence of an excess of concentrated phosphoric acid as a condensing agent the desired fatty acid is added to it, and the mixture heated on a, water bath until reaction occurs. Best results are obtained if the fatty acid is present slightly in excess of the theoretical amount needed. On completion of the reaction, the acid formed may be neutralized, as with sodium hydroxide, to form the salt; and the salt may be purified by recrystallization.
- the fatty-acid radical may be introduced at one or two of the three hydroxyl groups of the glycerol, and so may be phosphoric-acid radical; which makes possible the following glycerides:
- M ono-fatty-acid, di-phosphoric-acid esters There are two varieties of these:
- the fatty-acid radical is introduced at one hydroxyl group and the phosphoric-acid radical at the other hydroxyl group of the original ethylene glycol, as indicated by the following formula:
- salts may be alkali-metal salts, ammonium salts, or substituted-ammonium salts; obtainable by reacting these phosphoric-acid esters with a suitable alkalimetal carbonate or hydroxide, or with ammonium hydroxide, or with an alkyl amine such as NHz-CHJ or NH(CH3) 2 or NH2CH2CH2OH.
- Class I Class I .--M ono-fatty-acid, mono-phosphoric-acid esters b.
- Mono-chaulmoogrylp -glycero-phosphoric acid is one example under this class. It is prepared, according to Procedure B, by heating one mole of p-glycero-phosphoric acid with somewhat less than one mole of chaulmoogric acid for one hour at C.
- the acid was obtained as a soft, light brown, amorphous paste after clarification with bone charcoal. N0 definite melting point was obtained.
- the sodium salt of this ester is obtained by neutralization of a concentrated alcoholic solution of the acid with a slight excess of NaHCOa. and evaporating to dryness in vacuo.
- This sodium salt is a water-soluble solid.
- Class IIL-Di-fattv-acid, mono-phosphorlc-acid esters I give below several examples in sub-class a of this class:
- a-l.--1,3-di-chaulmoogrylglycero phosphoric acid is prepared as follows:
- Procedure 18 This method of preparation by Procedure 18 is less economical than preparation by Procedure A; as Procedure A permits recovery of sodium chaulmoograte, and Procedure B does not.
- 1,3-di-chlorohydrin is prepared from glycerol and hydrochloric acid, with acetic acid as a catalyst, by the method of Conant and Quayle, Organic Syntheses, vol. 2, page 29. At 14 mm. pressure it boils at '70-73 C. 1,3-dibromohydrin, 1,3-di-iodohydrin, or 1-chloro-3- iodohydrin may be used in place of 1,3-di-chlorohydrin. These are known. 1,3-di-chlorohydrin has the following formula:
- Sodium chaulmoograte which is known, is prepared by adding one mole of alcoholic sodium hydroxide to one mole of chaulmoogric acid, or to one mole of an alkyl chaulmoograte such as ethyl chaulmoograte, and evaporating to dryness.
- Other salts, as of potassium, ammonium, or calcium, may be similarly prepared.
- 1,3-di-chaulmoogrin which is new with me, is prepared from 1,3-halogen hydrin,.such as the 1,3-di-chlorohydrin above described, and a suitable salt of chaulmoogric acid.
- one mole of 1,3-di-chloro-hydrin is mixed with slightly more than two moles of sodium chaulmoograte in a bomb tube or pressure bottle containing an atomosphere of nitrogen, and heated for several hours, say about 4 to 8 hours if at 120 and about 24 hours if at about 100 0.; and the reaction mixture is taken up in ether, desirably clarified by boiling with bone charcoal, then filtered and the filtrate reduced to a small volume by evaporation and then cooled to about 0 C. for 8 to 10 hours to precipitate excess sodium chaulmoograte, decanted or filtered, and any remaining ether removed by evaporation in vacuo. If desired, carbon dioxide or nitrogen may be bubbled through to aid the removal of the ether.
- the 1,3-di-chaulm0ogrin thus obtained is a clear amber liquid, yielding small foci of white crystals on prolonged cooling at 0 C.
- 1,3-di-chaulm0ogryl-glycero phosphoric acid is prepared from 1,3-di-chaulmoogrin and phosphorus pentoxide. Equalweights of these are mixed thoroughly, and the mixture heated for about thirty minutes at 100 C., during which time the mixture changes from a paste to a solid. (As within ten minutes the mixture becomes dark brown without external heating, the several hours heating at 100-110 C. as recommended in Hundeshagen's method for making distearylglycero-phosphoric acid seems unnecessary if not undesirable.) The solid thus obtained is put in 80% alcohol, and crushed; and the resultant material is filtered.
