NL8201970A - Process for the preparation of cyclic alpha-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol, as well as alpha-amino derivatives of 2-substituted 1- (3, 4'-methylenedioxyphenyl). - Google Patents
Process for the preparation of cyclic alpha-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol, as well as alpha-amino derivatives of 2-substituted 1- (3, 4'-methylenedioxyphenyl). Download PDFInfo
- Publication number
- NL8201970A NL8201970A NL8201970A NL8201970A NL8201970A NL 8201970 A NL8201970 A NL 8201970A NL 8201970 A NL8201970 A NL 8201970A NL 8201970 A NL8201970 A NL 8201970A NL 8201970 A NL8201970 A NL 8201970A
- Authority
- NL
- Netherlands
- Prior art keywords
- methylenedioxyphenyl
- formula
- ethanol
- spectrum
- piperazinyl
- Prior art date
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims description 49
- 238000000034 method Methods 0.000 title claims description 15
- 125000004122 cyclic group Chemical group 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- -1 benzylpiperazinyl Chemical group 0.000 claims description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 231100000252 nontoxic Toxicity 0.000 claims description 6
- 230000003000 nontoxic effect Effects 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000002198 insoluble material Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 239000006286 aqueous extract Substances 0.000 claims 1
- 238000009835 boiling Methods 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 239000012452 mother liquor Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000002329 infrared spectrum Methods 0.000 description 50
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 30
- 229960005141 piperazine Drugs 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000000921 elemental analysis Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BMHMKWXYXFBWMI-UHFFFAOYSA-N 3,4-Methylenedioxyacetophenone Chemical compound CC(=O)C1=CC=C2OCOC2=C1 BMHMKWXYXFBWMI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JDPDLMITLVAWKZ-UHFFFAOYSA-N 1,3-dioxolan-4-yl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1COCO1 JDPDLMITLVAWKZ-UHFFFAOYSA-N 0.000 description 2
- QBXCVQVFPVXAGS-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-bromoethanone Chemical compound BrCC(=O)C1=CC=C2OCOC2=C1 QBXCVQVFPVXAGS-UHFFFAOYSA-N 0.000 description 2
- GSJXJZOWHSTWOX-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]piperazine Chemical compound C1=CC(Cl)=CC=C1CN1CCNCC1 GSJXJZOWHSTWOX-UHFFFAOYSA-N 0.000 description 2
- MGLUVVBFISROAH-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]piperazine Chemical compound C1=CC(OC)=CC=C1CN1CCNCC1 MGLUVVBFISROAH-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- NTPQGLLTGPTOAA-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-bromopropan-1-one Chemical compound CC(Br)C(=O)C1=CC=C2OCOC2=C1 NTPQGLLTGPTOAA-UHFFFAOYSA-N 0.000 description 1
- RNAXUUAJNMDESG-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]piperazine Chemical compound C1=CC(C)=CC=C1CN1CCNCC1 RNAXUUAJNMDESG-UHFFFAOYSA-N 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-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
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- NLZSYCRQYRMHOQ-UHFFFAOYSA-N C1OC2=C(O1)C=C(C=C2)C(=O)C(C3=CC=CC=C3)Br Chemical compound C1OC2=C(O1)C=C(C=C2)C(=O)C(C3=CC=CC=C3)Br NLZSYCRQYRMHOQ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical group CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000700159 Rattus Species 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003506 piperazine hexahydrate Drugs 0.000 description 1
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
V " N/30.946-Kp/Pf/vdM ï ? - 1 -F "N / 30946-Kp / Pf / vdM ï? - 1 -
Werkwijze voor de bereiding van cyclische α-aminoderivaten van 1-(3',4' -methyleendioxyfenyl) ethanol, alsmede ct-aminoderivaten van 2-gesubstitueerde 1-(31,41-methyleendioxyfenyl)ethanol.Process for the preparation of cyclic α-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol, as well as α-amino derivatives of 2-substituted 1- (31,41-methylenedioxyphenyl) ethanol.
De onderhavige uitvinding heeft betrekking op een werkwijze voor de bereiding van cyclische α-aminoderivaten van 1-(3',4'-methyleendioxyfenyl)ethanol met de algemene formule 1 van het formuleblad, waarin R^ staat voor waterstof, 5 methyl of fenyl en R2 morfolinyl, piperazinyl of benzylpipe-razinyl welke in de parapositie gesubstitueerd kan zijn met methyl, chloor of methoxy is, alsmede hun niet-toxische addi-tiezouten.The present invention relates to a process for the preparation of cyclic α-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol of the general formula 1 of the formula sheet, wherein R 1 represents hydrogen, 5 methyl or phenyl and R2 is morpholinyl, piperazinyl or benzylpiperazinyl which may be substituted in the para position with methyl, chlorine or methoxy, as well as their non-toxic addition salts.
De verbindingen met formule l, waarin R^ 10 waterstof is en R2 staat voor morfolinyl, piperazinyl of benzylpiperazinyl, welke in de parapositie al dan niet gesubstitueerd is met methyl, chloor of methoxy, zijn reeds beschreven in de Nederlandse octrooiaanvrage 81.05 310 van aanvraagster, als verkregen uitgaande van Piperonal door op-15 volgende behandeling met methylmagnesiumjodide, N-halogeen-succinimide en tenslotte met het betrokken amine. Deze verbindingen hebben hypotensor- en analgetische eigenschappen.The compounds of formula I, wherein R 10 is hydrogen and R 2 represents morpholinyl, piperazinyl or benzylpiperazinyl, which in the para position is substituted or unsubstituted with methyl, chlorine or methoxy, have already been described in the Netherlands patent application 81.05 310, as obtained from Piperonal by subsequent treatment with methyl magnesium iodide, N-halogen succinimide and finally with the amine concerned. These compounds have hypotensor and analgesic properties.
De verbindingen met formule 1, waarin R1 methyl of fenyl is en R2 staat voor morfolinyl, piperazinyl of 20 benzylpiperazinyl welke in de parapositie al dan niet gesubstitueerd kan zijn met methyl, chloor of methoxy, zijn nieuwe verbindingen.The compounds of formula 1, wherein R 1 is methyl or phenyl and R 2 is morpholinyl, piperazinyl or benzylpiperazinyl which may or may not be substituted in the para position with methyl, chlorine or methoxy, are new compounds.
Thans werd een algemene synthesewerkwijze ontwikkeld, welke in de grond bestaat uit de aminering van de 25 overeenkomstige α-broomketonen met formule 2 van het formuleblad, door middel van morfoline, piperazine, benzylpiperazine, of benzylpiperazinen met p-methyl-, p-chloor- of p-methoxy-substituenten en daaropvolgende reductie met metaalhydriden, zoals natriumboorhydride (zie het bijgaande reactieschemablad).A general synthesis process has now been developed, which basically consists of the amination of the corresponding α-bromo ketones of formula 2 of the formula sheet, by means of morpholine, piperazine, benzylpiperazine, or benzylpiperazines with p-methyl, p-chloro- or p-methoxy substituents and subsequent reduction with metal hydrides, such as sodium borohydride (see accompanying reaction schedule sheet).
30 Het is een eigenschap van de verbindingen met de algemene formule 1 wanneer R^ staat voor methyl of fenyl (maar niet wanneer R^ waterstof is) dat deze bestaan in de vorm van erythro- en threo-diastereoisomeren met elk van beide d en 1 optische isomeren. De toepassing van de regel van Cram 8201970 - 2 - (D.J. Cram en D.R. Wilson: J. Am. Chem. Soc., 8£, 1245, 1963; D.J. Cram en J.R. Kopecky: J. Am. Chem. Soc., 81., 2748, 1959) op de reductie van het a-ketoaminecarbonyl met formule 3 van het formuleblad - wanneer R^ methyl of fenyl is (maar niet 5 wanneer R^ waterstof is) - voorspelt de vorming van één van de diastereoisomeren, threo- wanneer R^ methyl is en erythro-wanneer R-j^ fenyl is.It is a property of the compounds of the general formula 1 when R ^ represents methyl or phenyl (but not when R ^ is hydrogen) that they exist in the form of erythro and threo diastereoisomers with both d and 1 optical isomers. The application of the rule of Cram 8201970 - 2 - (DJ Cram and DR Wilson: J. Am. Chem. Soc., 8 £, 1245, 1963; DJ Cram and JR Kopecky: J. Am. Chem. Soc., 81 ., 2748, 1959) to the reduction of the α-ketoamine carbonyl of the formula sheet - when R 1 is methyl or phenyl (but not 5 when R 1 is hydrogen) - predicts the formation of one of the diastereoisomers, threo when R 1 is methyl and erythro when R 1 is phenyl.
De stereochemie van de geïsoleerde produkten wordt bepaald met behulp van NMR door te vergelijken met de 10 reeds in de literatuur beschreven waarden (M.E. Munk, M.K. Meilahu en P. Franklin: J. Org. Chem., 3[3* 3480, 1968; J.B. Hyne: Can. J. Chem., 39.' 2356, 1961) voor de koppelingscon-stanten in 1,2-digesubstitueerde 2-aminoethanolsystemen (-CH0H-CH-N) van het minder afgeschermde ethaanproton, onge-15 twijfeld het -CHOH-. Terwijl de koppelingsconstante van het doublet voor threo-diastereoisomeren een frekwentie van 10 Hz heeft, bedraagt die voor erythro-diastereoisomeren 4 Hz. Het scheiden van een specifiek diastereoisomeer in optisch actieve isomeren wordt bereikt door fractionele herkristallisatie van 20 zijn zouten met optisch actieve zuren. De onderhavige uitvinding heeft betrekking op alle diastereoisomeren en optisch actieve isomeren, zowel gescheiden als in mengsel.The stereochemistry of the isolated products is determined by NMR by comparing with the values already described in the literature (ME Munk, MK Meilahu and P. Franklin: J. Org. Chem., 3 [3 * 3480, 1968; JB Hyne: Can. J. Chem., 39, 2356, 1961) for the coupling constants in 1,2-disubstituted 2-aminoethanol systems (-CH0H-CH-N) of the less shielded ethane proton, unquestionably -CHOH-. While the coupling constant of the doublet for threo diastereoisomers has a frequency of 10 Hz, that for erythro diastereoisomers is 4 Hz. Separation of a specific diastereoisomer into optically active isomers is accomplished by fractional recrystallization of its salts with optically active acids. The present invention relates to all diastereoisomers and optically active isomers, both separately and in mixture.
