NO132307B - - Google Patents
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- Publication number
- NO132307B NO132307B NO1382/70A NO138270A NO132307B NO 132307 B NO132307 B NO 132307B NO 1382/70 A NO1382/70 A NO 1382/70A NO 138270 A NO138270 A NO 138270A NO 132307 B NO132307 B NO 132307B
- Authority
- NO
- Norway
- Prior art keywords
- solution
- dioxo
- ether
- acid
- residue
- Prior art date
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 80
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 48
- -1 malonyl halide Chemical class 0.000 claims description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 20
- PAHVTLRWCQYFEB-UHFFFAOYSA-N 1,2-oxazolidine-3,5-dione Chemical class O=C1CC(=O)ON1 PAHVTLRWCQYFEB-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 230000010933 acylation Effects 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 5
- GNEVIACKFGQMHB-UHFFFAOYSA-N carbon suboxide Chemical compound O=C=C=C=O GNEVIACKFGQMHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 230000017538 malonylation Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000000243 solution Substances 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- 239000013078 crystal Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- CKRZKMFTZCFYGB-UHFFFAOYSA-N N-phenylhydroxylamine Chemical compound ONC1=CC=CC=C1 CKRZKMFTZCFYGB-UHFFFAOYSA-N 0.000 description 11
- 230000007717 exclusion Effects 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- ZCMMUGZVSPBESD-UHFFFAOYSA-N 4-cyclohexyl-2-phenyl-1,2-oxazolidine-3,5-dione Chemical compound O=C1ON(C=2C=CC=CC=2)C(=O)C1C1CCCCC1 ZCMMUGZVSPBESD-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- FWQNYUYRXNWOOM-UHFFFAOYSA-N 2-nonylpropanedioic acid Chemical compound CCCCCCCCCC(C(O)=O)C(O)=O FWQNYUYRXNWOOM-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 150000002443 hydroxylamines Chemical class 0.000 description 3
- 150000002691 malonic acids Chemical class 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 229960002895 phenylbutazone Drugs 0.000 description 3
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XVKQKBZYWIWKNA-UHFFFAOYSA-N 2-cyclohexylpropanedioyl dichloride Chemical compound ClC(=O)C(C(Cl)=O)C1CCCCC1 XVKQKBZYWIWKNA-UHFFFAOYSA-N 0.000 description 2
- KCDSBPHPBGFCGE-UHFFFAOYSA-N 2-phenyl-1,2-oxazolidine-3,5-dione Chemical compound O1C(=O)CC(=O)N1C1=CC=CC=C1 KCDSBPHPBGFCGE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- RQNOFUZGXHSHOT-UHFFFAOYSA-N 1-(diethylamino)ethanol Chemical class CCN(CC)C(C)O RQNOFUZGXHSHOT-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- CMPNRCVPWPYBNV-UHFFFAOYSA-N 2,4-diphenyl-1,2-oxazolidine-3,5-dione Chemical compound O=C1ON(C=2C=CC=CC=2)C(=O)C1C1=CC=CC=C1 CMPNRCVPWPYBNV-UHFFFAOYSA-N 0.000 description 1
- JAEJSNFTJMYIEF-UHFFFAOYSA-N 2-benzylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)CC1=CC=CC=C1 JAEJSNFTJMYIEF-UHFFFAOYSA-N 0.000 description 1
- OMQSILQQILEWFZ-UHFFFAOYSA-N 2-benzylpropanedioyl dichloride Chemical compound ClC(=O)C(C(Cl)=O)CC1=CC=CC=C1 OMQSILQQILEWFZ-UHFFFAOYSA-N 0.000 description 1
- MCRZWYDXIGCFKO-UHFFFAOYSA-N 2-butylpropanedioic acid Chemical compound CCCCC(C(O)=O)C(O)=O MCRZWYDXIGCFKO-UHFFFAOYSA-N 0.000 description 1
- ITTFEPALADGOBD-UHFFFAOYSA-N 2-butylpropanedioyl dichloride Chemical compound CCCCC(C(Cl)=O)C(Cl)=O ITTFEPALADGOBD-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- NOVVBEJYUYPYDJ-UHFFFAOYSA-N 2-ethyl-2-phenylpropanedioyl dibromide Chemical compound C(C)C(C(=O)Br)(C(=O)Br)C1=CC=CC=C1 NOVVBEJYUYPYDJ-UHFFFAOYSA-N 0.000 description 1
- NXROHJABHCSTOK-UHFFFAOYSA-N 2-ethyl-2-phenylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)(C(Cl)=O)C1=CC=CC=C1 NXROHJABHCSTOK-UHFFFAOYSA-N 0.000 description 1
- UPFSMSDGKQSRLD-UHFFFAOYSA-N 2-hexylpropanedioic acid Chemical compound CCCCCCC(C(O)=O)C(O)=O UPFSMSDGKQSRLD-UHFFFAOYSA-N 0.000 description 1
- HLYRPHOQWQARQR-UHFFFAOYSA-N 2-hexylpropanedioyl dichloride Chemical compound C(CCCCC)C(C(=O)Cl)C(=O)Cl HLYRPHOQWQARQR-UHFFFAOYSA-N 0.000 description 1
- DLTWEQZAWUHBDH-UHFFFAOYSA-N 2-phenylpropanedioyl dichloride Chemical compound ClC(=O)C(C(Cl)=O)C1=CC=CC=C1 DLTWEQZAWUHBDH-UHFFFAOYSA-N 0.000 description 1
- ZXPADYZQMMDSMN-UHFFFAOYSA-N 4-(cyclopentylmethyl)-2-phenyl-1,2-oxazolidine-3,5-dione Chemical compound C1(=CC=CC=C1)N1OC(C(C1=O)CC1CCCC1)=O ZXPADYZQMMDSMN-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- AHWHBMILVHUGEB-UHFFFAOYSA-N 4-butyl-2-phenyl-1,2-oxazolidine-3,5-dione Chemical compound O=C1C(CCCC)C(=O)ON1C1=CC=CC=C1 AHWHBMILVHUGEB-UHFFFAOYSA-N 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OFPVCGGSAHFRAE-UHFFFAOYSA-N C1(=CC=CC=C1)N1OC(C(C1=O)C1CCCC1)=O Chemical compound C1(=CC=CC=C1)N1OC(C(C1=O)C1CCCC1)=O OFPVCGGSAHFRAE-UHFFFAOYSA-N 0.000 description 1
- BPHLYVHYMGTLAL-UHFFFAOYSA-N C1(=CC=CC=C1)N1OC(C(C1=O)CCCCCC)=O Chemical compound C1(=CC=CC=C1)N1OC(C(C1=O)CCCCCC)=O BPHLYVHYMGTLAL-UHFFFAOYSA-N 0.000 description 1
- QQROBCUHABBFIC-UHFFFAOYSA-N C1(=CC=CC=C1)N1OC(C(C1=O)CCCCCCCCC)=O Chemical compound C1(=CC=CC=C1)N1OC(C(C1=O)CCCCCCCCC)=O QQROBCUHABBFIC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CWFINLADSFPMHF-UHFFFAOYSA-N N-hydroxynaphthalen-1-amine Chemical compound C1=CC=C2C(NO)=CC=CC2=C1 CWFINLADSFPMHF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- XDLDASNSMGOEMX-UHFFFAOYSA-N benzene benzene Chemical compound C1=CC=CC=C1.C1=CC=CC=C1 XDLDASNSMGOEMX-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- JRPGECJKHZKZMO-UHFFFAOYSA-N diethyl 2-nonylpropanedioate Chemical compound CCCCCCCCCC(C(=O)OCC)C(=O)OCC JRPGECJKHZKZMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002546 isoxazolidines Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- PSYRMEZGAWNWHV-UHFFFAOYSA-N methyl 2-methylsulfanylpyrimidine-5-carboxylate Chemical compound COC(=O)C1=CN=C(SC)N=C1 PSYRMEZGAWNWHV-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- SWWHCQCMVCPLEQ-UHFFFAOYSA-N propan-2-yl methanesulfonate Chemical compound CC(C)OS(C)(=O)=O SWWHCQCMVCPLEQ-UHFFFAOYSA-N 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
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- B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
- B63B—SHIPS OR OTHER WATERBORNE VESSELS; EQUIPMENT FOR SHIPPING
- B63B1/00—Hydrodynamic or hydrostatic features of hulls or of hydrofoils
- B63B1/02—Hydrodynamic or hydrostatic features of hulls or of hydrofoils deriving lift mainly from water displacement
- B63B1/04—Hydrodynamic or hydrostatic features of hulls or of hydrofoils deriving lift mainly from water displacement with single hull
- B63B1/08—Shape of aft part
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02T—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO TRANSPORTATION
- Y02T70/00—Maritime or waterways transport
- Y02T70/10—Measures concerning design or construction of watercraft hulls
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Description
Fremgangsmåte til fremstilling av terapeutisk virksomme Process for the production of therapeutically active
Gjenstand for nærværende oppfinnelse er en fremgangsmåte for fremstilling av 3,5-diokso-isoksazolidiner og deres salter med baser. The subject of the present invention is a process for the production of 3,5-dioxo-isoxazolidines and their salts with bases.