- the solid residue is then allowed to stand for 30 minutes under 80% alcohol at 30 C., to change any crude di-chaulmoogryl-glycero-metaphosphate present to dichaulmoogryl-glycero-phosphate.
- the mass is then again filtered, and the solid residue remaining is extracted in a small volume of hot 95% alcohol, decanted, and the liquid evaporated to dryness in vacuo.
- the residue from the evaporation is a brown pasty substance, slightly soluble in water, having an iodine number of 73.1.
- the salts may have a basic element or radical at one or both T's.
- the sodium salt of 1,3-di-chaulmoogryl-glycero-phosphoric acid may be prepared by the addition of a slight excess of finely powdered sodium carbonate to a hot alcoholic solution of 1,3-di-chaulmoogryl-glycero-phosphoric acid, illtration, and subsequent removal of the solvent by vacuum evaporation.
- the salt may be recrystallized from benzene. when so recrystallized it is a light brown solid, soluble in water (requiring less than 10 parts of water to dissolve it), and has an iodine number of 70.7.
- the yield of this sodium salt usually exceeds 35% of theory, on the basis of the sodium chaulmoograte originally used.
- the mono-sodium salt of 1,3-di-chaulmoogrylglycero-phosphoric acid has been found to be beneficial in the treatment of leprosy in leprous rats, by intradermal, subcutaneous, intravenous, and intraperitoneal administration.
- An advantageous pH for the solution is around 8.0.
- a fairly pure mono-sodium salt may be obtained.
- the di-sodium salt of 1,3-di-chaulmoogrylglycero-phosphoric acid is usually present to some extent with the mono-sodium salt at pH8. It may be obtained fairly pure by using the necessary molecular proportions in preparing the salt.
- a2 .1,3 -di-di-n-heptyl-acetyl-glycero phosphoric acid has been prepared by Procedure B given above, from di-n-heptyl acetic acid and sodium glycero-phosphate in the presence of an excess of concentrated phosphoric acid. It forms water-soluble salts with the alkali metals, ammonia, and alkyl amines. It is a brown, amorphous, waxy solid. Its sodium salt is a water-soluble, light-brown, amorphous solid. Its calcium salt, prepared from the acid and calcium carbonate, is a whitish, amorphous solid, slightly water-soluble.
- T has the same significance as before.
- the salts as of sodium or of calcium, may have a basic element or radical ateither or both Ts.
- the mono-sodium salt is a highly active bactericide.
- the 1,3-di-cyclo hexyl ethylheptyl-acetyl-glycero-phosphoric acid is a solid, and forms water-soluble salts with the alkalimetals, ammonia, and alkyl amines.
- the sodium salt is similar to the di-n-heptyl homologue, with about the same solubility.
- the ethanolamine salt forms a semi-solid paste, which in my experiments did not form a solid on prolonged vacuum desiccation.
- the salts may have a basic element or radical at either or both T's.
- Acids 11-2 and H may be prepared by either Procedure A or Procedure B.
- b.--2,3-di chaulmogryl glycero phosporic acid may be prepared by either Procedure A or Procedure B.
- a 2,3-halogen-hydrin is used instead of a 1,3-halogen-hydrin.
- the halogen-'hydrln in either case may as conveniently be a di-bromo-hydrin as a di-chloro-hydrin.
- 2,3-di-bromo-hydrin is prepared from substantially anhydrous allyl alcohol and bromine, in known manner.
- 2,3-di-chaulmoogrin is prepared from 2,3-dibromo-hydrin (or other 2,3-halogen-hydrin) and any salt of chaulmoogric acid, such as sodium chaulmoograte, in the same manner as has been described for the preparation of 1,3-di-chaulmoogrin from 1,3-chloro-hydrin and sodium chaulmoograte.
- the yields which have been obtained are rather poor.
- 2,3-di-chaulmoogryl-glycero phosphoric acid may be prepared from 2,3-di-chaulmoogrin and phosphorous pentoxide, in the same manner as has already been described for the preparation of 1,3- di-chaulmoogryl glycero phosphoric acid.
- alkali-metal salts such as the potassium salt for instance, may be obtained by precipitating a hot alcoholic solution of the acid with the carbonate of the desired alkali metal, such as potassium carbonate. These salts are freely water-soluble.