De verbindingen volgens de onderhavige uitvinding hebben hypotensor- en analgetische eigenschappen. De 25 farmacologische (hypotensie en analgesie) en de toxicologische bepalingen aan deze verbindingen zullen thans worden beschreven.The compounds of the present invention have hypotensor and analgesic properties. The pharmacological (hypotension and analgesia) and toxicological determinations on these compounds will now be described.
a) Hypotensoractiviteit. Deze werd bepaald bij verdoofde mannelijke SPFF-ratten door endoveneuze toedie- 30 ning van de produkten. Uit de verkregen hypotensieve waarden werd de ED2Q voor iedere verbinding berekend. De resultaten worden vermeld in tabel A.a) Hypotensor activity. This was determined in anesthetized male SPFF rats by endovenous administration of the products. The ED2Q for each compound was calculated from the hypotensive values obtained. The results are reported in Table A.
b) Analgetische activiteit. Deze werd bepaald bij mannelijke Swiss-muizen door orale toediening van de ver- 35 bindingen volgens de fenylchinon-proef, beschreven doorb) Analgesic activity. This was determined in male Swiss mice by oral administration of the compounds of the phenylquinone test described by
Siegmund e.a. (Proc. Soc. Exp. Biol. Med, £5, 729, 1957). Uit de verkregen analgesie-data werd de ED^q voor iedere verbinding berekend. De analgetische activiteit werd 0,5 h na toe- 8201970 Λ - 3 - $ * diening bepaald, met uitzondering van de verbinding volgens voorbeeld XVIb, waarbij de bepaling 1 h na toediening plaatsvond. De resultaten worden getoond in tabel A.Siegmund et al. (Proc. Soc. Exp. Biol. Med, £ 5, 729, 1957). The ED ^ q for each compound was calculated from the analgesia data obtained. The analgesic activity was determined 0.5 h after administration, with the exception of the compound of Example XVIb, the assay being made 1 h after administration. The results are shown in Table A.
c) Acute toxiciteit. Deze werd bepaald langs 5 orale weg bij Swiss-muizen van beiderlei sexen volgens de methode van Reed-Miiench, als gewijzigd door Pizzi (Human Biology, 22^ (3), 151-190, 1950). De resultaten worden getoond in tabel A.c) Acute toxicity. This was determined orally in Swiss mice of both sexes according to the method of Reed-Miiench, as modified by Pizzi (Human Biology, 22 ^ (3), 151-190, 1950). The results are shown in Table A.
De verbindingen volgens de onderhavige uit-10 vinding kunnen in mengsel met farmaceutisch aanvaardbare' dragers worden toegediend langs orale weg in de vorm van tabletten, kapsules, siropen, oplossingen, enz., of langs rectale weg, in dagelijkse doses van 500-5000 mg.The compounds of the present invention can be administered in mixture with pharmaceutically acceptable carriers by the oral route in the form of tablets, capsules, syrups, solutions, etc., or by the rectal route, in daily doses of 500-5000 mg. .
TABEL ATABLE A
.15 Farmacologische en toxicologische gegevens voor enige verbindingen met algemene formule 1 van het formuleblad r = -H hYP°~ 1 tensor- analge- acute zuur- activi- tische toxici- 20 R2 additie- voor- teit activi- teit zout beeld ED20 text ED^q ^50 piperazino 2 HCl Ilb 1,53* 75,1* 335* 4-benzylpiperazino 2 HCl IVb 1,25 29,5 200 4-(p-methylbenzyl)pipe- 25 razino 2 HCl VIb 0,82 33,9 175 4-(p-chloorbenzyl)piperazino 2 HCl VId 1,55 22 180 4-(p-methoxybenzyl)- piperazino 2 HCl Vlf 2,8 8,4 193 30 morfolino - VIg 1,5 113 1570 morfolino HCl Vlh 1,6 165 2150 R1 = -CH3 *2 threo-morfolino HCl VlIIb 6,2 165 880 35 threo-piperazino 2 HCl Xb 15,50 2,62 18,1 threo-4-benzylpipera- 2 . 0,54 15 100 zxno 8201970.15 Pharmacological and toxicological data for some compounds of general formula 1 of the formula sheet r = -H hYP ° ~ 1 tensor analgesic acid-active toxic- R2 addition activity salt picture ED20 text ED ^ q ^ 50 piperazino 2 HCl Ilb 1.53 * 75.1 * 335 * 4-benzylpiperazino 2 HCl IVb 1.25 29.5 200 4- (p-methylbenzyl) piperazino 2 HCl VIb 0.82 33 , 9 175 4- (p-chlorobenzyl) piperazino 2 HCl VId 1.55 22 180 4- (p-methoxybenzyl) piperazino 2 HCl Vlf 2.8 8.4 193 30 morpholino - VIg 1.5 113 1570 morpholino HCl Vlh 1.6 165 2150 R1 = -CH3 * 2 threo-morpholino HCl VlIIb 6.2 165 880 35 threo-piperazino 2 HCl Xb 15.50 2.62 18.1 threo-4-benzylpipera-2. 0.54 15 100 zxno 8201970
'j II
- 4 - TABEL A (vervolg) hypo- tensor- analge- acute = ”CH3 zuur- activi- tische toxici- 5 additie- voor- teit activi- text R2 zout beeld ED20 teit ED^ ^°50 threo-4-(p-methylbenzyl) piperazino 2 HCl Xlld 0,72 32,3 198 erythro-4-(p-methyl- 10 benzyl)piperazino 2 HCl XVIb 0,43 19,6 253 threo-4-(p-chloorben- zyl)piperazino 2 HCl Xllf 1,15 23 120 threo-4-(p-methoxy- benzyl)piperazino 2 HCl Xllg 3,15 34,5 163 15 R1 - -C6H5 R2 erythro-morfolino HCl XVb 4,4 156 600 erythro-4-benzyl- piperazino 2 HCl XVd 0,60 33,4 266 2 0 erythro-4-(p-chloor- benzyl)piperazino 2 HCl XVf inactief >100 345 codeïne 1,97 aminofenazon 23,4 acetylsalicylzuur 72 1 2 3 4 5 6 8201970 * mg/kg 2- 4 - TABLE A (continued) hypotensor analgesic = "CH3 acid-active toxic- addition activity activity R2 salt image ED20 ed ED ^ ^ ° 50 threo-4- (p -methylbenzyl) piperazino 2 HCl Xlld 0.72 32.3 198 erythro-4- (p-methyl-benzyl) piperazino 2 HCl XVIb 0.43 19.6 253 threo-4- (p-chlorobenzyl) piperazino 2 HCl Xllf 1.15 23 120 threo-4- (p-methoxybenzyl) piperazino 2 HCl Xllg 3.15 34.5 163 15 R1 - -C6H5 R2 erythro-morpholino HCl XVb 4.4 156 600 erythro-4-benzyl - piperazino 2 HCl XVd 0.60 33.4 266 2 0 erythro-4- (p-chlorobenzyl) piperazino 2 HCl XVf inactive> 100 345 codeine 1.97 aminophenazone 23.4 acetylsalicylic acid 72 1 2 3 4 5 6 8201970 * mg / kg 2
Een aantal voorbeelden zal thans op niet be 3 perkende wijze worden beschreven ter toelichting van de uit 4 vinding, maar natuurlijk kunnen in de industrie grotere hoe 5 veelheden dan zijn aangegeven worden gebruikt.A number of examples will now be described in a non-limiting manner to illustrate the invention, but, of course, larger amounts than those indicated may be used in the industry.
66
VOORBEELD IEXAMPLE I
2-(1-piperazinyl)-3’,41-methyleendioxyaceto-fenon (formule 3, R^ = H, R2 = 1-piperazinyl) a) Een mengsel van 6,85 g 2-broom-31,4 methyleendioxyacetofenon (28,2 mmol) en 16,42 g piperazine- 4 - 5 - > hexahydraat (84,6. mmol) in 50 ml ethanol werd gedurende 6 h bij 70°C verwarmd. De ethanol werd onder vacuum verwijderd, waarna het residu met 100 ml water werd verdund en het onoplosbare materiaal werd afgefiltreerd. Het filtraat werd daarop 5 drie maal geëxtraheerd met 100 ml methyleenchloride, de extracten werden drie maal gewassen met water en vervolgens gedroogd. Het na verdamping van het oplosmiddel verkregen residu had een gewicht van 5,2 g (opbrengst: 75 %), was harsachtig en kwam overeen met formule 3 (R^ = H, R2 = 1-piperazinyl).2- (1-piperazinyl) -3 ', 41-methylenedioxyaceto-phenone (Formula 3, R ^ = H, R2 = 1-piperazinyl) a) A mixture of 6.85 g of 2-bromo-31.4 methylenedioxyacetophenone (28 , 2 mmol) and 16.42 g of piperazine 4-5-5 hexahydrate (84.6 mmol) in 50 ml of ethanol was heated at 70 ° C for 6 h. The ethanol was removed under vacuum, the residue was diluted with 100 ml of water and the insoluble material was filtered off. The filtrate was then extracted three times with 100 ml of methylene chloride, the extracts were washed three times with water and then dried. The residue obtained after evaporation of the solvent had a weight of 5.2 g (yield: 75%), was resinous and corresponded to formula 3 (R 1 = H, R 2 = 1-piperazinyl).
10 b) Vorming van het dihydrochloride. Het boven genoemde materiaal werd opgelost in 50 ml droog methyleenchloride en onder koeling werd een ethanolische oplossing van HC1 met een sterkte van 11N toegevoegd tot aan volledige precipitatie. Na enige minuten werd dit neerslag afgefiltreerd 15 en gedroogd. Smeltpunt 185°C (ontl.) en juiste elementaire analyse.B) Formation of the dihydrochloride. The above material was dissolved in 50 ml of dry methylene chloride and an ethanolic solution of HCl of 11N strength was added with cooling until complete precipitation. After a few minutes, this precipitate was filtered off and dried. Melting point 185 ° C (dec.) And correct elemental analysis.
IR-spectrum (KBr), cm”1: 3420, 2930, 2800, 2720, 1675, 1600, 1505, 1450, 1260, 1035.IR spectrum (KBr), cm 1: 3420, 2930, 2800, 2720, 1675, 1600, 1505, 1450, 1260, 1035.
NMR-spectrum (dg-DMSO), ppm: (breed, 6H; 20 piperazine) , 2,99 (s, 2H; -CH2-NC ), 6,13 (s, 2H; 0-CH2-0), 7,04 (d, 1H, JQ= 8 Hz; H-Ar) , 7,43 (d, 1H, Jm= 2 Hz; Η-Ar) en 7,62 £dd, 1H, JQ= 8 Hz en Jm= 2 Hz; H-Ar).NMR spectrum (dg-DMSO), ppm: (broad, 6H; piperazine), 2.99 (s, 2H; -CH2-NC), 6.13 (s, 2H; 0-CH2-0), 7 .04 (d, 1H, JQ = 8 Hz; H-Ar), 7.43 (d, 1H, Jm = 2 Hz; Η-Ar) and 7.62 £ dd, 1H, JQ = 8 Hz and Jm = 2 Hz; H-Ar).