I den ene tautomere form tilsvarer disse 3,5-dioksoisoksazolidiner den generelle formel: In one tautomeric form, these 3,5-dioxoisoxazolidines correspond to the general formula:
i hvilken hvert av symbolene R, R, og R2 betyr hydrogen, eller, en hydrocarbonrest som er fri for alifatisk umettede bindinger, under den forutsetning at minst et og høyst to av symbolene R, R, og R2 betyr hydrogen. in which each of the symbols R, R, and R2 represents hydrogen, or, a hydrocarbon residue free of aliphatic unsaturated bonds, provided that at least one and at most two of the symbols R, R, and R2 represent hydrogen.
Av særlig interesse er de 3,5-diokso-isoksazolidiner med formel I i hvilke hvert av symbolene R, R, og R2 betyr hydrogen eller en hydrocarbonrest med høyst 14 carbonatomer, som er fri for alifatiske umettede bindinger, og minst et, dog høyst to av symbolene R, R, og R2 står for hydrogen. Innenfor denne gruppe er særlig de 3,5-diokso-isoksazolidiner verdifulle, i hvilke R, R, og R2 tilsammen høyst inneholder 20 carbonatomer. Of particular interest are the 3,5-dioxo-isoxazolidines of formula I in which each of the symbols R, R, and R2 means hydrogen or a hydrocarbon residue with at most 14 carbon atoms, which is free of aliphatic unsaturated bonds, and at least one, but at most two of the symbols R, R, and R2 stand for hydrogen. Within this group, the 3,5-dioxo-isoxazolidines are particularly valuable, in which R, R, and R2 together contain no more than 20 carbon atoms.
For disse forbindelser kommer også de ved de etterstående formler gjengitte tautomere former på tale: For these compounds, the tautomeric forms reproduced by the following formulas also come into play:
De i foranstående formler med R, R1 og R2 betegnede hydrocarborester kan være meget forskjellige, f. eks. rettkjedede eller forgrenede alkylrester, særlig slike med inntil 10 carbonatomer; cykloalkylrester, som f. eks. cyklobutyl, cyklopentyl, cykloheksyl eller cykloheptyl; kjernesubstituerte cykloalkylrester, særlig slike med inntil 10 carbonatomer, som f. eks. 4-metyl-cykloheksyl, 4-etyl-cykloheksyl eller 2,6-dim-etyl-cykloheksyl; cykloalkylalkylrester, særlig slike med inntil 10 carbonatomer, som f. eks. cyklobutyl-metyl, cyklobutyl-etyl, l-metyl-2-cyklobutyl-etyl eller 5-cyklopentyl-n-pentyl; arylrester, som f. eks. fenyl, (3-naftyl, tolyl, p-etylfenyl, p-pro-pylfenyl, p-butylfenyl eller 2,6-dimetylfe-nyl; eller aralkylr ester, særlig slike med inntil 14 carbonatomer, som f. eks. benzyl, fenyletyl, fenylpropyl, fenylbutyl, 2-metyl-2-fenylpropyl eller benzhydryl. The hydrocarbon residues denoted by R, R1 and R2 in the above formulas can be very different, e.g. straight-chain or branched alkyl radicals, especially those with up to 10 carbon atoms; cycloalkyl residues, such as e.g. cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; core-substituted cycloalkyl residues, especially those with up to 10 carbon atoms, such as e.g. 4-methyl-cyclohexyl, 4-ethyl-cyclohexyl or 2,6-dim-ethyl-cyclohexyl; cycloalkylalkyl residues, especially those with up to 10 carbon atoms, such as e.g. cyclobutyl-methyl, cyclobutyl-ethyl, 1-methyl-2-cyclobutyl-ethyl or 5-cyclopentyl-n-pentyl; aryl residues, such as phenyl, (3-naphthyl, tolyl, p-ethylphenyl, p-propylphenyl, p-butylphenyl or 2,6-dimethylphenyl; or aralkyl esters, especially those with up to 14 carbon atoms, such as e.g. benzyl, phenylethyl , phenylpropyl, phenylbutyl, 2-methyl-2-phenylpropyl or benzhydryl.
Fremgangsmåten etter oppfinnelsen for fremstillingen av 3,5-diokso-isoksazoli-dinene er karakterisert ved at man acylerer under ringslutning en forbindelse med formlen: med et usubstituert eller substituert malonylhalogenid eller med carbonsuboxyd som avgir resten med formelen: The process according to the invention for the production of the 3,5-dioxo-isoxazolidines is characterized by acylating during ring closure a compound with the formula: with an unsubstituted or substituted malonyl halide or with carbon suboxide which gives off the residue with the formula:
at man, når acyleringsproduktet er usubstituert i 4-stilling, eventuelt innfører i denne stilling en hydrocarbonrest R, på i og for seg kjent måte, hvorved hvert av symbolene R, R, og R2 betyr en hydrocarbonrest, som er fri for alifatiske, umettede bindinger, og minst et, dog høyst to av de nevnte symboler står for hydrogen, og that, when the acylation product is unsubstituted in the 4-position, optionally a hydrocarbon residue R is introduced in this position, in a manner known per se, whereby each of the symbols R, R, and R2 means a hydrocarbon residue, which is free of aliphatic, unsaturated bonds, and at least one, but at most two of the aforementioned symbols stand for hydrogen, and
at man hvis ønsket overfører det erholdte substituerte 3,5-diokso-isoksazolidin med en base i et salt. that, if desired, the obtained substituted 3,5-dioxo-isoxazolidine is transferred with a base in a salt.
De for fremgangsmåten ifølge oppfinnelsen anvendte utgangsstoffer er almin-nelig kjent og kan fremstilles etter i og for seg kjente analogimetoder. Som usubstituerte eller substituerte malonyliseringsmid-ler er egnet funksjonelle derivater av ma-lonsyren hemn. av mono- eller disubstituerte malonsyrer, med hvilke det kan acyleres under milde betingelser, d.v.s. under betingelser, under hvilke de oppstående isoksazolidiner ikke ødelegges. Som egnet har vist seg halogenidene, f. eks. kloridene og bromidene, særlig de lett tilgjengelige klorider av malonsyrene, henh. av mono-eller disubstituerte malonsyrer, såvel som carbonsuboksyd. The starting materials used for the method according to the invention are generally known and can be prepared according to analogue methods known per se. Functional derivatives of the malonic acid hemen are suitable as unsubstituted or substituted malonylation agents. of mono- or disubstituted malonic acids, with which it can be acylated under mild conditions, i.e. under conditions under which the resulting isoxazolidines are not destroyed. The halides have proven to be suitable, e.g. the chlorides and bromides, especially the readily available chlorides of the malonic acids, acc. of mono- or disubstituted malonic acids, as well as carbon suboxide.
Fremgangsmåten etter oppfinnelsen er i prinsipp en acylering, ved hvilken hydroksylamin henh. N-monosubstituert hydroksylamin acyleres såvel ved N- som ved O-atomet og hvorved en ringslutning sam-tidig finner sted. The method according to the invention is in principle an acylation, in which hydroxylamine acc. N-monosubstituted hydroxylamine is acylated both at the N and at the O atom, whereby a ring closure takes place at the same time.
Ved N- og ved O-atomet acylerte hydroksylaminer med åpen kjede er kjent som termolabile forbindelser (se L. Horner og H. Steppan, Ann. 606, 24—47 (1957)). Det var derfor på ingen måte å forutse om de her beskrevne heterocykliske forbindelser i det hele tatt kunne eksistere. Det er på overraskende måte lykkes ved hjelp av acylerings- og ringslutningsreaksjonen ifølge oppfinnelsen å fremstille 3,5-diokso-isoksazolidiner, som. riktignok generelt li-kesom de sammenlignbare, allerede kjente N.O-diacylerte hydroksylaminer er termisk labile, men som dog er holdbare ved opp-rettholdelse av enkle forsiktighetforan-staltninger. Overfor de N.O-diacylerte hydroksylaminer skiller de nye forbindelser seg ut ved sine utpregede sure egenskaper. Open-chain hydroxylamines acylated at the N- and at the O-atom are known as thermolabile compounds (see L. Horner and H. Steppan, Ann. 606, 24-47 (1957)). It was therefore in no way predictable whether the heterocyclic compounds described here could exist at all. It is surprisingly successful by means of the acylation and ring closure reaction according to the invention to produce 3,5-dioxo-isoxazolidines, which. however, in general, like the comparable, already known N.O-diacylated hydroxylamines, they are thermally labile, but which are, however, durable when simple precautions are taken. Compared to the N.O-diacylated hydroxylamines, the new compounds stand out due to their pronounced acidic properties.