- Ammonium salt and substituted-ammonium salts may also be prepared, in similar fashion.
- the salts may have a basic element or radical at either or both T's.
- Monochaulmoogryl-ethyleneglycolide is prepared by mixing one mole of ethylene-chlorohydrin with slightly more than one mole of sodium chaulmoograte, and heating at 100 C. for 48 to '12 hours in a nitrogen-filled bomb tube. It may also be prepared by heating together ethylene glycol and chaulmoogric acid for a prolonged period at higher temperature-4n the neighborhood of 120 to 140 C. but this involves considerable simultaneous production of di-chaulmoogryl glycol, and hence is less desirable because of the necessity of separating the monochaulmoogryl glycol from the di-chaulmoogryl glycol. Mono-chaulmoogryl glycol is a yellowish liquid which readily decomposes when heated in the air. It is represented by the following formula:
- Chaulmocgryl-glyco-phosphoric acid is prepared by adding an excess of phosphorus pentoxide to mono-chaulmoogryl glycolide, intimately mixing them, and heating together for an hour at 100 C.
- Alkali-metal salts of this acid may be formed by neutralizing a hot alcoholic solution of the acid with a corresponding alkalimetal carbonate.
- Ammonium salts and substituted-ammonium salts may be similarly prepared.
- the salts may have a basic element or radical at either or both Ts.
- Z in stance is the following radical:
- At least one inand R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any Z is hydrogen, the total number of carbon atoms in any Z which has carbon atoms is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that Z, and T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
- a substituted glycerol in which the following radical is introduced at at least one hydroxyl group:
- R represents either hydrogen or a cyclic 3.
- a substituted glycerol having the following formula:
- Ace represents the phosphoric-acid radical
- Aer represents the following fattyacid radical:
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl or a substituted ammonium.
- a substituted glycerol having the following in which Aer represents the phosphoric-acid radical, and Aer represents the following fattyacid radical:
- C Qr-B -o-gcn and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of R and R in any fattyacid radical is hydrogen
- the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical
- the phosphoric-acid radical has none, one, or both of its hydrogen atoms replaced by either an alkali metal, an alkaline-earth metal, ammonium, or a substituted ammonium.
- a substituted glycerol having the following formula:
- Acp represents the phosphoric-acid radical, and Ac;- represents the following fattyacid radical:
- CHDPR o t en and R represents either hydrogn or a cyclic group of the class. consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any fatty-acid radical is hydrogen, the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical, and the phosphoric-acid radical has none, one, or both of its hydrogen atoms replaced by either an alkali metal, an alkaline-earth metal, ammonium, or a substituted ammonium.
- a bactericidal compound which consists in introducing a phosphoric-acid radical at at least one hydroiw group but at less than all of the hydroxy groups of glycerol or of ethylene glycol; and at at least one other hydroxy group thereof introducing the following fatty-acid radical:
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of R and R in any fatty-acid radical is hydrogen
- the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical.
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group, only one of R and R is hydrogen, the total number of carbon atoms is between I! and It inclusive, and w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical; and then causing the glyceride or ethylene glycolide so obtained to react with phosphoric anhydride; and treating the ester so obtained with a reagent which converts the ester into a soluble salt.
- a bactericidal compound which consists in reacting a phosphoricacid-radical-containing compound of the class consisting of glycero-phosphoric acid, glycophosphoric acid, and their soluble salts, in the presence of an excess of concentrated phosphoric acid as a condensing agent, with a fatty acid containing the following radical:
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of R and R is hydrogen
- the total number of carbon atoms is between 12 and 18 inclusive
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical.
- a substituted glycerol in which the following radical is introduced at one hydroxyl group:
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of the R and R in any radical containing both is hydrogen
- the total number of carbon atoms in the first radical given above is between 12 and 18
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that radical
- T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
- a substituted glycerol in which the following radical is introduced at each oi. two hydroxyl groups:
- R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group
- R represents either hydrogen or a straight-chain aliphatic group
- only one of the R and R in any radical containing both is hydrogen
- the total number of carbon atoms in the first radical given above is between 12 and 18
- w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that radical
- T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
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Description
Patented July 30, 1935 UNITED STATES PATENT OFFICE SUBSTITUTED GLYCEROLS AND PROCESS OF PRODUCING SAME No Drawing. Application June 13, 1934, Serial No. 730,461
10 Claims. (onto-99.20)
It is the object of my invention to produce from certain fatty acids which are bactericidal or bacteriostatic to M. leprae, water-soluble derivatives which have certain advantages over the original acids and their salts; particularly in that they have good water-solubility, are effective in the treatment of leprosy on either oral or parenteral administration, and are less irritating and better tolerated when their solutions are administered parenterally than are those acids themselves or any previously known derivatives thereof.