VOORBEELD IIEXAMPLE II
1-(3',41-methyleendioxyfenyl)-2-(1-piperazi-25 nyl)ethanol (formule 1, R^ = H, R2 = 1- piperazinyl) a) Aan een suspensie van 5,0 g 2-(l-pipera-zinyl)-3^41-methyleendioxyacetofenondihydrochloride in 40 ml methanol werd een oplossing van 5 % natriumhydroxide onder 30 koeling in een ijswaterbad toegevoegd, totdat een enigszins basische pH was verkregen. Gedurende 45 min werd daarop geleidelijk 1,22 g natriumboorhydraat toegevoegd. Men liet het mengsel gedurende de nacht bij omgevingstemperatuur staan, waarna het onder vacuum werd drooggedampt, opgenomen in methy-35 leenchloride, gewassen, gedroogd en geconcentreerd. Het residu had een gewicht van 3,1 g, en kwam overeen met het a-amino-alcohol met formule 1 (R^, = H, R2 = 1-piperazinyl).1- (3 ', 41-methylenedioxyphenyl) -2- (1-piperazin-25-yl) ethanol (Formula 1, R 1 = H, R 2 = 1-piperazinyl) a) To a suspension of 5.0 g 2- ( 1-Piperazinyl) -3,41-methylenedioxyacetophenone dihydrochloride in 40 ml of methanol, a solution of 5% sodium hydroxide was added under cooling in an ice water bath until a slightly basic pH was obtained. 1.22 g of sodium borohydrate was gradually added thereto over 45 min. The mixture was allowed to stand at ambient temperature overnight, after which it was evaporated in vacuo, taken up in methylene chloride, washed, dried and concentrated. The residue weighed 3.1 g and corresponded to the α-amino alcohol of formula 1 (R 1, = H, R 2 = 1-piperazinyl).
b) Vorming van het dihydrochloride: boven ge- 8201970 f i - 6 - noemde base werd opgelost in 30 ml droog methyleenchloride en onder koeling met ijs-water werd 2,8 ml 11N ethanolische op- 1 lossing van HC1 toegevoegd. Het gevormde neerslag werd afgefiltreerd en gedroogd. Smp. 162°C (ontl.) en juiste elementaire 5 analyse voor C, Η, N en Cl.b) Formation of the dihydrochloride: The above-mentioned base was dissolved in 30 ml of dry methylene chloride and 2.8 ml of 11N ethanolic solution of HCl were added under cooling with ice-water. The precipitate formed was filtered and dried. Mp. 162 ° C (dec.) And correct basic analysis for C, Η, N and Cl.
IR-spectrum (KBr), cm 3470, 3330, 2980, 2920, 2830, 2700, 2660, 1490, 1475, 1435, 1240, 1030, 920, 805.IR spectrum (KBr), cm 3470, 3330, 2980, 2920, 2830, 2700, 2660, 1490, 1475, 1435, 1240, 1030, 920, 805.
VOORBEELD IIIEXAMPLE III
2-(4-benzyl-1-piperazinyl)-3',4'-methyleen-10 dioxyacetofenon (formule 3, R1 = H, R2 = 4-benzyl-1-piperazinyl)2- (4-Benzyl-1-piperazinyl) -3 ', 4'-methylene-10-dioxyacetophenone (Formula 3, R1 = H, R2 = 4-Benzyl-1-piperazinyl)
Een oplossing van 8,56 g 2-broom-3',4'-methyleendioxyacetofenon, 6,20 g benzylpiperazine en 4,28 g triethylamine in 100 ml ethanol werd gedurende 3 h onder 15 terugvloeiïng behandeld. De ethanol werd onder vacuum afgedampt, het residu werd opgelost in 100 ml methyleenchloride en deze oplossing werd drie maal gewassen met water tot aan neutralisatie. Het oplosmiddel werd afgedampt en 11,54 g (opbrengst: 9,72 %) van een vaste stof werd verkregen, welke uit 20 methanol werd geherkristalliseerd: 9,72 g (opbrengst: 82 %), smp. 94,5-95,9°C en juiste C-, H- en N-analyse.A solution of 8.56 g of 2-bromo-3 ', 4'-methylenedioxyacetophenone, 6.20 g of benzylpiperazine and 4.28 g of triethylamine in 100 ml of ethanol was refluxed for 3 h. The ethanol was evaporated in vacuo, the residue was dissolved in 100 ml of methylene chloride and this solution was washed three times with water until neutralization. The solvent was evaporated and 11.54 g (yield: 9.72%) of a solid were obtained, which was recrystallized from methanol: 9.72 g (yield: 82%), m.p. 94.5-95.9 ° C and proper C, H and N analysis.
IR-spectrum (KBr), cm 3010, 2970-2870, 2810, 2770, 1675, 1595, 1490, 1450, 1240, 1140, 1030, 985, 800.IR spectrum (KBr), cm 3010, 2970-2870, 2810, 2770, 1675, 1595, 1490, 1450, 1240, 1140, 1030, 985, 800.
NMR-spectrum (CDCl^), ppm: 2,52 (s, 8H; 25 piperazine), 3,42 (s, 2H; ^?N-CH2-Ar), 3,64 (s, 2H; -CO-CH2-NO, 5,90 (s, 2H; -0-CH2-0), 6,70 (d, 1H, JQ = 8 Hz; H-Ar), 7,20 (s, 5H; -Ar), 7,40 (d, 1H, Jm = 2 Hz; H-Ar), 7,49 en 7,64 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR spectrum (CDCl 3), ppm: 2.52 (s, 8H; piperazine), 3.42 (s, 2H; ^N-CH 2 -Ar), 3.64 (s, 2H; -CO- CH2-NO, 5.90 (s, 2H; -0-CH2-0), 6.70 (d, 1H, JQ = 8 Hz; H-Ar), 7.20 (s, 5H; -Ar), 7.40 (d, 1H, Jm = 2 Hz; H-Ar), 7.49 and 7.64 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).
VOORBEELD IVEXAMPLE IV
30 1-(3^41 -methyleendioxyf enyl) -2- (4-benzyl-1- piperazinyl)ethanol (formule 1, R^ = H, R2 = 4-benzyl-1-piperaz inyl) a) Aan 8,5 g van het boven genoemde a-amino-keton in 160 ml methanol werden enige druppels van een 6N 35 natriumhydroxide-oplossing toegevoegd totdat een pH ongeveer gelijk aan 9 werd bereikt. Onder koeling werd geleidelijk en voorzichting 1,92 g poedervormig natriumboorhydride toegevoegd.1- (3 ^ 41-methylenedioxyphenyl) -2- (4-benzyl-1-piperazinyl) ethanol (Formula 1, R ^ = H, R2 = 4-benzyl-1-piperazyl) a) At 8.5 g of the above α-amino ketone in 160 ml of methanol, a few drops of a 6N sodium hydroxide solution were added until a pH of approximately 9 was reached. Under cooling, 1.92 g of powdered sodium borohydride was added gradually and with caution.
Na een nacht bij kamertemperatuur werd de methanol afgedampt, 8201970 - 7 - werd het residu opgenomen in water, werd het onoplosbare materiaal afgefiltreerd en gedroogd. 7,84 g (opbrengst: 92 %) werd verkregen, smp. 136-137°C en juiste elementair.e analyse voor C, H en N.After overnight at room temperature, the methanol was evaporated, 8201970-7 - the residue was taken up in water, the insoluble material was filtered off and dried. 7.84 g (yield: 92%) were obtained, m.p. 136-137 ° C and proper elemental analysis for C, H and N.
5 IR-spectrum (KBr), cm-1: 3400, 3110, 2910, 2820, 2770, 1475, 1430, 1235, 1125, 1080, 1035, 935, 805.IR spectrum (KBr), cm-1: 3400, 3110, 2910, 2820, 2770, 1475, 1430, 1235, 1125, 1080, 1035, 935, 805.
NMR-spectrum (CDCl^), ppm: 2,2-2,9 (10H;NMR spectrum (CDCl 4), ppm: 2.2-2.9 (10H;
CH —CHCH —CH
-CH0~N ^ 2 2>^N-), 3,46 (s, 2H; )N-CH9 -Ar), 3,84 (s, 1H; 2 vch2-ch2^ 10 -OH), 4,56 (t, 1H, J = 6,7 Hz; -CHOH-) , 5,82 (s, 2H; -0-CH2-O), 6,70, 6,82 en 7,21 (m, 8H; Ar-).-CH0 ~ N ^ 2 2> ^ N-), 3.46 (s, 2H;) N-CH9 -Ar), 3.84 (s, 1H; 2 vch2-ch2 ^ 10 -OH), 4.56 (t, 1H, J = 6.7 Hz; -CHOH-), 5.82 (s, 2H; -O-CH2-O), 6.70, 6.82 and 7.21 (m, 8H; Ar -).
Vorming van het dihydrochloride: in droog methyleenchloride door toevoeging van 11N ethanolische oplossing van HC1. Het werd geïsoleerd in een kwantitatieve op-15 brengst, smp. 219,5-220°C en met juiste elementaire analyse voor C, Η, N en Cl.Formation of the dihydrochloride: in dry methylene chloride by addition of 11N ethanolic solution of HCl. It was isolated in a quantitative yield, m.p. 219.5-220 ° C and with proper elemental analysis for C, Η, N and Cl.
IR-spectrum (KBr), cm 3310, 2970, 2890, 2600,2250, 1480, 1435, 1245, 1065, 1030, 920, 810, 740.IR spectrum (KBr), cm 3310, 2970, 2890, 2600, 250, 1480, 1435, 1245, 1065, 1030, 920, 810, 740.
VOORBEELD VEXAMPLE V
20 Uitgaande van 2-broom-3',4'-methyleendioxy- acetofenon werden door reactie met 4-methylbenzylpiperazine, 4-chloorbenzylpiperazine, 4-methoxybenzylpiperazine en resp. morfoline, de volgende a-aminoketonen bereid volgens de werk-- wijze als beschreven in voorbeeld III (juiste analyses voor 25 C, Η, N en Cl): a) 2-/4-(p-Methylbenzyl)-l-piperazinyl7“3 *,4 ’-methyleendioxyacetofenon, smp., 103-103,5°C (ethanol), opbrengst 86 % (formule 3, Ηχ = H, R2 = 4-(p-methylbenzyl) -1-piperazinyl).Starting from 2-bromo-3 ', 4'-methylenedioxyacetophenone, reaction with 4-methylbenzylpiperazine, 4-chlorobenzylpiperazine, 4-methoxybenzylpiperazine and resp. morpholine, the following α-amino ketones prepared according to the procedure described in Example III (correct analyzes for C, Η, N and Cl): a) 2- / 4- (p-Methylbenzyl) -1-piperazinyl7 " 3 *, 4'-methylenedioxyacetophenone, mp, 103-103.5 ° C (ethanol), 86% yield (formula 3,, = H, R2 = 4- (p-methylbenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm *: 2980, 2900, 2800, 30 2760, 1665, 1590, 1435, 1235, 1095, 1025, 980, 795.IR spectrum (KBr), cm *: 2980, 2900, 2800, 30 2760, 1665, 1590, 1435, 1235, 1095, 1025, 980, 795.