Ifølge en utførelsesform etter oppfinnelsen acyleres usubstituert eller N-monosubstituert ihydroksylamin med et usubstituert eller substituert malonylhalogenid, f. eks. et klorid eller bromid, i et organisk oppløsnings- eller fortynningsmiddel i nærvær av et syrebindende middel ved lave temperaturer, hensiktsmessig mellom —20 og +30° C og med fordel i en oksygenfri atmosfære, f. eks. i nitrogen. Som organisk oppløsnings- eller fortynningsmiddel kan man anvende hydrocarboner, som f. eks. benzol eller toluol; halogenerte hydrocarboner, som f. eks. kloroform; videre etre, som f. eks. dietyleter, og andre for acyleringen egnede oppløsningsmidler. Som syrebindende middel anvender man hensiktsmessig et organisk ikke acylerbart amin, f. eks. pyridin eller trietylamin. Omsetningen av det usubstituerte eller N-mo-nosubstituerte hydroksylamin med det usubstituerte eller substituerte malonylhalogenid kan også skje i vandig medium. I dette tilfelle anvender man med fordel et uorganisk syrebindende middel, f. eks. natriumhydrogencarbonat eller kalsiumkar-bonat. I vandig medium kan omsetningen gjennomføres ved romtemperatur. According to an embodiment according to the invention, unsubstituted or N-monosubstituted ihydroxylamine is acylated with an unsubstituted or substituted malonyl halide, e.g. a chloride or bromide, in an organic solvent or diluent in the presence of an acid-binding agent at low temperatures, suitably between -20 and +30° C and advantageously in an oxygen-free atmosphere, e.g. in nitrogen. Hydrocarbons can be used as organic solvents or diluents, such as e.g. benzene or toluene; halogenated hydrocarbons, such as chloroform; further ethers, such as diethyl ether, and other solvents suitable for the acylation. An organic non-acylatable amine is suitably used as an acid-binding agent, e.g. pyridine or triethylamine. The reaction of the unsubstituted or N-monosubstituted hydroxylamine with the unsubstituted or substituted malonyl halide can also take place in an aqueous medium. In this case, it is advantageous to use an inorganic acid-binding agent, e.g. sodium bicarbonate or calcium carbonate. In an aqueous medium, the reaction can be carried out at room temperature.
Ifølge en ytterligere utførelsesform for fremgangsmåten etter nærværende oppfinnelse anvender man som malonyliseringsmiddel carbonsuboksyd. Man lar car-bonsuboksydet hensiktsmessig innvirke i et inert, organisk medium, f. eks. i tetrahy-drofuran eller dietylenglykol-dimetyleter, ved moderate temperaturer, f. eks. mellom 10 og 60° C på et N-monosubstituert hydroksylamin. Ved denne fremgangsmåte får man 3,5-diokso-isoksazolidiner, som er usubstituerte i 4-stillingen. Disse forbindelser er verdifulle mellomprodukter for fremstillingen av andre terapeutisk virksomme 3,5-dioksy-isoksazolidiner. According to a further embodiment of the method according to the present invention, carbon suboxide is used as the malonylating agent. The carbon suboxide is suitably allowed to act in an inert, organic medium, e.g. in tetrahydrofuran or diethylene glycol dimethyl ether, at moderate temperatures, e.g. between 10 and 60° C on an N-monosubstituted hydroxylamine. This method gives 3,5-dioxo-isoxazolidines, which are unsubstituted in the 4-position. These compounds are valuable intermediates for the preparation of other therapeutically active 3,5-dioxy-isoxazolidines.
I de ved acylering av det N-suibstitu-erte hydroksylamin med et usubstituert malonyliseringsmiddel erholdte, i 4-stilling usubstituerte 3,5-diokso-isoksazolidiner kan man, hvis ønsket, i 4-stilling inn-føre en hydrocarbonrest R, ifølge foranstående definisjon. Denne substitusjon kan skje etter i og for seg kjente metoder, f. eks. ved omsetning med alkyl-, cykloalkyl-eller aralkylestre av sterke syrer, som f. eks. butylbromid, benzylklorid, dimetyl-sulfat, 2-metyl-cyklobutylmetylester av p-toluolsulfonsyre eller metansulfonsyre-iso-propylester, eller ved reduktiv kondensa-sjon med cartaonylforbindelser, som f. eks. benzaldéhyd eller cykloheksanon. In the 4-position unsubstituted 3,5-dioxo-isoxazolidines obtained by acylation of the N-substituted hydroxylamine with an unsubstituted malonylation agent, one can, if desired, introduce a hydrocarbon residue R in the 4-position, according to the above definition . This substitution can take place according to methods known per se, e.g. by reaction with alkyl, cycloalkyl or aralkyl esters of strong acids, such as e.g. butyl bromide, benzyl chloride, dimethyl sulfate, 2-methyl-cyclobutyl methyl ester of p-toluenesulfonic acid or methanesulfonic acid iso-propyl ester, or by reductive condensation with cartaonyl compounds, such as e.g. benzaldehyde or cyclohexanone.
Da de etter oppfinnelsen oppnåelige 3,5-diokso-isoksazolidiner har utpregede sure egenskaper lar de seg etter vanlige metoder ved omsetning med uorganiske eller organiske baser i ekvivalente mengder lett overføre i salter. De med alkalier, am-moniakk eller med organiske baser, som metylamin, etanolamin, dietanolamin, di-etylaminoetanol, trietylamin og morfolin, oppstående salter er for det meste farge-løse, lett vannoppløselige forbindelser, som løser seg i vann med praktisk talt neutral reaksjon. Det lar seg også lett fremstille salter med andre kationer. Jordalkalime-tallsaltene, f. eks. kalsium- og magnesium-saltene av de ifølge oppfinnelsen fremstilte forbindelser er for det meste tungtopp-løselige i vann. As the 3,5-dioxo-isoxazolidines obtainable according to the invention have pronounced acidic properties, they can easily be converted into salts by reaction with inorganic or organic bases in equivalent amounts according to usual methods. Those with alkalis, ammonia or with organic bases, such as methylamine, ethanolamine, diethanolamine, diethylaminoethanol, triethylamine and morpholine, the resulting salts are mostly colourless, easily water-soluble compounds, which dissolve in water of practically neutral reaction. It is also easy to prepare salts with other cations. The alkaline earth salts, e.g. the calcium and magnesium salts of the compounds produced according to the invention are mostly sparingly soluble in water.
De etter oppfinnelsen erholdelige 3,5-diokso-isoksazolidiner utmerker seg ved sin verdifulle biologiske virksomhet. De vir-ker inflamasjonshemmende, analgetisk eller lokalanestetisk og skal derfor anvendes i medisinen som legemidler, særlig for bekjempelse av sykdommer som begynner med inf lamas jonsprosesser, som f. eks. re-umatiske sykdommer. Med hensyn til den biologiske virksomhet står de nye stoffer de kjente pyrazoliderivater, antipyrin, 4-dimetylamlnoantipyrin og fenylbutazon nærmest. Sammenligningen av fenylbutazon f. eks. med 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazolidin har gitt at den infla-masj onshemmende og antireumatiske virkning av sistnevnte forbindelse ved samme dosering gjennomsnittlig er minst like sterk som den for fenylbutazonet, og at det siste er betydelig giftigere og forårsaker langt flere uønskede bivirkninger enn det The 3,5-dioxo-isoxazolidines obtainable according to the invention are distinguished by their valuable biological activity. They have an anti-inflammatory, analgesic or local anesthetic effect and are therefore to be used in medicine as pharmaceuticals, particularly for combating diseases that begin with inflammatory processes, such as e.g. rheumatic diseases. With regard to the biological activity, the new substances are closest to the known pyrazole derivatives, antipyrine, 4-dimethylamlnoantipyrine and phenylbutazone. The comparison of phenylbutazone e.g. with 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazolidine has shown that the anti-inflammatory and anti-rheumatic effect of the latter compound at the same dosage is on average at least as strong as that of phenylbutazone, and that the latter is significantly more toxic and causes far more unwanted side effects than that
■som eksempel anførte isoksazolidin. Særlig godt virksomme og lite giftige er de 3,5-diokso-isoksazolidiner, i hvilke R er fe-nylresten, R1 en hydrocarbonrest med 4—7 carbonatomer og R2 er hydrogen. ■as an example cited isoxazolidine. The 3,5-dioxo-isoxazolidines, in which R is the phenyl residue, R1 a hydrocarbon residue with 4-7 carbon atoms and R2 is hydrogen, are particularly effective and not toxic.