These new water-soluble derivatives, and certain intermediates which are included within the scope of my claims,- are all compounds which are represented by the following general formula:
- H 1 H- i -H m I in which :1: equals 2 or 3, Z in at least one instance is the following fatty-acid radical:
and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any Z is hydrogen, the total number of carbon atoms in any Z which has carbon atoms is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that Z, and T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
There are a number of fatty acids, and their salts, which are known to have bactericidal and bacteriostatic eifect .against M. lepraa, both in vitro and in vivo. The effects in vivo have in many cases been proven on leprous rats. The tests of my products in vivo have also been made on leprous rats.
These fatty acids which are known to have this bactericidal and bacteriostatic action against M,
leprae may be represented by the following formula:
(CHI)I R in which R, R, and 10 have the same significance as stated above. Among these acids may be mentioned the following:
a. chaulmoogric acid;
b. hydnocarpic acid;
0. the total fatty acids of chaulmoogra oil, hydnocarpus oil, carpotroche oil, macrocarpa oil, and/or oil of gorli;
d. certain fatty acids containing between 12 and 18 carbon atoms, of the type disclosed in the Adams Patent No. 1,878,732, of August 23, 1932. But in general these fatty acids are not sufficiently soluble for effective use in the treatment of leprosy, and have other disadvantages; 20 and when their salts have suflicient solubility, such salts also generally have certain irritating qualities which interfere with their eifective administration. Some of these salts have other untoward physiological efiects in addition to causing local irritation, such as the production of hemolysis, sclerosis, hematuria, nephritis, and liver damage. These untoward physiological effects are in many instances so great that they preclude continued parenteral use of the substances, even in cases where promising initial results had been obtained.
I have discovered that by introducing the effective radicals of these fatty acids in compounds of the type shown in Formula 1, and/or in readily obtained derivatives of such compounds, I am able to get both the desired solubility and the desired freedom from irritating, heir olytic, and sclerosing properties.
In general I form my new compounds by either of the following procedures:
Procedure A.First I form a glycerol or ethylene-glycol ester of the initial fatty acid, by reacting the desired dichloro-hydrin or chlorohydrin, or other halogen hydrin, with the sodium, potassium, ammonium, calcium, or other soluble salt of the desired fatty acid; or by reacting the free fatty acid with the desired glycol or glycerol, with heat. This yields a dior mono-glyceride or an ethylene mono-glycolide, in which there is at least one unsubstituted hydroxyl, and sometimes (in the case of the mono-glycerides) two unsubstituted hydroxyls. The glyceride or ethylene glycolide thus obtained is caused to react with phosphoric anhydride, to introduce a phosphoricacid radical at one or each of the hydroxyl groups of the glyceride or ethylene glycolide. The metaphosphoric ester of the glyceride or ethylene glycolide is first formed; and this may be converted into the phosphoric-acid ester by reaction with aqueous alcohol, and into a phosphate thereof by reaction with a suitable base, such as sodium carbonate or bicarbonate or hydroxide.
Procedure B.-First a suitable glycero-phosphoric acid or glyco-phosphoric acid, or conveniently its sodium salt, is suitablyprepared; and in the presence of an excess of concentrated phosphoric acid as a condensing agent the desired fatty acid is added to it, and the mixture heated on a, water bath until reaction occurs. Best results are obtained if the fatty acid is present slightly in excess of the theoretical amount needed. On completion of the reaction, the acid formed may be neutralized, as with sodium hydroxide, to form the salt; and the salt may be purified by recrystallization.