NMR-spectrum (CDC13), ppm: 2,28 (s, 3H; CH3~ Ar-), 2,51 (£,‘ 8H; piperazine), 3,41 (s, 2H; ^N-CH2“Ar), 3,61 (s, 2H; -C0-CH2-NO , 5,90 (s, 2H; -0-CH2-0-) , 6,70 (d, 1H, JQ = 8 HZ; H-Ar), 7,02 (s, 4H; Ar-), 7,36 (d, 1H, Jm = 2 Hz; 35 H-Ar-), 7,46 en 7,60 ( dd , 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR spectrum (CDCl3), ppm: 2.28 (s, 3H; CH3-Ar-), 2.51 (,, 8H; piperazine), 3.41 (s, 2H; N-CH2 “Ar) , 3.61 (s, 2H; -CO-CH 2 -NO, 5.90 (s, 2H; -0-CH 2 -O-), 6.70 (d, 1H, JQ = 8 HZ; H-Ar) , 7.02 (s, 4H; Ar-), 7.36 (d, 1H, Jm = 2 Hz; 35 H-Ar-), 7.46 and 7.60 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).
b) 2-/4-(p-Chloorbenzyl)-l-piperazinyl7-3 *,4'- 8201970 - 8 - methyleendioxyacetofenon, smp. 99-l0l,5°C (ethanol), opbrengst 76 % (formule 3, RA = H, R2 = 4-(p-chloorbenzyl)-1-piper aziryl.b) 2- / 4- (p-Chlorobenzyl) -1-piperazinyl-7-3 *, 4'-8201970-8-methylenedioxyacetophenone, m.p. 99-101.5 ° C (ethanol), 76% yield (formula 3, RA = H, R2 = 4- (p-chlorobenzyl) -1-piper aziryl.
IR-spectrum (KBr), cm 2980-2880, 2800, 2760, 1675, 1600, 1485, 1440, 1240, 1105, 1030, 920, 810.IR spectrum (KBr), cm 2980-2880, 2800, 2760, 1675, 1600, 1485, 1440, 1240, 1105, 1030, 920, 810.
5 NMR-spectrum (CDCl^), ppm: 2,52 (s, 8H; piperazine), 3,43 (s, 2H; ^N-CEL^-Ar), 3,66 (£, 2H; -CO-CH2-N^), 5,96 (s, 2H; -0-CH2-0-), 6,76 (d, 1H, JQ = 8 Hz; H-Ar)., 7,20 (s, 4H; Ar-), 7,44 (d, 1H, Jm = 2 Hz), 7,54 en 7,66 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).5 NMR Spectrum (CDCl2), ppm: 2.52 (s, 8H; piperazine), 3.43 (s, 2H; ^ N-CEL ^ -Ar), 3.66 (£, 2H; -CO- CH2 -N2), 5.96 (s, 2H; -O-CH2 -O-), 6.76 (d, 1H, JQ = 8Hz; H-Ar)., 7.20 (s, 4H; Ar-), 7.44 (d, 1H, Jm = 2 Hz), 7.54 and 7.66 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).
10 c) 2-/4-(p-Methoxybenzyl)-l-piperazinyl7“ 3',4'-methyleendioxyacetofenon, smp. 89-90,5°C (ethanol), opbrengst 55 %. (Formule 3, R^ = H, R2 = 4-(p-methoxybenzyl)- 1-piperazinyl).C) 2- / 4- (p-Methoxybenzyl) -1-piperazinyl7 "3 ', 4'-methylenedioxyacetophenone, m.p. 89-90.5 ° C (ethanol), yield 55%. (Formula 3, R 1 = H, R 2 = 4- (p-methoxybenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm-1: 3000-2900, 2800,2760, 15 1675, 1600, 1505, 1490, 1450, 1240, 1100, 1030, 985, 800.IR spectrum (KBr), cm-1: 3000-2900, 2800, 2760, 15 1675, 1600, 1505, 1490, 1450, 1240, 1100, 1030, 985, 800.
NMR-spectrum (CDCl^), ppm: 2,4-2,7 ((H; piperazine) 3,48 (s, 2 H;^N-CH2-Ar), 3,70 (s, 2H;*-CO-CH2-NO, 3,80 (s, 3H; CH-jO-) , 6,03 (s, 2H; -0-CH2-0-), 6,75-7,35 (AA'~ BB'-systeem 4 H en d, 1 H, JQ = 8 Hz), 7,53 (d, 1H, Jm = 20 2 Hz; H-Ar-), 7,63 en 7,77 (dd, 1H, JQ = 8 Hz en Jm = 2 Hz; H-Ar-).NMR spectrum (CDCl2), ppm: 2.4-2.7 ((H; piperazine) 3.48 (s, 2H; ^ N-CH2-Ar), 3.70 (s, 2H; * - CO-CH2-NO, 3.80 (s, 3H; CH-jO-), 6.03 (s, 2H; -0-CH2-0-), 6.75-7.35 (AA '~ BB' system 4 H and d, 1 H, JQ = 8 Hz), 7.53 (d, 1H, Jm = 20 2 Hz; H-Ar-), 7.63 and 7.77 (dd, 1H, JQ = 8 Hz and Jm = 2 Hz; H-Ar-).
d) Dihydrochloride: smp. 234-237°C (ontl.) e) 2-Morfolino-3',4'-methyleendioxyacetofenon, vloeistof, opbrengst: 94 %. (Formule 3, R^ = H, R2 = morfoli- 25 nyl).d) Dihydrochloride: m.p. 234-237 ° C (dec.) E) 2-Morfolino-3 ', 4'-methylenedioxyacetophenone, liquid, yield: 94%. (Formula 3, R 1 = H, R 2 = morpholinyl).
IR-spectrum (KBr), cm”1: 3040, 2990-2680, 1675, 1590, 1510, 1490, 1440, 1240, 1100, 1035, 940.IR spectrum (KBr), cm 1: 3040, 2990-2680, 1675, 1590, 1510, 1490, 1440, 1240, 1100, 1035, 940.
NMR-spectrum (CDCl^), ppm: 2,55 (t, 4H, J = 4,.6 Hz; N . ), 3,50 (s, 2H; -CO-CH.-nO, 3,70 (t,4H, J = 4,6Hz; CH ^CH — ^ °^CH2-)f 5'9^ (-' 2H? “0‘CH2"0)' 6'78 (£' 1H' J0 = 30 8 Hz;2H-Ar), 7,42 (d, 1H, Jm = 2 Hz; H-Ar), 7,50 en 7,64 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR spectrum (CDCl 3), ppm: 2.55 (t, 4H, J = 4, 6 Hz; N.), 3.50 (s, 2H; -CO-CH.-nO, 3.70 ( t, 4H, J = 4,6Hz; CH ^ CH - ^ ° ^ CH2-) f 5'9 ^ (- '2H? “0'CH2” 0)' 6'78 (£ '1H' J0 = 30 8 Hz; 2H-Ar), 7.42 (d, 1H, Jm = 2 Hz; H-Ar), 7.50 and 7.64 (dd, 1H, JQ = 8 Hz, Jm = 2 Hz; H-Ar ).
f) Hydrochloride: smp. 220°C (ontl.). VOORBEELD VIf) Hydrochloride: mp. 220 ° C (dec.). EXAMPLE VI
Uitgaande van de α-aminoketonen die zijn be-35 schreven in voorbeeld V en door reductie met natriumboorhydri-de werden de volgende derivaten bereid volgens de methode als beschreven in voorbeeld IV (juiste analyse voor C, Η, N en Cl): 8201970 - 9 - a) 1-(3/4'-Methyleendioxyfenyl)-2-^4-(p- methylbenzyl)-l-piperazinyl7ethanol, sxnp. 158-160°C, opbrengst: 93 %. (Formule 1, = H, Rj = 4-(p-methylbenzyl)-i-piperazi- nyl).Starting from the α-amino ketones described in Example V and by reduction with sodium borohydride, the following derivatives were prepared according to the method described in Example IV (correct analysis for C, Η, N and Cl): 8201970 - 9 - a) 1- (3 / 4'-Methylenedioxyphenyl) -2- [4- (p-methylbenzyl) -1-piperazinyl] ethanol, sxnp. 158-160 ° C, yield: 93%. (Formula 1, = H, Rj = 4- (p-methylbenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm 3460, 2900, 2800, 1470, 1430, 1230, 1025, 920, 790.IR spectrum (KBr), cm 3460, 2900, 2800, 1470, 1430, 1230, 1025, 920, 790.
NMR-spectrum (CDCl^), ppm: 2,32 (s, 3H; CH3-Ar-), 2,35-2,9 (10H; 3,46 (s, 2H; CH2-CH2^ >N-CH2-Ar), 3,9 (1H? -OH), 4,60 (t, 1H, J = 7 Hz; -CHOH-) , 5,88 (s, 2H? -OCH2-0-), 6,6-6,9 en 7,13 (7H; Ar).NMR spectrum (CDCl2), ppm: 2.32 (s, 3H; CH3-Ar-), 2.35-2.9 (10H; 3.46 (s, 2H; CH2-CH2 ^> N-CH2) -Ar), 3.9 (1H? -OH), 4.60 (t, 1H, J = 7 Hz; -CHOH-), 5.88 (s, 2H? -OCH2-0-), 6.6 -6.9 and 7.13 (7H; Ar).
b) Dihydrochloride: smp. 248-252°C (ontl.). IR-spectrum (KBr), cm 1: 3400, 3010, 2970, 2700-2300, 1490, 1435, 1245, 1230, 1030, 920, 800.b) Dihydrochloride: m.p. 248-252 ° C (dec.). IR spectrum (KBr), cm 1: 3400, 3010, 2970, 2700-2300, 1490, 1435, 1245, 1230, 1030, 920, 800.
c) 1-(3,4'-Methyleendioxyfenyl)-2-^4-(p-chloorbenzyl)-l-piperazinyl7ethanol, smp. 142-144°C, opbrengst 95 % (formule 1, R^ = H, R2 = 4-(p-chloorbenzyl)-1-piperazinyl).c) 1- (3,4'-Methylenedioxyphenyl) -2- (4- (p-chlorobenzyl) -1-piperazinyl] ethanol, m.p. 142-144 ° C, yield 95% (formula 1, R 1 = H, R 2 = 4- (p-chlorobenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm-1: 3400, 3100, 2920, 2800, 2760, 1475, 1430, 1235, 1085, 1035, 1000, 930, 800.IR spectrum (KBr), cm-1: 3400, 3100, 2920, 2800, 2760, 1475, 1430, 1235, 1085, 1035, 1000, 930, 800.
NMR-spectrum (CDC1,), ppm: 2,3-2,9 (10H; .CH^-CH-v -CH9-Nx ' .N-) , 3,49 (s, 2H; >N-CH„-Ar) , 3,9 (s, 1H; xch2-ch2^ ά -OH), 4,56 (t, 1H, J = 6,7 Hz; -CHOH), 5,89 (s, 2H; -O-CHj-O-), 6,8-7,2 (7H; Ar-).NMR spectrum (CDCl 3), ppm: 2.3-2.9 (10H; .CH 1 -CH-v -CH9-Nx '.N-), 3.49 (s, 2H;> N-CH " -Ar), 3.9 (s, 1H; xch2-ch2 ^ ά -OH), 4.56 (t, 1H, J = 6.7 Hz; -CHOH), 5.89 (s, 2H; -O -CHj-O-), 6.8-7.2 (7H; Ar-).
d) Dihydrochloride: smp. 258-262°C (ontl.). IR-spectrum (KBr), cm 3540, 3370, 2960, 2600-2300, 1490, 1435, 1250, 1230, 1080, 1030, 920, 800.d) Dihydrochloride: m.p. 258-262 ° C (dec.). IR spectrum (KBr), cm 3540, 3370, 2960, 2600-2300, 1490, 1435, 1250, 1230, 1080, 1030, 920, 800.
e) 1-(31,4'-Methyleendioxyfenyl)-2-^4-(p-methoxybenzyl)-l-piperazinyl7ethanol, smp. 130-132°C, opbrengst: 91 % (formule 1, R^ = H, R2 = 4-(p-methoxybenzyl)-1-piperazinyl).e) 1- (31,4'-Methylenedioxyphenyl) -2- (4- (p-methoxybenzyl) -1-piperazinyl] ethanol, m.p. 130-132 ° C, yield: 91% (formula 1, R 1 = H, R 2 = 4- (p-methoxybenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm-1: 3400, 3120, 2920, 2820, 1500, 1475, 1230, 1030, 930, 800.IR spectrum (KBr), cm-1: 3400, 3120, 2920, 2820, 1500, 1475, 1230, 1030, 930, 800.