De nye 3,5-diokso-isoksazolidiner kan administreres som sådanne eller i form av sine salter med baser i fast form for terapeutiske formål oralt, f. eks. etter for-arbeiding til tabletter eller dragéer eller i gelatinkapsler. De vannoppløselige salter av 3,5-diokso-isoksazolidiner med baser kan administreres parenteralt. I de tilfeller i hvilke saltene ikke er ubegrenset holdbare i vandig oppløsning kan man for den parenterale administrering fylle det tør-rede salt i ampuller og løse det opp friskt i vann umiddelbart før injeksjonen. Man kan imidlertid også løse opp saltene i ikke-giftige oppløsningsmidler, i hvilke de er bestandige, f. eks. i propylenglykol eller po-lyetylenglykol. The new 3,5-dioxo-isoxazolidines can be administered as such or in the form of their salts with bases in solid form for therapeutic purposes orally, e.g. after processing into tablets or dragées or in gelatin capsules. The water-soluble salts of 3,5-dioxo-isoxazolidines with bases can be administered parenterally. In those cases in which the salts are not indefinitely stable in aqueous solution, for parenteral administration, the dried salt can be filled into ampoules and dissolved fresh in water immediately before the injection. However, the salts can also be dissolved in non-toxic solvents in which they are stable, e.g. in propylene glycol or polyethylene glycol.
Oppfinnelsen forklares i de etterføl-gende utførelseseksempler i hvilke tempe-raturene er angitt i Celsius-grader. The invention is explained in the subsequent examples in which the temperatures are indicated in degrees Celsius.
Eksempel 1. Example 1.
Under utelukkelse av fuktighet opp-varmes 12,8 g benzylmalonsyre med 25 ems tionylklorid i 2 timer under tilbakeløp. Det tiloversblevne tionylklorid fordampes derpå i delvis vakuum og den gule oljeaktige rest tas opp i 20 til 30 ems absolutt kloroform. While excluding moisture, 12.8 g of benzylmalonic acid are heated with 25 ems of thionyl chloride for 2 hours under reflux. The remaining thionyl chloride is then evaporated in partial vacuum and the yellow oily residue taken up in 20 to 30 ems of absolute chloroform.
1 løpet av 20 til 30 minutter tilsetter man dråpevis under utelukkelse av fuktighet i en nitrogenatmosfære denne oppløsning til et godt omrørt, til —10° kjølt blanding av 35 cm3 absolutt pyridin og 200 oms absolutt kloroform. Man tilsetter på engang 4,6 g hydroksylamin-hydroklorid og rører sammen i 1 time i et bad på 0° og derpå i 2 timer ved 20 til 25°. Hydroksylamin-hy-drokloridet går etter kort tid i oppløsning. For opparbeidelsen ryster man reaksjonsblandingen to ganger med 100 cm3 2-n saltsyre og derpå med 100 cm3 vann. Man trekker omsetningsproduktet ut av kloro-formoppløsningen ved å ryste ut tre ganger med 200 ems n-sodaoppløsning. De forenede sodaoppløsninger vaskes med litt eter, kjøles av fra 0 til 5° og gjøres kongosure med 6-n saltsyre. Den slik erholdte delvis kry-stallinske felling tas opp i eter, eteroppløs-ningen vaskes neutral med vann og tørkes med natriumsulfat. Den eteriske oppløs-ning, som inneholder 5,1 g råprodukt, filtreres ved en søyle av 15 g neutral aluminiumoksyd >av aktivitet Etter eluering med 300 cm» eter inndamper man ved høyst 40 til 50°, til slutt i vakuum ved romtemperatur. Resten består av 4-benzyl-3,5-diokso-isoksazolidin, som ved omkrystallisasjon fra benzol-bensin og eddiksyre-etylester-pertoleter kan oppnåes i analy-seren, fargeløs form med smeltepunkt 98 1 in the course of 20 to 30 minutes, this solution is added dropwise under the exclusion of moisture in a nitrogen atmosphere to a well-stirred, cooled to -10° mixture of 35 cm3 of absolute pyridine and 200 om of absolute chloroform. 4.6 g of hydroxylamine hydrochloride are added all at once and stirred for 1 hour in a bath at 0° and then for 2 hours at 20 to 25°. The hydroxylamine hydrochloride dissolves after a short time. For the preparation, the reaction mixture is shaken twice with 100 cm3 of 2-N hydrochloric acid and then with 100 cm3 of water. The reaction product is extracted from the chloroform solution by shaking out three times with 200 ems n-soda solution. The combined soda solutions are washed with a little ether, cooled from 0 to 5° and made congo acid with 6-n hydrochloric acid. The partially crystalline precipitate thus obtained is taken up in ether, the ether solution is washed neutrally with water and dried with sodium sulphate. The ethereal solution, which contains 5.1 g of crude product, is filtered through a column of 15 g of neutral alumina. The remainder consists of 4-benzyl-3,5-dioxo-isoxazolidine, which can be obtained by recrystallization from benzene-benzene and acetic acid-ethyl ester pertol ether in the analyzer, colorless form with melting point 98
—99° -99°
På den i eksempel 1 beskrevne måte kan under anvendelse av hydroksylamin-hydroklorid og de tilsvarende substituerte malonylhalogenider også følgende forbindelser fremstilles: In the manner described in example 1, using hydroxylamine hydrochloride and the corresponding substituted malonyl halides, the following compounds can also be prepared:
Eksempel 5. Example 5.
En oppløsning av 7,35 g a-fenyl-a-etyl-malonylklorid i 25 cm3 absolutt kloroform tilsettes dråpevis i løpet av 20 til 30 minutter under utelukkelse av fuktighet i en nitrogenatmosfære en omrørt, inntil —10° kjølt blanding av 15 ems absolutt pyridin og 100 cm3 absolutt kloroform. Man tilsetter 2,1 g hydroksylamin hydroklorid til den gulbrune oppløsning, som etter kort tid oppløser seg. Derpå røres om ytterligere i 4 timer ved 20 til 30°. Man ryster to ganger med 50 cm3 2-n saltsyre og en gang med vann. Derpå trekker man ut omsetningsproduktet fra kloroformoppløsnin-gen ved rysting tre ganger med 50 cm3 2-n sodaoppløsning. De forenede sodaopp-løsninger vaskes med eter, kjøles av til 0 til 5° og gjøres kongosure med 6-n saltsyre. Den utskilte olje tas opp i 200 cm3 eter, eteroppløsningen vaskes neutral med vann og tørkes med natriumsulfat. Den inneholder 4,5 g rødt 4-etyl-4-fenyl-3,5-diok-soisoksazolidin. For rensing filtreres den eteriske oppløsning ved en søyle av 22,5 g neutral aluminiumoksyd av aktivitet I og elueres med 300 crns eter. Etter inndamp-ning med høyst 40 til 50°, til slutt i vakuum ved romtemperatur, får man en far-geløs krystallinsk rest, som etter omkrystallisering fra bensin-benzol kan overfø-res i fargeløse krystaller med smeltepunkt 66 til 67°. A solution of 7.35 g of a-phenyl-a-ethyl-malonyl chloride in 25 cm3 of absolute chloroform is added dropwise over the course of 20 to 30 minutes under the exclusion of moisture in a nitrogen atmosphere to a stirred, cooled to -10° mixture of 15 ems absolute pyridine and 100 cm3 of absolute chloroform. 2.1 g of hydroxylamine hydrochloride is added to the yellow-brown solution, which dissolves after a short time. The mixture is then stirred for a further 4 hours at 20 to 30°. Shake twice with 50 cm3 of 2-N hydrochloric acid and once with water. The reaction product is then extracted from the chloroform solution by shaking three times with 50 cm3 of 2-n soda solution. The combined soda solutions are washed with ether, cooled to 0 to 5° and made congoacid with 6-n hydrochloric acid. The separated oil is taken up in 200 cm3 of ether, the ether solution is washed neutral with water and dried with sodium sulphate. It contains 4.5 g of red 4-ethyl-4-phenyl-3,5-dioxoisoxazolidine. For purification, the ethereal solution is filtered through a column of 22.5 g of neutral alumina of activity I and eluted with 300 crns of ether. After evaporation at no more than 40 to 50°, finally in vacuum at room temperature, a colorless crystalline residue is obtained, which after recrystallization from benzine-benzene can be transferred into colorless crystals with a melting point of 66 to 67°.
Ved den ovenfor beskrevne omsetning kan man i stedet for 'hydroksylamin-hydroklorid også anvende fritt hydroksylamin eller hydroksylaminsulfat og istedet for a-etyl-a-fenyl-malonylklorid anvende den ekvivalente mengde a-etyl-a-fenyl-malonylbromid. In the reaction described above, instead of hydroxylamine hydrochloride, free hydroxylamine or hydroxylamine sulfate can also be used, and instead of α-ethyl-α-phenyl-malonyl chloride, the equivalent amount of α-ethyl-α-phenyl-malonyl bromide can be used.