By these procedures, it is possible in the case of the glycerides to get a number of variations. The fatty-acid radical may be introduced at one or two of the three hydroxyl groups of the glycerol, and so may be phosphoric-acid radical; which makes possible the following glycerides:
I. Mono-fatty-acid, mono-phosphoric-acid esters There are three varieties of these:
a. With the fatty-acid radical introduced at the middle hydroxyl of the glycerol, as indicated by the following formula:
0. with the middle hydroxyl unsubstituted, as shown by the following formula:
II. M ono-fatty-acid, di-phosphoric-acid esters There are two varieties of these:
a. With the fatty-acid radical introduced at the middle hydroxyl of the glycerol, as shown by v the following formula:
12. With the fatty-acid radical introduced at There are two varieties of these:
a. With the phosphoric-acid radical introduced at the middle hydroxyl of the glycerol, as shown by the following formula:
b. With the phosphoric-acid radical introduced at an end hydroxyl of the glycerol, as shown by the following formula:
L i l 11- c- C-H Ace Aer Aer IV. In the case of the ethylene glycolides, the fatty-acid radical is introduced at one hydroxyl group and the phosphoric-acid radical at the other hydroxyl group of the original ethylene glycol, as indicated by the following formula:
In the case of some of these compounds, certain of the intermediate glycerides or ethylene glycolides are also new.
Further, in all of these instances where a phosphoric-acid radical has been introduced, it is possible to obtain salts. These salts may be alkali-metal salts, ammonium salts, or substituted-ammonium salts; obtainable by reacting these phosphoric-acid esters with a suitable alkalimetal carbonate or hydroxide, or with ammonium hydroxide, or with an alkyl amine such as NHz-CHJ or NH(CH3) 2 or NH2CH2CH2OH.
The following are some examples of the various esters which are included in my invention; and of some of the new intermediates and salts.
Class I .--M ono-fatty-acid, mono-phosphoric-acid esters b. Mono-chaulmoogrylp -glycero-phosphoric acid is one example under this class. It is prepared, according to Procedure B, by heating one mole of p-glycero-phosphoric acid with somewhat less than one mole of chaulmoogric acid for one hour at C.
The acid was obtained as a soft, light brown, amorphous paste after clarification with bone charcoal. N0 definite melting point was obtained.
The sodium salt of this ester is obtained by neutralization of a concentrated alcoholic solution of the acid with a slight excess of NaHCOa. and evaporating to dryness in vacuo. This sodium salt is a water-soluble solid.
This ester and its salts are represented by the following formula:
CH=CH as before. radical at in which T has the same significance as before. Class IIL-Di-fattv-acid, mono-phosphorlc-acid esters I give below several examples in sub-class a of this class:
a-l.--1,3-di-chaulmoogrylglycero phosphoric acid is prepared as follows:
(16) OH CH CHI-CH1 B1 Procedure B.-Sodium glycero-phosphate is mixed with an excess of concentrated phosphoric acid, and chaulmoogric acid is added to the mixture in slight excess over the two equivalents required. The total mixture is then heated to about 100 C. until a reaction takes place, which requires from to 24 hours. The completion of the reaction is evidenced by the formation of a hard tacky mass, which is the free di-chaulmoogryl-glycero-phosphoric acid. This is then neutralized, as with sodium hydroxide; and purlfled, as by recrystallization from benzene or other suitable solvent. The longer the time required before the reaction occurs, the less the yield; as chaulmoogric acid slowly breaks down under heat.
This method of preparation by Procedure 18 is less economical than preparation by Procedure A; as Procedure A permits recovery of sodium chaulmoograte, and Procedure B does not.
By Procedure A.'1,3-di-chlorohydrin is prepared from glycerol and hydrochloric acid, with acetic acid as a catalyst, by the method of Conant and Quayle, Organic Syntheses, vol. 2, page 29. At 14 mm. pressure it boils at '70-73 C. 1,3-dibromohydrin, 1,3-di-iodohydrin, or 1-chloro-3- iodohydrin may be used in place of 1,3-di-chlorohydrin. These are known. 1,3-di-chlorohydrin has the following formula:
l l): l
Sodium chaulmoograte, which is known, is prepared by adding one mole of alcoholic sodium hydroxide to one mole of chaulmoogric acid, or to one mole of an alkyl chaulmoograte such as ethyl chaulmoograte, and evaporating to dryness. Other salts, as of potassium, ammonium, or calcium, may be similarly prepared.