NMR-spectrum (CDC1,), ppm: 2,3-2,9 (10 H; /CH2“CH2\ -CH--N. * /N“)/ 3,39 (s, 2H; >N-CH9-Ar), 3,72 (s, 3H; XCH2-CH2 CH,0-), 4,60 (t, 1H, J = 6,8 Hz; -CHOH-), 5,83 (s, 2H; 8201970 - 10 - -0-CH2-0) en 6,7-7,4 (7H; Ar-).NMR spectrum (CDC1,), ppm: 2.3-2.9 (10 H; / CH2 “CH2 \ -CH-N. * / N“) / 3.39 (s, 2H;> N-CH9 -Ar), 3.72 (s, 3H; XCH2-CH2 CH, O-), 4.60 (t, 1H, J = 6.8 Hz; -CHOH-), 5.83 (s, 2H; 8201970 - 10 - (0-CH 2 - 0) and 6.7 - 7.4 (7H; Ar-).
f) Dihydrochloride: smp. 200-202°C (ontl.). 1 IR-spectrum (KBr), cm 3240, 2970, 2900, 2680-2340, 1505, 1430, 1245, 1230, 1020, 915, 850.f) Dihydrochloride: m.p. 200-202 ° C (dec.). 1 IR spectrum (KBr), cm 3240, 2970, 2900, 2680-2340, 1505, 1430, 1245, 1230, 1020, 915, 850.
5 g) 1-(3',41-Methyleendioxyfenyl)-2-morfolino- ethanol, smp. 94-95°C, opbrengst: 95 %. (Formule 1, R = H, R2 = morfolinyl).5 g) 1- (3 ', 41-Methylenedioxyphenyl) -2-morpholinoethanol, m.p. 94-95 ° C, yield: 95%. (Formula 1, R = H, R2 = morpholinyl).
__ NMR-spectrum (CDC1-), ppm: 2,61 (m, 6H; -CH2-Nn ^ ), 3,75 (t, 4H; J = 5,3 Hz; Q' *2 ^ CH2~ X ch2-10 1H; J = 7,3 Hz; -CH0H-), 5,97 (s, 2H; -0“CH2-0) en 6,90 (m, 3H; Ar-).__ NMR spectrum (CDCl-), ppm: 2.61 (m, 6H; -CH2-Nn ^), 3.75 (t, 4H; J = 5.3 Hz; Q '* 2 ^ CH2 ~ X ch2 -10 1H; J = 7.3 Hz; -CH0H-), 5.97 (s, 2H; -0 “CH2-0) and 6.90 (m, 3H; Ar-).
h) Hydrochloride: smp. 194,5-195,5°C.h) Hydrochloride: mp. 194.5-195.5 ° C.
IR-spectrum (KBr), cm 1: 3300, 3010, 2960, 2700-2460, 1480, 1435, 1250, 1240, 1125,.1030, 870, 820.IR spectrum (KBr), cm 1: 3300, 3010, 2960, 2700-2460, 1480, 1435, 1250, 1240, 1125, .1030, 870, 820.
15 VOORBEELD VIIEXAMPLE VII
2-Morfolino-3',4'-methyleendioxypropiofenon (formule 3, Rj^ = CH3, R2 “ morf°HnYl) a) Een mengsel van 29,67 g 2-broom-31,4'-methyleendioxypropiofenon, 40,2 g morfoline, (4 eq.) en 190 ml 20 absolute ethanol werd gedurende 3 h onder terugvloeiïng behandeld. De ethanol werd afgedampt onder vacuum, aan het residu werd 100 ml water toegevoegd en vervolgens werd achtereenvolgens met 250 en 100 ml methyleenchloride geëxtraheerd. De organische extracten werden gewassen met water en gedroogd.2-Morfolino-3 ', 4'-methylenedioxypropiophenone (Formula 3, R 1 = CH 3, R 2 "morph HnYl) a) A mixture of 29.67 g of 2-bromo-31,4'-methylenedioxypropiophenone, 40.2 g morpholine, (4 eq.) and 190 ml of absolute ethanol were refluxed for 3 h. The ethanol was evaporated in vacuo, 100 ml of water was added to the residue and then extracted successively with 250 and 100 ml of methylene chloride. The organic extracts were washed with water and dried.
25 Het residu dat hierop door concentrering werd verkregen, was een viskeuze vloeistof met een gewicht van 29,3 g (opbrengst: 96 %) en bleek chromatografisch zuiver.The residue obtained by concentration on this was a viscous liquid weighing 29.3 g (yield: 96%) and appeared to be chromatographically pure.
IR-spectrum (film), cm 1: 3040, 3000-2700, 1675, 1600-1500, 1485, 1435, 1355, 1250, 1150, 1035, 30 930, 875, 780.IR spectrum (film), cm 1: 3040, 3000-2700, 1675, 1600-1500, 1485, 1435, 1355, 1250, 1150, 1035, 30 930, 875, 780.
NMR-spectrum (CDC1,), ppm: 1,37 (d, 3H; J = 3 ρττ 6,7 Hz? CH3-), 2,56 (t, 4H, J = 4,7 Hz; N^n2-} ^ ,( .CH„- CH2“ 4H, J = 4,7 Hz? O ), 3,91 (q, 1H; J = 6,7 Hz? ^CH-), xch2- 5,99 (s, 2H? -0CH2-0-), 6,80 (d, 1H, JQ = 8 Hz? H-Ar), 7,57 35 (d, 1H, Jm - 2 Hz? H-Ar), 7,75 (dd, 1H? JQ = 8 Hz? Jm = 2Hz? H-Ar).NMR spectrum (CDC1,), ppm: 1.37 (d, 3H; J = 3 ρττ 6.7 Hz? CH3-), 2.56 (t, 4H, J = 4.7 Hz; N ^ n2- } ^, (.CH "- CH2" 4H, J = 4.7 Hz? O), 3.91 (q, 1H; J = 6.7 Hz? ^ CH-), xch2- 5.99 (s, 2H? -0CH2-0-), 6.80 (d, 1H, JQ = 8 Hz? H-Ar), 7.57 35 (d, 1H, Jm - 2 Hz? H-Ar), 7.75 ( dd, 1H? JQ = 8 Hz? Jm = 2Hz? H-Ar).
8201970 - 11 - b) Vorming van het hydrochloride: de boven genoemde base werd opgelost in watervrije ethylether en onder koeling met een ijs-waterbad en onder roeren werd 14 ml van een 11N ethanolische oplossing van HC1 toegevoegd (geringe 5 overmaat). Na 30 min werd het verkregen witte neerslag afgefiltreerd, gewassen met ether en gedroogd. 32,8 g dihydrochlo-ride (opbrengst: 96 %) werd verkregen met een smeltpunt van 233-234°C en juiste elementaire analyse voor C, Η, N en Cl.8201970-11 - b) Formation of the hydrochloride: The above base was dissolved in anhydrous ethyl ether and under cooling with an ice-water bath and stirring, 14 ml of an 11N ethanolic solution of HCl was added (slight excess). After 30 min, the resulting white precipitate was filtered off, washed with ether and dried. 32.8 g of dihydrochloride (yield: 96%) were obtained with a melting point of 233-234 ° C and correct elemental analysis for C, Η, N and Cl.
IR-spectrum (KBr), cm 1: 3450, 3010, 2980, 10 2920, 2760-2420, 1670, 1600, 1510, 1490, 1450, 1255, 1100, 1030, 920, 880.IR spectrum (KBr), cm 1: 3450, 3010, 2980, 10 2920, 2760-2420, 1670, 1600, 1510, 1490, 1450, 1255, 1100, 1030, 920, 880.
VOORBEELD VIIIEXAMPLE VIII
d,1-threo-1-(3',4'-methyleendioxyfenyl) -2 - morfolinopropan-l-ol (formule 1, Rj = CH^, 15 R2 = morfolinyl).d, 1-threo-1- (3 ', 4'-methylenedioxyphenyl) -2-morpholinopropan-1-ol (formula 1, R1 = CH2,12 R2 = morpholinyl).
a) Aan een geroerde suspensie van 32,5 g van het boven genoemde a-aminoketondihydrochloride in 275 ml methanol welke werd gekoeld in een ijs-waterbad, werd langzaam een 5 % natriumhydroxide-oplossing toegevoegd totdat een pH gelijk 20 aan 9 was bereikt. Aan de verkregen oplossing werd binnen 15 min 8,15 g eveneens gekoeld natriumboorhydride toegevoegd, waarna het roeren gedurende een nacht bij kamertemperatuur werd voortgezet. De methanol werd afgedampt onder vacuum, enig water werd toegevoegd en daarop werden extracties met achter-25 eenvolgens 250 ml en 100 ml methyleenchloride uitgevoerd; de extracten werden gewassen met water en gedroogd. Door droog-dampen werd 27,6 g (97 %) van een geelachtige vaste stof verkregen, welke door herkristallisatie uit ca. 50 ml acetonitril 17,5 g (opbrengst: 61 %) witte kristallen opleverde met een 30 smp. van 111-112,5°C en correcte elementaire analyse voor C, H en N.a) To a stirred suspension of 32.5 g of the above-mentioned α-amino ketone dihydrochloride in 275 ml of methanol which was cooled in an ice-water bath was slowly added a 5% sodium hydroxide solution until a pH equal to 20 was reached. 8.15 g of also cooled sodium borohydride was added to the resulting solution within 15 min and stirring was continued overnight at room temperature. The methanol was evaporated under vacuum, some water was added and extractions with 250 ml and 100 ml of methylene chloride successively were then made; the extracts were washed with water and dried. Evaporation gave 27.6 g (97%) of a yellowish solid, which, by recrystallization from approx. 50 ml of acetonitrile, gave 17.5 g (yield: 61%) of white crystals with a 30 mp. of 111-112.5 ° C and correct elemental analysis for C, H and N.
IR-spectrum (KBr), cm"1: 3390, 2980, 2290, 2840, 2820, 1480, 1435, 1285, 1240, 1220, 1105, 1020, 920, 850, 810.IR spectrum (KBr), cm -1: 3390, 2980, 2290, 2840, 2820, 1480, 1435, 1285, 1240, 1220, 1105, 1020, 920, 850, 810.