På den i eksempel 5 beskrevne måte kan under anvendelse av hydroksylamin-hydroklorid og de tilsvarende disubstituerte malonylhalogenider også fremstilles følgende forbindelser. In the manner described in example 5, using hydroxylamine hydrochloride and the corresponding disubstituted malonyl halides, the following compounds can also be prepared.
Eksempél 9. Example 9.
Under utelukkelse av fuktighet kokes 55,8 g cykloheksylrnalonsyre med 150 cm3 tionylklorid i 6 timer under tilbakeløp. Det tiloversblevne tionylklorid damper man derpå av i vakuum og fortynner den fly-tende gule rest, som består av cykloheksylmalonylklorid, med 50 cm» absolutt kloroform. Denne oppløsning tilsetter man dråpevis i løpet av 20 til 30 minutter under utelukkelse av fuktighet og oksygen i en nitrogenatmosfære en omrørt, fra —10 til —15° avkjølt blanding av 100 ems absolutt pyridin og 1000 oms absolutt kloroform. Til den slik erholdte, gulbrune oppløsning tilsetter man på en gang en oppslemming av 32,7 g N-fenylhydroksylamin i ca. 100 cm» absolutt kloroform, hvorved den gulbrune farge straks slår om til gul. Man rører en-nå en time under avkjøling med isvann og i to timer ved romtemperatur. Oppløsnin-gen rystes nå to ganger, hver gang med 600 cm3 2-n saltsyre og en gang med 500 ems vann, og derpå tre ganger, hver gang med 500 cm» 2-n sodaoppløsning. De forenede gule, noe uklare sodaoppløsninger vaskes med 250 ems eter, kjøles av méd isvann og gjøres kongosure med 6-n saltsyre. Den derved erholdte felling oppløses ved tilsetning av 1000 ems eter. Den med vann vaskede eteroppløsning tørkes over natriumsulfat og man damper eteren av ved høyst 40°, til slutt i vakuum ved romtemperatur. Resten veier 61,4 g og består av gullige krystaller. Disse kan renses ytterligere, idet de omkrystalliseres fra 60 om3 metanol. Man får på denne måte 58,0 g fargeløst 2-fenyl-4-cykloheksyl-3,5-di-oksoisoksazolidin med smeltepunkt 65° C. Den nye forbindelse kan ytterligere omkrystalliseres fra cykloheksan, hvorved smeltepunktet ikke forandres. With the exclusion of moisture, 55.8 g of cyclohexylrnanoic acid are boiled with 150 cm 3 of thionyl chloride for 6 hours under reflux. The remaining thionyl chloride is then evaporated off in a vacuum and the liquid yellow residue, which consists of cyclohexylmalonyl chloride, is diluted with 50 cm" of absolute chloroform. This solution is added dropwise over the course of 20 to 30 minutes under the exclusion of moisture and oxygen in a nitrogen atmosphere to a stirred, from -10 to -15° cooled mixture of 100 ems absolute pyridine and 1000 ems absolute chloroform. To the yellow-brown solution obtained in this way, a slurry of 32.7 g of N-phenylhydroxylamine is added at once in approx. 100 cm" of absolute chloroform, whereby the yellow-brown color immediately changes to yellow. The mixture is stirred for one hour while cooling with ice water and for two hours at room temperature. The solution is now shaken twice, each time with 600 cm3 of 2-N hydrochloric acid and once with 500 ems of water, and then three times, each time with 500 cm3 of 2-N soda solution. The combined yellow, somewhat cloudy soda solutions are washed with 250 ems ether, cooled with ice water and made congo acid with 6-n hydrochloric acid. The resulting precipitate is dissolved by adding 1000 ems of ether. The water-washed ether solution is dried over sodium sulphate and the ether is evaporated off at a maximum of 40°, finally in vacuum at room temperature. The rest weighs 61.4 g and consists of yellowish crystals. These can be purified further, as they are recrystallized from 60 om3 of methanol. In this way, 58.0 g of colorless 2-phenyl-4-cyclohexyl-3,5-dioxoisoxazolidine with a melting point of 65° C are obtained. The new compound can be further recrystallized from cyclohexane, whereby the melting point does not change.
Eksempel 10. Example 10.
Til en med is-koksalt avkjølt blanding på 11 cm» absolutt pyridin og 300 ems absolutt eter tilsetter man dråpevis under utelukkelse av fuktighet og oksygen i en nitrogenatmosfære under omrøring 11,8 g n-butylmalonylklorid, hvorved en lysegul felling danner seg. Man tilsetter nå fort 6,6 g N-fenylhydroksylamin til 50 ems absolutt eter og rører om i tre timer under avkjøling i et isvannbad og i en time ved romtemperatur. Oppslemmingens gule farge forsvinner, og det danner seg et hvitt bunnfall. Reaksjonsblandingen vaskes med 100 ems og derpå to ganger hver gang med 50 cm.3 2-n saltsyre, og med 50 cm3 vann. Den slik rensede eteroppløsning rystes derpå tre ganger med 50 cm» 2-n sodaoppløsning. De forenede alkaliske opp-løsninger vaskes med kloroform og gjøres derpå kongosure med 2-n saltsyre under avkjøling med isvann. Den oljeaktige utskillelse som oppnåes ved dette tar man opp i 100 cm<3> eter og ryster den sure vandige oppløsning ennå to ganger med 50 ems eter. De med natriumsulfat tørkede, forenede eteroppløsninger dampes inn i vakuum, hvorved man får 10,9 g av en gul To a mixture of 11 cm" of absolute pyridine and 300 ems of absolute ether cooled with ice-cold salt, 11.8 g of n-butylmalonyl chloride are added dropwise under the exclusion of moisture and oxygen in a nitrogen atmosphere with stirring, whereby a pale yellow precipitate forms. 6.6 g of N-phenylhydroxylamine is now quickly added to 50 ems of absolute ether and stirred for three hours while cooling in an ice water bath and for one hour at room temperature. The yellow color of the slurry disappears and a white precipitate forms. The reaction mixture is washed with 100 ems and then twice each time with 50 cm.3 2-n hydrochloric acid, and with 50 cm3 of water. The thus purified ether solution is then shaken three times with 50 cm" of 2-n soda solution. The combined alkaline solutions are washed with chloroform and then made congoacid with 2-n hydrochloric acid while cooling with ice water. The oily secretion obtained by this is taken up in 100 cm<3> of ether and the acidic aqueous solution is shaken twice more with 50 ems of ether. The combined ether solutions, dried with sodium sulfate, are evaporated in vacuo, whereby 10.9 g of a yellow
20 20
olje med brytningsindeks n — = 1,5370. oil with refractive index n — = 1.5370.
Man oppløser denne olje i 150 cm» petroleter, filtrerer oppløsningen over en søyle av 100 g aluminiumoksyd med aktivitetstrinnet I og eluerer tre ganger, hver gang med 150 cm.3 petroleter. Man damper nå elua-tet inn i vakuum og tørker resten i seks timer ved romtemperatur i høyvakuum. Denne veier 4,2 g, viser en brytningsin-20 This oil is dissolved in 150 cm3 of petroleum ether, the solution is filtered over a column of 100 g aluminum oxide with activity level I and eluted three times, each time with 150 cm3 of petroleum ether. The eluate is now evaporated in a vacuum and the residue is dried for six hours at room temperature in a high vacuum. This weighs 4.2 g, shows a refractive index of 20
deks på n — = 1,5395 og består av analyserent 2-fenyl-4-n-butyl-3,5-diokso-isoksazolidin. Den nye forbindelse krystalliserer ved lengere henstand ved 10 til 20°. Disse krystaller smelter ved ca. 25°. De er ikke bestandige ved høyere temperaturer og kan derfor ikke destilleres uspaltet i høyva-kuum. dex of n — = 1.5395 and consists of analytically pure 2-phenyl-4-n-butyl-3,5-dioxo-isoxazolidine. The new compound crystallizes on longer standing at 10 to 20°. These crystals melt at approx. 25°. They are not stable at higher temperatures and therefore cannot be distilled unsplit in high vacuum.
Eksempel 11. Example 11.