1,3-di-chaulmoogrin, which is new with me, is prepared from 1,3-halogen hydrin,.such as the 1,3-di-chlorohydrin above described, and a suitable salt of chaulmoogric acid. For example: one mole of 1,3-di-chloro-hydrin is mixed with slightly more than two moles of sodium chaulmoograte in a bomb tube or pressure bottle containing an atomosphere of nitrogen, and heated for several hours, say about 4 to 8 hours if at 120 and about 24 hours if at about 100 0.; and the reaction mixture is taken up in ether, desirably clarified by boiling with bone charcoal, then filtered and the filtrate reduced to a small volume by evaporation and then cooled to about 0 C. for 8 to 10 hours to precipitate excess sodium chaulmoograte, decanted or filtered, and any remaining ether removed by evaporation in vacuo. If desired, carbon dioxide or nitrogen may be bubbled through to aid the removal of the ether. The 1,3-di-chaulm0ogrin thus obtained is a clear amber liquid, yielding small foci of white crystals on prolonged cooling at 0 C.
It has an iodine number of 82.4. On prolonged heating at 60 in the air it decomposes, with some charring. It is an easily iniectable liquid, suitable for intradermal or subcutaneous injec- It is represented by the following formula:
The foregoing method of producing 1,3-dichaulmoogrin follows in general the Guth method for the preparation of diolein. (Zeitschrift fiir Biologie, vol. 44, p. 78, for 1903.)
1,3-di-chaulm0ogryl-glycero phosphoric acid is prepared from 1,3-di-chaulmoogrin and phosphorus pentoxide. Equalweights of these are mixed thoroughly, and the mixture heated for about thirty minutes at 100 C., during which time the mixture changes from a paste to a solid. (As within ten minutes the mixture becomes dark brown without external heating, the several hours heating at 100-110 C. as recommended in Hundeshagen's method for making distearylglycero-phosphoric acid seems unnecessary if not undesirable.) The solid thus obtained is put in 80% alcohol, and crushed; and the resultant material is filtered. The solid residue is then allowed to stand for 30 minutes under 80% alcohol at 30 C., to change any crude di-chaulmoogryl-glycero-metaphosphate present to dichaulmoogryl-glycero-phosphate. The mass is then again filtered, and the solid residue remaining is extracted in a small volume of hot 95% alcohol, decanted, and the liquid evaporated to dryness in vacuo. The residue from the evaporation is a brown pasty substance, slightly soluble in water, having an iodine number of 73.1.
This free acid has not as yet been used therapeutically, for the therapeutic work involving it has been done with its salts. 1,3-di-chaulaLLi.
CH=CH Hz-CH! in which T has the same significance as before.
The salts may have a basic element or radical at one or both T's.
The sodium salt of 1,3-di-chaulmoogryl-glycero-phosphoric acid may be prepared by the addition of a slight excess of finely powdered sodium carbonate to a hot alcoholic solution of 1,3-di-chaulmoogryl-glycero-phosphoric acid, illtration, and subsequent removal of the solvent by vacuum evaporation. The salt may be recrystallized from benzene. when so recrystallized it is a light brown solid, soluble in water (requiring less than 10 parts of water to dissolve it), and has an iodine number of 70.7. The yield of this sodium salt usually exceeds 35% of theory, on the basis of the sodium chaulmoograte originally used.
This procedure follows in general that of Hundeshagen, (J. f. prakt. Chem., volume 136, p. 219, for the year 1883,) for distearyl-glycerophosphoric acid.
The mono-sodium salt of 1,3-di-chaulmoogrylglycero-phosphoric acid has been found to be beneficial in the treatment of leprosy in leprous rats, by intradermal, subcutaneous, intravenous, and intraperitoneal administration. An advantageous pH for the solution is around 8.0. By using the theoretical molecular proportions and evaporating to dryness, a fairly pure mono-sodium salt may be obtained.
The di-sodium salt of 1,3-di-chaulmoogrylglycero-phosphoric acid is usually present to some extent with the mono-sodium salt at pH8. It may be obtained fairly pure by using the necessary molecular proportions in preparing the salt.
a2 .1,3 -di-di-n-heptyl-acetyl-glycero phosphoric acid has been prepared by Procedure B given above, from di-n-heptyl acetic acid and sodium glycero-phosphate in the presence of an excess of concentrated phosphoric acid. It forms water-soluble salts with the alkali metals, ammonia, and alkyl amines. It is a brown, amorphous, waxy solid. Its sodium salt is a water-soluble, light-brown, amorphous solid. Its calcium salt, prepared from the acid and calcium carbonate, is a whitish, amorphous solid, slightly water-soluble.