35 NMR-spectrum (CDC13), ppm: 0,82 (d, 3H; J = 6.7 Hz? CH3-), 2,3-2,9 (m, 5H; ^CH_N^CH2 )f 3/87 (t, 4H; J * xch9-NMR spectrum (CDCl3), ppm: 0.82 (d, 3H; J = 6.7 Hz? CH3-), 2.3-2.9 (m, 5H; ^ CH_N ^ CH2) f 3/87 (t , 4H; J * xch9-
/CV/RESUME
4.7 Hz; O ), 4,29 (d, 1H, J = 10 Hz;>CHOH-), 5,044.7 Hz; O), 4.29 (d, 1H, J = 10Hz;> CHOH-), 5.04
Nch2- 8201970 - 12 - (breed, 1H; -OH), 6,08 (s, 2H; 0-CH2-0), 6,94 en 7,04 (3H;Nch2-8201970-12 - (broad, 1H; -OH), 6.08 (s, 2H; O-CH2-O), 6.94, and 7.04 (3H;
Ar-).Ar-).
b) Vorming van het hydrochloride: aan een in een ijs-waterbad gekoelde oplossing van 17,03 g van de boven 5 genoemde base in 90 ml droog methyleenchloride en 300 ml droge ethylether werd 8 ml van een 11N ethanolische oplossing van HC1 toegevoegd, waardoor het hydrochloride werd neergeslagen. Toen de toevoeging was voltooid werd het roeren gedurende nog 30 min voortgezet, waarna het neerslag werd afgefiltreerd, 10 gewassen met ethylether en gedroogd onder vacuum. 19,10 g van het hydrochloride werd verkregen, met een smeltpunt van 183-184,5°C en correcte elementaire analyse voor C, Η, N en Cl.b) Formation of the hydrochloride: To a solution of 17.03 g of the above base in 90 ml of dry methylene chloride and 300 ml of dry ethyl ether, cooled in an ice-water bath, was added 8 ml of an 11N ethanolic solution of HCl, whereby the hydrochloride was precipitated. When the addition was complete, stirring was continued for an additional 30 min, after which the precipitate was filtered off, washed with ethyl ether and dried under vacuum. 19.10 g of the hydrochloride were obtained, with a melting point of 183-184.5 ° C and correct elemental analysis for C, Η, N and Cl.
IR-spectrum (KBr), cm 3300, 3020, 3000-2600, 1495, 1440, 1235, 1095, 1035, 920, 805.IR spectrum (KBr), cm 3300, 3020, 3000-2600, 1495, 1440, 1235, 1095, 1035, 920, 805.
15 VOORBEELD IXEXAMPLE IX
2-(1-piperazinyl)-3^41-methyleendioxypropio-fenon (formule 3, R1 = CH3; R2 = 1-piperazi-nyl) a) Een mengsel van 11,7 g 2-broom-3',4'-methy-20 leendipxypropiofenon en 26,51 g piperazinehexahydraat in 85 ml ethanol werd gedurende 3 h onder terugvloeiïng behandeld. De alcohol werd afgedampt, 100 ml water werd toegevoegd en gedurende 30 min werd geroerd. Het onoplosbare produkt werd afgefiltreerd en de waterige oplossing werd drie maal geëxtraheerd 25 met 100 ml methyleenchloride, de extracten werden gewassen met water en vervolgens gedroogd. Verdamping van het oplosmiddel leverde 10,3 g (86 %) half-vaste stof op.2- (1-piperazinyl) -3-4'-methylenedioxypropio-phenone (formula 3, R1 = CH3; R2 = 1-piperazinyl) a) A mixture of 11.7 g of 2-bromo-3 ', 4'- methyl-20-dipoxypropiophenone and 26.51 g of piperazine hexahydrate in 85 ml of ethanol were refluxed for 3 h. The alcohol was evaporated, 100 ml of water was added and stirred for 30 min. The insoluble product was filtered off and the aqueous solution was extracted three times with 100 ml of methylene chloride, the extracts were washed with water and then dried. Evaporation of the solvent gave 10.3 g (86%) of semi-solid.
IR-spectrum (film): 3310, 2960-2660, 166Q, 1595, 1490, 1475, 1425, 1240, 1105, 1025, 925, 860, 800.IR spectrum (film): 3310, 2960-2660, 166Q, 1595, 1490, 1475, 1425, 1240, 1105, 1025, 925, 860, 800.
30 NMR-spectrum (CDCl^), ppm: 1,24 (d, 3H; J = 6.7 Hz; CH^-) , 2,4-3,1 (m, 8H; piperazine), 3,92 (c[ , 1H; J = 6.7 Hz; /CH-), 4,30 (s, 1H; >NH), 5,90 (s, 2H; 0-CH2-0), 6,71 (d, 1H; JQ = 8 Hz; H-Ar), 7,40 (d, 1H; Jm = 2 Hz; Η-Ar) en 7,59 (dd,lH; JQ = 8 Hz, Jm = 2 Hz; H-Ar).30 NMR spectrum (CDCl 3), ppm: 1.24 (d, 3H; J = 6.7 Hz; CH 2 -), 2.4-3.1 (m, 8H; piperazine), 3.92 (c [ , 1H; J = 6.7 Hz; / CH-), 4.30 (s, 1H;> NH), 5.90 (s, 2H; 0-CH2-0), 6.71 (d, 1H; JQ = 8 Hz; H-Ar), 7.40 (d, 1H; Jm = 2 Hz; Η-Ar) and 7.59 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).
35 b) Vorming van het dihydrochloride: in droog methyleenchloride volgens de methode als beschreven in voorbeeld VIII. Smeltpunt: 242,5-243,5°C (ontl.) en juiste elementaire analyse.B) Formation of the dihydrochloride: in dry methylene chloride by the method described in Example VIII. Melting point: 242.5-243.5 ° C (dec.) And proper elemental analysis.
8201970 - 13 - IR-spectrum (KBr), cm 3400, 3010, 2980, 2800-2400, 1660, 1595, 1490, 1440, 1365, 1290, 1250, 1100, 1025.8201970 - 13 - IR spectrum (KBr), cm 3400, 3010, 2980, 2800-2400, 1660, 1595, 1490, 1440, 1365, 1290, 1250, 1100, 1025.
VOORBEELD XEXAMPLE X
5 d,l-threo-l-(3',4'-methyleendioxyfenyl)-2- (l-piperazinyl)propan-l-ol (formule l, R = CH3, R2 = 1-piperazinyl) a) 94 % ruw materiaal met een smeltpunt van 121-127°C, werd volgens de methode beschreven in voorbeeld 10 VIII geïsoleerd. Het werd gekristalliseerd uit een mengsel van water-methanol (4 : 1) (opbrengst: 57 %), smp. 136-137,5°C en juiste elementaire analyse voor C, H en N.5 d, 1-threo-1- (3 ', 4'-methylenedioxyphenyl) -2- (1-piperazinyl) propan-1-ol (formula 1, R = CH3, R2 = 1-piperazinyl) a) 94% crude material with a melting point of 121-127 ° C, was isolated according to the method described in Example 10 VIII. It was crystallized from a water-methanol mixture (4: 1) (yield: 57%), mp. 136-137.5 ° C and proper elemental analysis for C, H and N.
IR-spectrum (KBr), cm 1; 3400, 3220, 3100, 2970-2700, 1475, 1425, 1230, 1120, 1030, 915, 850, 830, 800.IR spectrum (KBr), cm 1; 3400, 3220, 3100, 2970-2700, 1475, 1425, 1230, 1120, 1030, 915, 850, 830, 800.
15 NMR-spectrum (CDCl^), ppm: 0,77 (d, 3H? J = 6,7 Hz; CH3-), 2,2-3,3 U0H; NCH_N m) f 42l ^2-^2^ 1H; J = 10 Hz,OCH0H), 5,97 (s, 2H; 0-CH2-O) , 6,86 en 6,97 (3H; Ar-).NMR spectrum (CDCl 3), ppm: 0.77 (d, 3H? J = 6.7 Hz; CH 3 -), 2.2-3.3 U0H; NCH_N m) f 421 ^ 2- ^ 2 ^ 1H; J = 10 Hz, OCHOH), 5.97 (s, 2H; O-CH2-O), 6.86 and 6.97 (3H; Ar-).
b) Vorming van het dihydrochloride: door het 20 oplossen van de base in methyleenchloride en toevoeging van ethanolische HCl-oplossing onder kwantitatieve opbrengst. Smeltpunt 205-206°C en juiste elementaire analyse.b) Formation of the dihydrochloride: by dissolving the base in methylene chloride and adding ethanolic HCl solution in quantitative yield. Melting point 205-206 ° C and proper elemental analysis.
IR-spectrum (KBr), cm 1: 3400, 3300, 2900·* 2400, 1490 1440 1235, 1025, 1005, 920, 820.IR spectrum (KBr), cm 1: 3400, 3300, 2900 * 2400, 1490 1440 1235, 1025, 1005, 920, 820.
25 VOORBEELD XIEXAMPLE XI
Uitgaande van 2-broom-3’,4'-methyleendioxy-propiofenon werden door reactie met benzylpiperazine f4-methyl-benzylpiperazine , 4-chloorbenzylpiperazine resp. 4-methoxy-benzylpiperazine, de volgende α-aminoketonen bereid volgens de 30 werkwijze beschreven in voorbeeld III: a) 2-(4-Benzyl-l-piperazinyl)-3',4'-methy-leendioxypropiofenon, vloeistof, opbrengst 98 %. (Formule 3, R1 = CH^, R2 = 4-benzyl-1-piperazinyl).Starting from 2-bromo-3 ', 4'-methylenedioxy-propiophenone, f4-methyl-benzylpiperazine, 4-chlorobenzylpiperazine, resp. 4-methoxy-benzylpiperazine, the following α-amino ketones prepared according to the method described in Example III: a) 2- (4-Benzyl-1-piperazinyl) -3 ', 4'-methylenedioxypropiophenone, liquid, 98% yield . (Formula 3, R1 = CH2, R2 = 4-Benzyl-1-piperazinyl).
IR-spectrum (film), cm 1: 3030, 3020, 2960-35 2750, 2680, 1665, 1500, 1490, 1475, 1430, 1350, 1250, 1125, 1030, 1000, 925, 800, 730.IR spectrum (film), cm 1: 3030, 3020, 2960-35 2750, 2680, 1665, 1500, 1490, 1475, 1430, 1350, 1250, 1125, 1030, 1000, 925, 800, 730.