Man tilsetter dråpevis en blanding av 9,2 ems trietylamin og 10 cm3 absolutt kloroform under utelukkelse av fuktighet og luftoksygen i en nitrogenatmosfære til en omrørt, inntil —10° avkjølt oppløsning av 2,8 g malonylklorid og 2,2 g N-fenylhydroksylamin i 100 cm3 absolutt kloroform. Man rører derpå blandingen i en time ved 0 til 5° og i to timer ved 20 til 30°. Den brune oppløsning rystes med 50 om3 2-n saltsyre og derpå ennå to ganger, hver gang med 20 cm» 2-n saltsyre og en gang med 25 cm<3 >vann. Man trekker omsetningsproduktet ut ved tre gangers rysting med 25 ems so-daoppløsning, vasker denne med litt eter, kjøler av til 0° og gjør denne kongosur med 2-n saltsyre. Den slik erholdte felling nutsjes, vaskes med vann og tørkes i vakuum-eksikkator over fosforpentoksyd. De brune krystaller veier 1,7 g og smelter ved 118— 128°. For rensing oppløser man dem i kloroform, filtrerer oppløsningen ved en søyle av den 5-dobbelte mengde neutralt aluminiumoksyd av aktivitetstrinnet I og eluerer med 100 ems kloroform. A mixture of 9.2 ems of triethylamine and 10 cm3 of absolute chloroform is added dropwise under the exclusion of moisture and atmospheric oxygen in a nitrogen atmosphere to a stirred, cooled to -10° solution of 2.8 g of malonyl chloride and 2.2 g of N-phenylhydroxylamine in 100 cm3 of absolute chloroform. The mixture is then stirred for one hour at 0 to 5° and for two hours at 20 to 30°. The brown solution is shaken with 50 om3 of 2-N hydrochloric acid and then two more times, each time with 20 cm» of 2-N hydrochloric acid and once with 25 cm<3> of water. The reaction product is extracted by shaking three times with 25 ems soda solution, washed with a little ether, cooled to 0° and made congo acid with 2-N hydrochloric acid. The precipitate obtained in this way is ground, washed with water and dried in a vacuum desiccator over phosphorus pentoxide. The brown crystals weigh 1.7 g and melt at 118-128°. For purification, they are dissolved in chloroform, the solution is filtered through a column of 5 times the amount of neutral aluminum oxide of activity step I and eluted with 100 ems chloroform.
Den etter fjerning av kloroformen til-bakeblivende rest er lett krystalliserbar fra benzol-bensin og fra metanol. Det ana-lyserene, fargeløse 2-fenyl-3,5-diokso-isoksazolidin smelter ved 132!—133°. The residue remaining after removal of the chloroform is easily crystallizable from benzene-gasoline and from methanol. The analysers, colorless 2-phenyl-3,5-dioxo-isoxazolidine melt at 132!—133°.
Den samme forbindelse kan også oppnåes når man rører 0,5 g fenylhydroxyl-amin i 10 ml absolutt eter ved ca. —80°, og temmelig fort tilsetter en likeledes dyp-kjølt oppløsning av 0,4 g carbonsutooxyd i eter. Man lar reaksjonsblandingen langsomt oppvarme til 0° og lar henstå over natt ved denne temperatur. Ved å nutsje av de utfallende krystaller og vasking med litt kold eter, får man 0,58 g rent 2-fenyl-3,5-dioxo-isoxazolidin. Ved ekstrahering av moderluten med 2-n sodaoppløsning og ansyring med saltsyre ved 0°, får man ytterligere mengder av den nye forbindelse i krystallinsk form. The same compound can also be obtained when stirring 0.5 g of phenylhydroxylamine in 10 ml of absolute ether at approx. -80°, and rather quickly add a similarly deep-cooled solution of 0.4 g of carbon dioxide in ether. The reaction mixture is allowed to slowly warm to 0° and allowed to stand overnight at this temperature. By sifting off the precipitated crystals and washing with a little cold ether, 0.58 g of pure 2-phenyl-3,5-dioxo-isoxazolidine is obtained. By extracting the mother liquor with 2-n soda solution and acidifying with hydrochloric acid at 0°, additional amounts of the new compound are obtained in crystalline form.
Eksempel 12. Example 12.
5,16 g cyklopentylmalonsyre overføres ved kokning med 15 cm3 tionylklorid i di-kloridet. Som beskrevet i eksempel 9 om-setter man dette med 3,3 g N-fenyl-hydroksylamin og isolerer reaksjonsproduktet på samme måte. Etter omkrystallisering fra metanol får man 4,9 g fargeløst 2-fenyl-4-cyklopentyl-3,5-diokso-isoksazolidin,som smelter med 34-35°. 5.16 g of cyclopentylmalonic acid is transferred by boiling with 15 cm3 of thionyl chloride in the dichloride. As described in example 9, this is reacted with 3.3 g of N-phenyl-hydroxylamine and the reaction product is isolated in the same way. After recrystallization from methanol, 4.9 g of colorless 2-phenyl-4-cyclopentyl-3,5-dioxo-isoxazolidine are obtained, melting at 34-35°.
Eksempel 13. Example 13.
Som beskrevet i eksempel 9 omsettes fenylmalonylklorid (oppnådd fra 10,8 g fenylmalonsyre og 30 cm» tionylklorid) med 6,6 g N-fenylhydroksylamin. Etter opparbeidelse av reaksjonsblandingen får man det nye 2,4-difenyl-3,5-diokso-isoksazolin i et utbytte på 6,6 g. Den nye forbindelse er krystallinsk og krystaliserbar fra eddikester eller aceton. Den smelter ved 108— 109° under spaltning. As described in example 9, phenylmalonyl chloride (obtained from 10.8 g of phenylmalonic acid and 30 cm" of thionyl chloride) is reacted with 6.6 g of N-phenylhydroxylamine. After working up the reaction mixture, the new 2,4-diphenyl-3,5-dioxo-isoxazoline is obtained in a yield of 6.6 g. The new compound is crystalline and can be crystallized from acetic acid or acetone. It melts at 108-109° during decomposition.
Eksempel 14. Example 14.
(Cyklopentyl) -malonylklorid (oppnådd fra 5,58 g (cyklopemtylmetyl)-malonsyre og 15 ems tionylklorid omsettes, som beskrevet i eksempel 9, med 3,3 g N-fenylhydroksylamin. Etter opparbeidelse av reaksjonsblandingen får man 4,15 g fra metanol av omkrystallisert 2-fenyl-4-cyklopentylme-tyl-3,5-diokso-isoksazolidin i form av far-geløse krystaller, som smelter ved 64 til 65°. (Cyclopentyl)-malonyl chloride (obtained from 5.58 g of (cyclopemthylmethyl)-malonic acid and 15 ems thionyl chloride is reacted, as described in example 9, with 3.3 g of N-phenylhydroxylamine. After working up the reaction mixture, 4.15 g are obtained from methanol of recrystallized 2-phenyl-4-cyclopentylmethyl-3,5-dioxo-isoxazolidine in the form of colorless crystals, melting at 64 to 65°.
Eksempel 15. Example 15.
7,5 g n-heksylmalonsyre overføres ved kokning med 15 cm3 tionylklorid i kloridet. Etter fjerning av det overskytende tionylklorid cykliseres n-heksylmalonylkloridet, som beskrevet i eksempel 9, med 4,4 g N-fenylhydroksylamin. Ved opparbeidelse av reaksjonsblandingen krystalliserer 2-fenyl-4-n-heksyl-3,5-diokso-isoksazolinet ut fra den ansyrende vandige sodaoppløsning. Etter omkrystallisasjon fra metanol får man 4,95 g isoksazolidinforbindelse i form av fargeløse krystaller, som smelter ved 45 til 46°. 7.5 g of n-hexylmalonic acid is transferred by boiling with 15 cm3 of thionyl chloride in the chloride. After removal of the excess thionyl chloride, the n-hexylmalonyl chloride is cyclized, as described in Example 9, with 4.4 g of N-phenylhydroxylamine. When working up the reaction mixture, the 2-phenyl-4-n-hexyl-3,5-dioxo-isoxazoline crystallizes from the acidifying aqueous soda solution. After recrystallization from methanol, 4.95 g of the isoxazolidine compound are obtained in the form of colorless crystals, which melt at 45 to 46°.
Eksempel 16. Example 16.
På den i eksempel 9 beskrevne måte får man fra 6,0 g (cykloheksylmetyl)-malonsyre, 15 cm3 tionylklorid og 3,3 g N-fenylhydroksylamin 5,2 g analyserent 2-fenyl-4-cykloheksylmetyl-3,5-diokso-isoksazolidin i form av gullige krystaller, ,som smelter ved 79—80°. Den nye forbindelse kan lett omkrystalliseres fra metanol eller cykloheksan. In the manner described in example 9, 5.2 g of analytically pure 2-phenyl-4-cyclohexylmethyl-3,5-dioxo- isoxazolidine in the form of yellowish crystals, which melt at 79-80°. The new compound can be easily recrystallized from methanol or cyclohexane.
Eksempel 17. Example 17.