The formula for 1,3-di-di-n-heptyl-acetylglycero-phosphoric acid and its salts is as follows:
in which T has the same significance as before. The salts, as of sodium or of calcium, may have a basic element or radical ateither or both Ts.
The mono-sodium salt is a highly active bactericide.
CH=OH 0-3.-l,3-di-cyclo-hexyl-ethyl-heptyl acetylglycero-phosphoric acid may also be prepared, desirably by Procedure A; from cyclo-hexyl-ethylheptyl acetic acid and sodium glycerophosphate, in the presence of an excess of concentrated phosphoric acid. The 1,3-di-cyclo hexyl ethylheptyl-acetyl-glycero-phosphoric acid is a solid, and forms water-soluble salts with the alkalimetals, ammonia, and alkyl amines.
The sodium salt is similar to the di-n-heptyl homologue, with about the same solubility. The ethanolamine salt forms a semi-solid paste, which in my experiments did not form a solid on prolonged vacuum desiccation.
This acid and its salts are represented by the following formula:
in which T has the same significance as before. The salts may have a basic element or radical at either or both T's.
Acids 11-2 and H, like acid a-l, may be prepared by either Procedure A or Procedure B.
b.--2,3-di chaulmogryl glycero phosporic acid may be prepared by either Procedure A or Procedure B.
In Procedure A, of course, a 2,3-halogen-hydrin is used instead of a 1,3-halogen-hydrin. The halogen-'hydrln in either case may as conveniently be a di-bromo-hydrin as a di-chloro-hydrin.
2,3-di-bromo-hydrin is prepared from substantially anhydrous allyl alcohol and bromine, in known manner.
2,3-di-chaulmoogrin is prepared from 2,3-dibromo-hydrin (or other 2,3-halogen-hydrin) and any salt of chaulmoogric acid, such as sodium chaulmoograte, in the same manner as has been described for the preparation of 1,3-di-chaulmoogrin from 1,3-chloro-hydrin and sodium chaulmoograte. The yields which have been obtained are rather poor.
2,3-di-chaulmoogryl-glycero phosphoric acid may be prepared from 2,3-di-chaulmoogrin and phosphorous pentoxide, in the same manner as has already been described for the preparation of 1,3- di-chaulmoogryl glycero phosphoric acid. Its alkali-metal salts, such as the potassium salt for instance, may be obtained by precipitating a hot alcoholic solution of the acid with the carbonate of the desired alkali metal, such as potassium carbonate. These salts are freely water-soluble.
Ammonium salt and substituted-ammonium salts may also be prepared, in similar fashion.
2,3-di-chauhnoogryl-glycero phosphoric acid m) OH:- H:
in which T has the same significance as before. The salts may have a basic element or radical at either or both T's.
IV. Mono-fatty-acid, mono-phosphoric acid ethyleneglycolide is prepared as follows:
Monochaulmoogryl-ethyleneglycolide is prepared by mixing one mole of ethylene-chlorohydrin with slightly more than one mole of sodium chaulmoograte, and heating at 100 C. for 48 to '12 hours in a nitrogen-filled bomb tube. It may also be prepared by heating together ethylene glycol and chaulmoogric acid for a prolonged period at higher temperature-4n the neighborhood of 120 to 140 C. but this involves considerable simultaneous production of di-chaulmoogryl glycol, and hence is less desirable because of the necessity of separating the monochaulmoogryl glycol from the di-chaulmoogryl glycol. Mono-chaulmoogryl glycol is a yellowish liquid which readily decomposes when heated in the air. It is represented by the following formula:
CH: H:
Chaulmocgryl-glyco-phosphoric acid is prepared by adding an excess of phosphorus pentoxide to mono-chaulmoogryl glycolide, intimately mixing them, and heating together for an hour at 100 C. Alkali-metal salts of this acid may be formed by neutralizing a hot alcoholic solution of the acid with a corresponding alkalimetal carbonate. Ammonium salts and substituted-ammonium salts may be similarly prepared. The chaulmoogryl-glyco-phosphoric acid and its saltsare represented by the following formula:
in which T has the same meaning as before. The salts may have a basic element or radical at either or both Ts.
In the foregoing I have not attempted to give examples of all the fatty-acid radicals which may be used instead of the chaulmoogric-acid radical, but in general any can be used which come within the definition given hereinbefore.