NMR-spectrum (CDCl^), ppm: 1,20 (d, 3H; J = 8201970 ·. ** - 14 - 6.7 Hz; CHg”), 2,3-2,8 (breed, 8H; piperazine), 3;49 (£, 2H; ^N-CH2-Ar), 4,00 (g, 1H; J = 6,7 Hz; -CH^), 6,00 (s, 2H; 0-CH2-0), 6,80 (d, 1H; JQ = 8 Hz; H-Ar), 7,24 (s, 5H; Ar-), 7,58 (d, 1H; Jm = 2 Hz; Η-Ar) en 7,75 (dd, 1H; JQ = 8 Hz, 5 Jm = 2 Hz; H-Ar).NMR spectrum (CDCl 3), ppm: 1.20 (d, 3H; J = 8201970. ** - 14 - 6.7 Hz; CHg ”), 2.3-2.8 (broad, 8H; piperazine), 3.49 (,, 2H; ^ N-CH2-Ar), 4.00 (g, 1H; J = 6.7 Hz; -CH2), 6.00 (s, 2H; 0-CH2-0) , 6.80 (d, 1H; JQ = 8Hz; H-Ar), 7.24 (s, 5H; Ar-), 7.58 (d, 1H; Jm = 2Hz; Η-Ar) and 7 .75 (dd, 1H; JQ = 8 Hz, 5 Jm = 2 Hz; H-Ar).
b) Dihydrochloride: smp. 228-230°C (90 %). IR-spectrum (KBr), cm 3400, 3010, 2980, 2800-2300, 1675, 1600, 1495, 1440, 1260, 1025, 970, 740.b) Dihydrochloride: m.p. 228-230 ° C (90%). IR spectrum (KBr), cm 3400, 3010, 2980, 2800-2300, 1675, 1600, 1495, 1440, 1260, 1025, 970, 740.
c) 2-/4-(p-Methylbenzyl)-l-piperazinyl7-31,4'-10 methyleendioxypropiofenon, vloeistof, opbrengst 99 %. (Formule 3, R1 = CH3, R2 = 4-(p-methylbenzyl)-l-piperazinyl).c) 2- / 4- (p-Methylbenzyl) -1-piperazinyl7-31,4'-10 methylenedioxypropiophenone, liquid, 99% yield. (Formula 3, R1 = CH3, R2 = 4- (p-methylbenzyl) -1-piperazinyl).
IR-spectrum (film), cm 3070, 3040, 2980-2690, 1670, 1600, 1490, 1475, 1430, 1345, 1240, 1125, 1030, 925, 815.IR spectrum (film), cm 3070, 3040, 2980-2690, 1670, 1600, 1490, 1475, 1430, 1345, 1240, 1125, 1030, 925, 815.
15 NMR-spectrum (CDCl^)u ppm: 1,27 (d, 3H; J = 6.7 Hz; CH3-CH\)/ 2,32 (s, 3H; CH3-Ar), 2,4-2,8 (8H; piperazine), 3,58 (s, 2H; ^N-CH2-Ar) , 3,98 (3, 1H; J= 6,7 Hz; >CH-), 6,03 (s, 2H; 0-CH2-0), 6,86 (d, 1H; JQ = 8 Hz; H-Ar), 7,19 (s, 4H; Ar-), 7,63 (d, 1H; Jm = 2 Hz; -H-Ar), en 7,82 (dd, 20 1H; JQ = 8 Hz; Jm = 2 Hz; H-Ar).15 NMR spectrum (CDCl 3) uppm: 1.27 (d, 3H; J = 6.7 Hz; CH3-CH \) / 2.32 (s, 3H; CH3-Ar), 2.4-2.8 (8H; piperazine), 3.58 (s, 2H; NN-CH 2 -Ar), 3.98 (3.1H; J = 6.7 Hz;> CH-), 6.03 (s, 2H; 0-CH 2 -O), 6.86 (d, 1H; JQ = 8 Hz; H-Ar), 7.19 (s, 4H; Ar-), 7.63 (d, 1H; Jm = 2 Hz; -H-Ar), and 7.82 (dd, 1H; JQ = 8 Hz; Jm = 2 Hz; H-Ar).
d) Dihydrochloride: smp. 235°C (ontl.), opbrengst 86 %.d) Dihydrochloride: m.p. 235 ° C (dec.), Yield 86%.
IR_spectrum (KBr), cm 1: 3400, 3000, 2920, 2800-2400, 1670, 1600, 1500, 1450, 1255, 1030, 925, 810.IR_spectrum (KBr), cm 1: 3400, 3000, 2920, 2800-2400, 1670, 1600, 1500, 1450, 1255, 1030, 925, 810.
25 e) 2-/4-(p-Chloorbenzyl)-l-piperazinyl7-3',4 '- methyleendioxypropiofenon, vloeistof, opbrengst 98 %. (Formule 3, R1= CH3, R2 = 4-(p-chloorbenzyl)-1-piperazinyl).E) 2- / 4- (p-Chlorobenzyl) -1-piperazinyl-7-3 ', 4' - methylenedioxypropiophenone, liquid, 98% yield. (Formula 3, R1 = CH3, R2 = 4- (p-chlorobenzyl) -1-piperazinyl).
IR-spectrum (film), cm 3400,3000-2680, 1665, 1600, 1480, 1430, 1350, 1250, 1130, 1080, 1035, 1005, 30 930, 795.IR spectrum (film), cm 3400,3000-2680, 1665, 1600, 1480, 1430, 1350, 1250, 1130, 1080, 1035, 1005, 30 930, 795.
NMR-spectrum (CDC13), ppm: 1,27 (d, 3H; J = 6.7 Hz; CH3~), 2,4-2,8 (8H; piperazine), 3,59 (s, 2H; >N-CH2-Ar), 4,01 (3, 1H; J = 6,7 Hz;>CH-), 6,19 (s, 2H; 0-CH2-0), 6,90 (d^lH; JQ = 8 Hz; H-Ar), 7,31 (s, 4H; Ar-), 35 7,67 (d, 1H; Jm = 2 Hz; H-Ar), 7,84 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR spectrum (CDCl3), ppm: 1.27 (d, 3H; J = 6.7 Hz; CH3 ~), 2.4-2.8 (8H; piperazine), 3.59 (s, 2H;> N- CH2-Ar), 4.01 (3.1H; J = 6.7 Hz;> CH-), 6.19 (s, 2H; 0-CH2-0), 6.90 (d ^ 1H; JQ = 8 Hz; H-Ar), 7.31 (s, 4H; Ar-), 7.67 (d, 1H; Jm = 2 Hz; H-Ar), 7.84 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).
f) Dihydrochloride: smp. 230°C (ontl.)} (87 %). IR-spectrum (KBr), cm *: 3400, 3020, 2920, 8201970 - 15 - \ 2900, 2700-2200, 1670, 1595, 1485, 1435, 1250, 1085, 1030, 920, 805.f) Dihydrochloride: m.p. 230 ° C (dec.)} (87%). IR spectrum (KBr), cm *: 3400, 3020, 2920, 8201970 - 15 - \ 2900, 2700-2200, 1670, 1595, 1485, 1435, 1250, 1085, 1030, 920, 805.
g) 2-/4-(p-Methoxybenzyl)-l-piperazinyl7-3',4U methyleendioxypropiofenon, vloeistof, opbrengst 98 % (formule 53, R^ = CH3' R2 = (p“methoxybenzyl)-1-piperazinyl).g) 2- / 4- (p-Methoxybenzyl) -1-piperazinyl-7-3 ', 4U methylenedioxypropiophenone, liquid, yield 98% (formula 53, R 3 = CH 3' R 2 = (p-methoxybenzyl) -1-piperazinyl).
IR-spêctrum (KBr), cm *: 3060, 3000-2680, 1670, 1605, 1505, 1480, 1430, 1350, 1240, 1100, 1030, 1000, 930, 800, 750.IR Sprum (KBr), cm *: 3060, 3000-2680, 1670, 1605, 1505, 1480, 1430, 1350, 1240, 1100, 1030, 1000, 930, 800, 750.
NMR-spectrum (CDCl^)/ ppm: 1,27 (d, 3H; J = 10 6,7 Hz; CH^-), 2,3-2,8 (8H; piperazine), 3,42 (£, 2H; >N-CH2-Ar), 3,80 (s, 3H; CE^O-), 3,95 (£, 1H; J = 6,7 Hz; >CH-), 6,02 (s, 2H; 0-CH2-0), 6,75-7,30 (AA'BB'-systeem, 4H en d, 1H; JQ = 8 Hz), 7,62 (d, 1H; Jm = 2 Hz; H-Ar), 7,74 en 7,88 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR spectrum (CDCl 3) / ppm: 1.27 (d, 3H; J = 10 6.7 Hz; CH 2 -), 2.3-2.8 (8H; piperazine), 3.42 (£, 2H;> N-CH2-Ar), 3.80 (s, 3H; CE ^ O-), 3.95 (,, 1H; J = 6.7 Hz;> CH-), 6.02 (s, 2H; 0-CH2-0), 6.75-7.30 (AA'BB'-system, 4H and d, 1H; JQ = 8 Hz), 7.62 (d, 1H; Jm = 2 Hz; H -Ar), 7.74 and 7.88 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).
15 VOORBEELD XIXEXAMPLE XIX
Uitgaande van de in het voorgaande voorbeeld beschreven α-aminoketonen werden door reductie met natrium-boorhydride de volgende derivaten bereid volgens de werkwijze zoals beschreven in voorbeeld VIII (correcte elementaire ana-20 lyse voor C, Η, N en Cl).Starting from the α-amino ketones described in the previous example, the following derivatives were prepared by reduction with sodium borohydride according to the procedure described in example VIII (correct elemental analysis for C, Η, N and Cl).
a) d,1-erythro-l-(31,4'-Methyleendioxyfenyl)-2-/4-benzyl-l-piperazinyl7propan-l-ol, smp. 117-119°C (methanol-water, 2:1), opbrengst: 70 S. (Formule 1, Rj a CHy R2 ss 4-benzyl-l-piperazinyl).a) d, 1-erythro-1- (31,4'-Methylenedioxyphenyl) -2- / 4-benzyl-1-piperazinyl-7-propan-1-ol, m.p. 117-119 ° C (methanol-water, 2: 1), yield: 70 S (Formula 1, Rj a CHy R 2 ss 4-benzyl-1-piperazinyl).
25 IR-spectrum (KBr), cm 1: 3340, 3010, 2960- 2760, 1480, 1440, 1240, 1130, 1030, 925, 815, 740, 690.IR spectrum (KBr), cm 1: 3340, 3010, 2960-2760, 1480, 1440, 1240, 1130, 1030, 925, 815, 740, 690.
NMR-spectrum (CDCl^), ppm: 0,74 (d, 3H; J = 6,7 Hz; CH3-), 2,4-2,9 OH; ^CH_N^ 2 .2\N_^ 3f62 2H; CVCH2 30 ^N-CH2-Ar), 4,24 (d, 1H; J = 10 Hz; >CHOH) , 6,07 (s, 2H; -0-CH2-0), 6,94 en 7,06 (3H; Ar-), 7,51 (s, 5H; Ar-).NMR spectrum (CDCl 4), ppm: 0.74 (d, 3H; J = 6.7 Hz; CH 3 -), 2.4-2.9 OH; ^ CH_N ^ 2 .2 \ N_ ^ 3f62 2H; CVCH2 (30N-CH2-Ar), 4.24 (d, 1H; J = 10Hz;> CHOH), 6.07 (s, 2H; -0-CH2-0), 6.94 and 7.06 (3H; Ar-), 7.51 (s, 5H; Ar-).
b) Dihydrochloride: smp. 215-216°C (opbrengst 99 % betrokken op de base).b) Dihydrochloride: m.p. 215-216 ° C (yield 99% based on the base).