I en nitrogenatmosfære rører man energisk om under utelukkelse av oksygen 2,2 g N-fenylhydroksylamin med 50 cm3 benzol og 120 ems vandig mettet natrium-hydrogenkarbonatoppløsning. Man tilsetter langsomt og dråpevis en oppløsning av 4,62 g benzylmalonylklorid i 5 ems absolutt benzol og rører godt om over natt. Omsetningen gjennomføres ved romtemperatur. Ingen temperaturendring som er forårsaket av reaksjonen kan iakttas. Man blander med 25 cm3 benzol, skiller det vandige sjikt fra og ryster benzoloppløsningen ennå to ganger, hver gang med 2-n saltsyre. De forenede vandige sjikter vaskes med litt eter og gjøres kongosure med saltsyre under isavkjøling. Den oljeaktige utskillelse tas opp i 100 ems eter, og man får etter vasking med vann, tørking og fjerning av eteren en rest på 5,15 g. Denne er delvis kry-stalinsk og brunfarget. Ved omkrystallisasjon fra litt metanol får man rent 2-fenyl-4-benzyl-3,5-diokso-isoksazolidin i form av svakt gullige krystaller med smeltepunkt 81 til 83°. In a nitrogen atmosphere, 2.2 g of N-phenylhydroxylamine with 50 cm 3 of benzene and 120 ems of aqueous saturated sodium bicarbonate solution are vigorously stirred under the exclusion of oxygen. A solution of 4.62 g of benzylmalonyl chloride in 5 ems of absolute benzene is added slowly and dropwise and stirred well overnight. The turnover is carried out at room temperature. No temperature change caused by the reaction can be observed. Mix with 25 cm3 of benzene, separate the aqueous layer and shake the benzene solution twice more, each time with 2N hydrochloric acid. The combined aqueous layers are washed with a little ether and acidified with hydrochloric acid under ice-cooling. The oily secretion is taken up in 100 ems of ether, and after washing with water, drying and removing the ether, a residue of 5.15 g is obtained. This is partly crystalline and brown in colour. By recrystallization from a little methanol, pure 2-phenyl-4-benzyl-3,5-dioxo-isoxazolidine is obtained in the form of slightly yellowish crystals with a melting point of 81 to 83°.
På samme måte som de i de ovenfor nevnte eksempler 9—17 beskrevne forbindelser kan også de i følgende tabell sam-menfattede substanser fremstilles: In the same way as the compounds described in the above-mentioned examples 9-17, the substances summarized in the following table can also be prepared:
Eksempel 28. Example 28.
6,4 g n-butylmalonsyre kokes under til-bakeløp i noen timer med tionylklorid under utelukkelse av fuktighet. Etter fjerning av det overskytende tionylklorid i vakuum tas resten opp i 25 ems absolutt kloroform og tilsettes dråpevis under omrøring ved ca. —10° i 200 cm3 absolutt kloroform og 15 cm3 absolutt pyridin. Man tilsetter derpå 6,36 g a-naftylhydroksylamin, rører blandingen i kort tid under isavkjøling og derpå ytterligere i tre timer ved romtemperatur. Som beskrevet i eksempel 9 trekker man pyridinet og andre sideprodukter ut fra kloroformoppløsningen med 2-n- saltsyre 6.4 g of n-butylmalonic acid are refluxed for a few hours with thionyl chloride to the exclusion of moisture. After removal of the excess thionyl chloride in vacuum, the residue is taken up in 25 ems absolute chloroform and added dropwise with stirring at approx. —10° in 200 cm3 absolute chloroform and 15 cm3 absolute pyridine. 6.36 g of α-naphthylhydroxylamine is then added, the mixture is stirred for a short time under ice cooling and then for a further three hours at room temperature. As described in example 9, the pyridine and other side products are extracted from the chloroform solution with 2-n-hydrochloric acid
og derpå omsetningsproduktet med l-n sodaoppløsning. Man tar den ved ansyrin-gen av sodaoppløsningen oppstående felling opp i 200 cm3 eter, vasker oppløsnin-gen med vann og tørker den med natriumsulfat. Den etter fjerning av eteren tilbake-blivende rest består av 4,5 g av en brunlig krystallinsk masse av rått 2-a-naftyl-4-bu-tyl-3,5-diokso-isoksazolidinet. Por rensing kan man oppta massen i eter og filtrere oppløsningen ved en søyle av 20 g nøytralt aluminiumoksyd med aktivitetstrinnet I. Ved eluering med eter får man fargeløse nåleformede krystaller med smeltepunkt 208—209°. Smeltepunktet er etter omkrystallisasjon fra eddikester-petroeter eller metanol uforandret. and then the turnover product with l-n soda solution. The precipitate formed by acidizing the soda solution is taken up in 200 cm3 of ether, the solution is washed with water and dried with sodium sulphate. The residue remaining after removal of the ether consists of 4.5 g of a brownish crystalline mass of crude 2-a-naphthyl-4-butyl-3,5-dioxo-isoxazolidine. For purification, the mass can be taken up in ether and the solution filtered through a column of 20 g of neutral aluminum oxide with activity level I. Elution with ether gives colorless needle-shaped crystals with a melting point of 208-209°. The melting point is unchanged after recrystallization from acetic ester-petroleum or methanol.
For fremstillingen av en vandig opp-løsning av natriumsaltet kan man oppløse den nye forbindelse i kokende metanol, avkjøle oppløsningen til romtemperatur og tilsette 1 mol vandig natriumhydroksyd-oppløsning til den slik erholdte krystall-oppslemming. Metanolen fjernes i vakuum ved romtemperatur og det blir en klar vandig oppløsning tilbake. For the preparation of an aqueous solution of the sodium salt, one can dissolve the new compound in boiling methanol, cool the solution to room temperature and add 1 mol of aqueous sodium hydroxide solution to the thus obtained crystal slurry. The methanol is removed in vacuo at room temperature and a clear aqueous solution remains.
Eksempel 29. Example 29.
11,5 g n-nonyl-malonsyre kokes under tilbakeløp med 25 cm3 tionylklorid i iy2 time under utelukkelse av fuktighet. Det overskytende tionylklorid fjernes i vakuum. Man tar resten opp i 25 ems absolutt kloroform og tilsetter dråpevis oppløsningen under omrøring til en til —10° kjølt blanding av 20 cm3 absolutt pyridin og 150 cm3 absolutt kloroform. Man tilsetter nå 5,45 g N-fenylhydroksylamin, slemmer opp i litt absolutt kloroform og rører først om ved 0° og derpå ved 20 til 30° i ennå noen timer. Pyridinet trekkes ut fra kloroformoppløs-ningen ved rysting flere ganger med 2-n saltsyre. Man ryster derpå tre ganger med 100 oms sodaopplysning og ansyrer denne med 6-n saltsyre etter vasking med litt eter. Det i krystallinsk form utfelte råprodukt nutsjes og vaskes med vann. Det veier 12,55 g og kan oppnåes ved omkrystallisering fra metanol i form av rene fargeløse krystaller, som smelter ved 44°. Det slik 11.5 g of n-nonyl-malonic acid are refluxed with 25 cm 3 of thionyl chloride for 1/2 hour while excluding moisture. The excess thionyl chloride is removed in vacuo. The residue is taken up in 25 ems of absolute chloroform and the solution is added dropwise with stirring to a mixture cooled to -10° of 20 cm3 of absolute pyridine and 150 cm3 of absolute chloroform. 5.45 g of N-phenylhydroxylamine are now added, dissolved in a little absolute chloroform and stirred first at 0° and then at 20 to 30° for a few more hours. The pyridine is extracted from the chloroform solution by shaking several times with 2-n hydrochloric acid. The mixture is then shaken three times with 100 om of soda solution and acidified with 6-n hydrochloric acid after washing with a little ether. The crude product precipitated in crystalline form is ground and washed with water. It weighs 12.55 g and can be obtained by recrystallization from methanol in the form of pure colorless crystals, which melt at 44°. That way
erholdte 2-fenyl-4-n-nonyl-3,5-diokso-isoksazolidin er lett oppløselig i benzol, petroleter og eddikester. The 2-phenyl-4-n-nonyl-3,5-dioxo-isoxazolidine obtained is easily soluble in benzene, petroleum ether and acetic acid.