All of these new compounds which have been described are eil'ective in the treatment of leprosy in leprous rats. They are best administered in the form of salts, most conveniently the sodium salt, although other alkali-metal salts as well as the ammonium salts and substitutedammonium salts may be used with good effect. Effective results may be obtained on oral administration, intradermal administration, subcutaneous administration, intravenous injection, intraperitoneal injection, and intramuscular administration.
I claim as my invention: 1. The new bactericidal compounds which are represented by the following formula:
a l i in which 0: equals 2 or 3, Z in stance is the following radical:
at least one inand R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any Z is hydrogen, the total number of carbon atoms in any Z which has carbon atoms is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that Z, and T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
2. A substituted glycerol, in which the following radical is introduced at at least one hydroxyl group:
and in which the following radical is introduced at at least one other hydroxyl group:
and R represents either hydrogen or a cyclic 3. A substituted glycerol having the following formula:
in which Ace represents the phosphoric-acid radical, and Aer represents the following fattyacid radical:
and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl or a substituted ammonium.
4. A substituted glycerol having the following in which Aer represents the phosphoric-acid radical, and Aer represents the following fattyacid radical:
0 (C Qr-B -o-gcn and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any fattyacid radical is hydrogen, the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical, and the phosphoric-acid radical has none, one, or both of its hydrogen atoms replaced by either an alkali metal, an alkaline-earth metal, ammonium, or a substituted ammonium.
5. A substituted glycerol having the following formula:
Hill...
in which Acp represents the phosphoric-acid radical, and Ac;- represents the following fattyacid radical:
0 (CHDPR o t en and R represents either hydrogn or a cyclic group of the class. consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any fatty-acid radical is hydrogen, the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical, and the phosphoric-acid radical has none, one, or both of its hydrogen atoms replaced by either an alkali metal, an alkaline-earth metal, ammonium, or a substituted ammonium.
6. The process of producing a bactericidal compound, which consists in introducing a phosphoric-acid radical at at least one hydroiw group but at less than all of the hydroxy groups of glycerol or of ethylene glycol; and at at least one other hydroxy group thereof introducing the following fatty-acid radical:
0 (CH1) ..-R -O(|!}-CH/ in which R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R in any fatty-acid radical is hydrogen, the total number of carbon atoms in any fatty-acid radical is between 12 and 18 inclusive, and w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical.
7. The process of producing a bactericidal compound, which consists in reacting a 2-carbon .or 3-carbon halogen hydrin with a soluble salt of a fatty acid having the following fatty-acid radical:
in which R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R is hydrogen, the total number of carbon atoms is between I! and It inclusive, and w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical; and then causing the glyceride or ethylene glycolide so obtained to react with phosphoric anhydride; and treating the ester so obtained with a reagent which converts the ester into a soluble salt.
8. The process of producing a bactericidal compound, which consists in reacting a phosphoricacid-radical-containing compound of the class consisting of glycero-phosphoric acid, glycophosphoric acid, and their soluble salts, in the presence of an excess of concentrated phosphoric acid as a condensing agent, with a fatty acid containing the following radical:
in which R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of R and R is hydrogen, the total number of carbon atoms is between 12 and 18 inclusive, and w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that fatty-acid radical.
9. A substituted glycerol, in which the following radical is introduced at one hydroxyl group:
0 (CHflr-R --0-( -CH I R! and in which the following radical is introduced at each of the other two hydroxyl groups:
or o-1 =o and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of the R and R in any radical containing both is hydrogen, the total number of carbon atoms in the first radical given above is between 12 and 18, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that radical, and T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
10. A substituted glycerol, in which the following radical is introduced at each oi. two hydroxyl groups:
and in which the following radical is introduced at the third hydroxyl group:
and R represents either hydrogen or a cyclic group of the class consisting of the cyclo-pentyl group, the cyclo-hexyl group, the cyclo-pentenyl group, and the cyclo-hexenyl group, R represents either hydrogen or a straight-chain aliphatic group, only one of the R and R in any radical containing both is hydrogen, the total number of carbon atoms in the first radical given above is between 12 and 18, w is an integer of the necessary value to make that number (12 to 18) of carbon atoms in that radical, and T is either hydrogen or an alkali metal or an alkaline-earth metal or ammonium or a substituted ammonium.
GEORGE A. EMERSON.
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US730461A US2009988A (en) | 1934-01-24 | 1934-06-13 | Substituted glycerols and process of producing same |
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US730461A US2009988A (en) | 1934-01-24 | 1934-06-13 | Substituted glycerols and process of producing same |
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