Den ved ovenfor nevnte omsetning anvendte n-nonylmalonsyre kan man fremstille på følgeride^måte: Man oppløser 33,5 g n-nonyl-malonsyredietylester i 50 ems etanol, tilsetter en opløsning av 18,5 g ka-liumhydroksyd i 50 cm3 vann og koker under tilbakeløp i % time. Alkoholen destilleres av ved forminsket trykk, den vandige oppløsning gjøres kongosur under iskjø- The n-nonylmalonic acid used in the above-mentioned reaction can be prepared as follows: 33.5 g of n-nonylmalonic acid diethyl ester is dissolved in 50 ems of ethanol, a solution of 18.5 g of potassium hydroxide in 50 cm3 of water is added and boiled during reflux for % hour. The alcohol is distilled off under reduced pressure, the aqueous solution is made Congolese under ice
ling og ekstraheres to ganger med 100 om3 ling and extracted twice with 100 om3
eter. Den med litt vann vaskede eteropp-løsning tørkes med natriumsulfat og dam- ether. The ethereal solution washed with a little water is dried with sodium sulfate and dam-
pes inn. Man får en krystallinsk rest, som man omkrystalliserer fra bensin. Den slik erholdte n-nonyl-malonsyre danner farge- pee in. You get a crystalline residue, which you recrystallize from gasoline. The n-nonyl-malonic acid thus obtained forms color-
løse krystaller og smelter under spaltning ved 99 til 102°. Ved den elektrometriske ti-trering får man den beregnede verdi. loose crystals and melts with decomposition at 99 to 102°. The calculated value is obtained by the electrometric titration.
Eksempel 30. Example 30.
Dietylaminoetanolsalt av 2-fenyl-4-cykloheksyl-3,5-dioksoisoksazolidinet Diethylaminoethanol salt of 2-phenyl-4-cyclohexyl-3,5-dioxoisoxazolidine
i vandig oppløsning. in aqueous solution.
2,59 g av det i eksempel 9 beskrevne 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazoli- 2.59 g of the 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazoli-
din røres om med 10,5 cm3 l-n dietylamino-etanoloppløsning og med 9 cm3 vann, hvor- your is stirred with 10.5 cm3 l-n diethylamino-ethanol solution and with 9 cm3 water, where-
ved man etter kort tid ved romtemperatur får en klar oppløsning. Denne fortynnes til 25,9 ems og kan anvendes i medisinen etter filtrering ved et bakteriefilter for parente- when a clear solution is obtained after a short time at room temperature. This is diluted to 25.9 ems and can be used in medicine after filtering with a bacterial filter for parenteral
ral applikasjon. Oppløsningen reagerer surt på fenylftalein og skiler det ut, ved an- ral application. The solution reacts acidic to phenylphthalein and separates it, on
syring med mineralsyre ved 0 til 20°, 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazoli- acidification with mineral acid at 0 to 20°, 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazoli-
dinet i krystallinsk form. dined in crystalline form.
Eksempel 31. Example 31.
Natriumsalt av 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazolidinet i fast form. Sodium salt of 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazolidine in solid form.
Man gjør 2,59 g 2-fenyl-4-cykloheksyl-3,5-diokso isoksazolidin deigaktig med litt absolutt metanol og tilsetter langsomt un- 2.59 g of 2-phenyl-4-cyclohexyl-3,5-dioxo isoxazolidine is made pasty with a little absolute methanol and slowly added un-
der avkjøling med isvann og under utelukkelse av fuktighet 2 cm3 5-n natrium-etylatoppløsning i metanol. pH for den slik erholdte klare oppløsning skal være 8 til 8,5. Om nødvendig innstilles pH på denne verdi ved tilsetning av natriummetylatopp-løsning henh. av 2-fenyl-4-cykloheksyl-3,5-dioksoisoksazolidin. Man damper nå inn til tørhet ved høyst ca. 20° i vakuum og får ved dette en pulveraktig, hvit rest. Denne utgjør natriumsaltet av 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazolidin, som er hy-droskopisk og derfor må oppbevares under utelukkelse av fuktighet. where cooling with ice water and under the exclusion of moisture 2 cm 3 5-n sodium ethylate solution in methanol. The pH of the clear solution thus obtained should be 8 to 8.5. If necessary, the pH is adjusted to this value by adding sodium methyl atom solution acc. of 2-phenyl-4-cyclohexyl-3,5-dioxoisoxazolidine. It is now evaporated to dryness at a maximum of approx. 20° in vacuum and thereby obtains a powdery, white residue. This constitutes the sodium salt of 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazolidine, which is hydroscopic and must therefore be stored under the exclusion of moisture.
For å fastslå om den organiske forbin- To determine whether the organic compound
delse ikke er blitt spaltet ved behandlingen med natriummetylat og ved lagringen ble en prøve oppløst i destillert vann etter lag- part has not been split during the treatment with sodium methylate and during storage a sample was dissolved in distilled water after layer-
ring i 1 måned. Fra denne klare oppløsning kunne ved ansyring med mineralsyre en hvit krystallinsk felling oppnåes, som etter call for 1 month. From this clear solution a white crystalline precipitate could be obtained by acidification with mineral acid, as follows
engangsomkrystallisasjon fra litt metanol ga ensartede krystaller med smeltepunkt 65°. Blandingssmeltepunktet viste ingen depressjon med autentisk 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazolidin. single recrystallization from a little methanol gave uniform crystals with melting point 65°. The mixture melting point showed no depression with authentic 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazolidine.
Eksempel 32. Example 32.
5,5 g fenylhydroksylamin røres om i Stir in 5.5 g of phenylhydroxylamine
60 ml metylenklorid under utelukkelse av 60 ml of methylene chloride to the exclusion of
fuktighet, den indre temperatur holdes ved ytre avkjøling pø 0—10° og i løpet av 10 humidity, the internal temperature is maintained by external cooling at 0-10° and within 10
min. tilsettes dråpevis en blanding av 11,2 my. a mixture of 11.2 is added dropwise
g cykloheksylmalonylklorid (kp. 106—108°) g cyclohexylmalonyl chloride (bp. 106—108°)
og 15 ml metylenklorid. Klorhydrogen ut- and 15 ml of methylene chloride. Chlorine hydrogen out-
vikles, hvilket for størstedelens vedkom-mende kan fjernes ved innledning av nitro- is wound, which for the most part can be removed by introducing nitro-
gen. Man rører ennå om i 15 min. ved 0— gen. Stir again for 15 minutes. at 0—
5° og derpå 1 time ved 20°. 5° and then 1 hour at 20°.
Hovedmengden metylenklorid fjerner The main amount of methylene chloride removes
man i vakuum og har resten opp i 50 ml eter. Eteroppløsningen ryster man 2 gan- under vacuum and dissolve the residue in 50 ml of ether. The ether solution is shaken twice
ger efter hverandre med 50 ml vann og 40 successively with 50 ml of water and 40
ml 2 n kaliumkarbonatoppløsning og derpå ennå 2 ganger med 40 ml n-kaliumkarbonat-oppløsning. Alle alkaliske vandige sjikt vaskes i en annen skilletrakt med 50 ml frisk eter og innstilles med 6n saltsyre på ml 2 n potassium carbonate solution and then 2 more times with 40 ml n-potassium carbonate solution. All alkaline aqueous layers are washed in another separatory funnel with 50 ml of fresh ether and adjusted with 6N hydrochloric acid on
pH 3—4. Det skiller seg da ut en olje, som efter noen tid stivner til en krystallmasse. pH 3-4. An oil then separates, which after some time solidifies into a crystalline mass.
Man metsjer av vasker nøytralt med vann Wash off sinks neutrally with water
og tørrer resten ved 20° over fosforpentok- and dries the residue at 20° over phosphorus pentoc-
syd. Man får 13 g rått 2-fenyl-4-cykloheksyl-3,5-diokso-isoksazolidin, som efter en gangs omkrystallisasjon fra 20 ml metanol under avkjøling til —17° oppnår f arveløse krystaller med smp. 65° og i et utbytte på 11 g. south. 13 g of crude 2-phenyl-4-cyclohexyl-3,5-dioxo-isoxazolidine are obtained, which after a single recrystallization from 20 ml of methanol while cooling to -17° yield colorless crystals with m.p. 65° and in a yield of 11 g.
Claims (3)
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NO132307C NO132307C (en) | 1975-10-22 |
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DE (1) | DE2019219A1 (en) |
ES (1) | ES378670A1 (en) |
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NO (1) | NO132307C (en) |
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US4286537A (en) * | 1979-01-10 | 1981-09-01 | Hvide J Erik | Seagoing separable tug and barge construction |
DE102004054061B4 (en) * | 2004-11-05 | 2017-10-12 | Siemens Aktiengesellschaft | Sea going ship |
WO2008099462A1 (en) * | 2007-02-13 | 2008-08-21 | Mitsubishi Heavy Industries, Ltd. | Stern shape of displacement type ship |
JP2011098639A (en) * | 2009-11-05 | 2011-05-19 | Mitsubishi Heavy Ind Ltd | Stern structure of marine vessel |
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US1779041A (en) * | 1928-01-26 | 1930-10-21 | Hogner Einar Gustaf Evald | Hull of ships |
US2729182A (en) * | 1950-06-03 | 1956-01-03 | Giovanni B Tommasi | Ship's hull having forked canal in bottom |
CH474401A (en) * | 1967-05-31 | 1969-06-30 | Sulzer Ag | Seaworthy ship |
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