IR-spectrum (KBr), cm 3280, 3080, 2960, 35 2935, 2800-2400, 1485, 1430, 1230, 1025, 910, 740, 690.IR spectrum (KBr), cm 3280, 3080, 2960, 35 2935, 2800-2400, 1485, 1430, 1230, 1025, 910, 740, 690.
c) d,1-erythro-1-(3 *,4'-Methyleendioxyfenyl)-2-/4-(p-methylbenzyl)-l-piperazinyl7propan-l-ol, smp. 122-124°C (methanol-water, 3 : 1), opbrengst: 74 %. (Formule 1, R^ = CH3, 8201970 - 16 - R2 = 4-(p-methylbenzyl)-1-piperazinyl).c) d, 1-erythro-1- (3 *, 4'-methylenedioxyphenyl) -2- / 4- (p-methylbenzyl) -1-piperazinyl-7-propan-1-ol, m.p. 122-124 ° C (methanol-water, 3: 1), yield: 74%. (Formula 1, R 3 = CH 3, 8201970-16 - R2 = 4- (p-methylbenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm 3400, 3010, 2960-2680, 1475, 1435, 1235, 1125, 1030, 1000, 925, 800.IR spectrum (KBr), cm 3400, 3010, 2960-2680, 1475, 1435, 1235, 1125, 1030, 1000, 925, 800.
NMR-spectrum (CDCl^), ppm: 0,77 (d, 3H; J = 5 6,7 Hz; CH3-), 2,37 (s, 3H? CH3-Ar), 2,4-2,9 (9H; ^CH-N * Δ * N-) , 3,54 (S, 2H? >N-CH9-Ar) , 4,12 (d, 1H; xch2-ch2 J = 10 Hz;>CHOH), 6,01 (s, 2H; 0-CH2-0) , 6,87 en 6,97 (s, 3H; Ar-) en 7,28 (s, 4H? Ar-).NMR spectrum (CDCl2), ppm: 0.77 (d, 3H; J = 5 6.7 Hz; CH3-), 2.37 (s, 3H? CH3-Ar), 2.4-2.9 (9H; ^ CH-N * Δ * N-), 3.54 (S, 2H?> N-CH9-Ar), 4.12 (d, 1H; xch2-ch2 J = 10 Hz;> CHOH), 6.01 (s, 2H; 0-CH 2 -O), 6.87 and 6.97 (s, 3H; Ar-) and 7.28 (s, 4H? Ar-).
d) Dihydrochloride: smp. 252-254°C (ontl.), 10 opbrengst 99 %.d) Dihydrochloride: m.p. 252-254 ° C (dec.), Yield 99%.
IR-spectrum (KBr), cm 3300, 2960, 2880, 2800-2400, 1490, 1430, 1235, 1030, 915, 800.IR spectrum (KBr), cm 3300, 2960, 2880, 2800-2400, 1490, 1430, 1235, 1030, 915, 800.
e) d,1 - erythro-1-(3',4'-Methyleendioxy-fenyl)-2-^4-(p-chloorbenzyl)-l-piperazinyl7propan-l-ol, smp.e) d, 1- erythro-1- (3 ', 4'-Methylenedioxy-phenyl) -2- (4-chlorobenzyl) -1-piperazinyl-7-propan-1-ol, m.p.
15 136-137°C (methanol : water, 3:1), opbrengst 67 %. (Formule 1, = CH3, R2 = 4-(p-chloorbenzyl)-1-piperazinyl).136-137 ° C (methanol: water, 3: 1), yield 67%. (Formula 1, = CH3, R2 = 4- (p-chlorobenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm 3300, 2960-2760, 1475, 1439, 1230, 1130, 1080, 1030, 1000, 925, 810.IR spectrum (KBr), cm 3300, 2960-2760, 1475, 1439, 1230, 1130, 1080, 1030, 1000, 925, 810.
NMR-spectrum (CDC1-), ppm: 0,79 (d, 3H; J = 20 6,7 Hz; CH3-), 2,3-2,9 3,53 <£; 2H.NMR spectrum (CDCl-), ppm: 0.79 (d, 3H; J = 20 6.7 Hz; CH3-), 2.3-2.9 3.53 ≤ £; 2H.
ch2-ch/ >N-CH2-At), 4,20 (d, 1H; J = 10 Hzy^CHOH), 5,99 (s, 2H; 0-CH2-0), 6,83 en 6,93 (s, 2H; Ar-), 7,34 (s, 4H? Ar-).ch2-ch2> N-CH2-At), 4.20 (d, 1H; J = 10 Hzy ^ CHOH), 5.99 (s, 2H; 0-CH2-0), 6.83 and 6.93 (s, 2H; Ar-), 7.34 (s, 4H? Ar-).
f) Dihydrochloride: smp. 235-237°C (ontl.), opbrengst 99 %.f) Dihydrochloride: m.p. 235-237 ° C (dec.), Yield 99%.
25 IR-spectrum (KBr), cm 3300, 2960, 2880, 2800-2400, 1470, 1430, 1230, 1080, 1025, 910.IR spectrum (KBr), cm 3300, 2960, 2880, 2800-2400, 1470, 1430, 1230, 1080, 1025, 910.
g) d,l-erythro-l-(3',41-Methyleendioxyfenyl)-2-^4-(p-methoxybenzyl)-l-piperazinyl7propan-l-ol. (Formule 1, R1 = CH^, R2 = 4-(p-methoxybenzyl)-1-piperazinyl).g) d, 1-erythro-1- (3 ', 41-methylenedioxyphenyl) -2- (4-methoxybenzyl) -1-piperazinyl-propan-1-ol. (Formula 1, R1 = CH2, R2 = 4- (p-methoxybenzyl) -1-piperazinyl).
30 Dihydrochloride: smp. 222-222,5°C (methanol), opbrengst 41 %.Dihydrochloride: mp. 222-222.5 ° C (methanol), 41% yield.
IR-spectrum (KBr), cm 1: 3400, 3000, 2980, 2900, 2700-2300, 1515, 1485, 1435, 1250, 1025, 810.IR spectrum (KBr), cm 1: 3400, 3000, 2980, 2900, 2700-2300, 1515, 1485, 1435, 1250, 1025, 810.
NMR-spectrum (DMSO-dg), ppm: 0,98 (d, 3H; J = 35 7 Hz; CH3-) , 3,0-4,0 2 ^jj-) en 3,77 (-OCH,), 8201970 - 17 - 12H; 4,30 (s, 2H;>N-CH2-Ar), 4,65 (d, 1H; J = 10 Hz;^CHOH), 6,0 (s, 2H? o-CH2-0), 6,9-7,8 (m, 7H; Ar-).NMR spectrum (DMSO-dg), ppm: 0.98 (d, 3H; J = 35 Hz; CH3-), 3.0-4.0 2 yy-) and 3.77 (-OCH,) 8201970-17-12H; 4.30 (s, 2H;> N-CH2-Ar), 4.65 (d, 1H; J = 10 Hz; CHCHOH), 6.0 (s, 2H? O-CH2-0), 6, 9-7.8 (m, 7H; Ar-).
VOORBEELD XIIIEXAMPLE XIII
2-Fenyl-2-morfolino-3 *,4'-methyleendioxy-5 acetofenon (formule 3, R_L = CgHg, R2 = morfolinyl) a) Een mengsel van 10,21 g 2-broom-2-fenyl- 3',4'-methyleendioxyacetofenon en 11,15 g morfoline (4 eq.) in 80 ml ethanol werd gedurende 3 h onder terugvloeiïng behandeld. 10 Na koeling werd de alcohol afgedampt onder vacuum en werd het residu opgenomen in 50 ml water en 150 ml methyleenchloride.2-Phenyl-2-morpholino-3 *, 4'-methylenedioxy-5-acetophenone (formula 3, R_L = CgHg, R2 = morpholinyl) a) A mixture of 10.21 g of 2-bromo-2-phenyl-3 ', 4'-methylenedioxyacetophenone and 11.15 g of morpholine (4 eq.) In 80 ml of ethanol were refluxed for 3 h. After cooling, the alcohol was evaporated under vacuum and the residue was taken up in 50 ml of water and 150 ml of methylene chloride.
De organische fase werd gedecanteerd en de waterige fase werd met 50 ml methyleenchloride geëxtraheerd; de samengevoegde organische extracten werden gewassen met water en daarop ge-15 droogd. Het verkregen residu had een gewicht van 10,5 g (opbrengst: 100 %), was harsachtig en chromatografisch zuiver (silicagel, CHC13-CH30H 95 : 5).The organic phase was decanted and the aqueous phase was extracted with 50 ml of methylene chloride; the combined organic extracts were washed with water and dried thereon. The resulting residue weighed 10.5 g (yield: 100%), was resinous and chromatographically pure (silica gel, CHCl 3 -CH 3 OH 95: 5).
IR-spectrum (film), cm *: 3040, 2980-2700, 2680, 260Q, 1655, 1590, 1470, 1430, 1340, 1230, 1100, 1030, 20 920.IR spectrum (film), cm *: 3040, 2980-2700, 2680, 260Q, 1655, 1590, 1470, 1430, 1340, 1230, 1100, 1030, 20 920.
NMR-spectrum (CDC13), ppm: 2,57 (t, 4H; J = CH — CH “ 4,6 Hz? -N^ 2 ), 3,80 (t, 4H; J = 4,6 Hz? 0^ 2 ), 4,86NMR spectrum (CDCl3), ppm: 2.57 (t, 4H; J = CH - CH 4,6 Hz? -N ^ 2), 3,80 (t, 4H; J = 4,6 Hz? 0 ^ 2), 4.86
Nch2 nch2- (s, 1H? ^>CH-), 6,00 (s, 2H? 0-CH2-0), 6,80 (d, 1H; JQ = 8 Hz? Η-Ar), 7,2-7,6 (m, 6H? -Ar), 7,67 en 7,81 (dd, 1H; JQ = 8 Hz, 25 J= 2 Hz? H-Ar). m b) Vorming van het hydrochloride: de geïsoleerde base werd opgelost in 175 ml watervrije ethylether en onder koeling werd een equivalente hoeveelheid 11N ethanoli-sche oplossing van HC1 toegevoegd. Het hydrochloride werd ver- 30 kregen in een opbrengst van 95 %, was een witte vaste stof met een smeltpunt van 228-230°C (ontL) en correcte elementaire analyse.Nch2 nch2- (s, 1H? ^> CH-), 6.00 (s, 2H? 0-CH2-0), 6.80 (d, 1H; JQ = 8 Hz? Η-Ar), 7.2 -7.6 (m, 6H? -Ar), 7.67 and 7.81 (dd, 1H; JQ = 8 Hz, 25 J = 2 Hz? H-Ar). m b) Formation of the hydrochloride: The isolated base was dissolved in 175 ml anhydrous ethyl ether and an equivalent amount of 11N ethanolic solution of HCl was added with cooling. The hydrochloride was obtained in 95% yield, was a white solid with a melting point of 228-230 ° C (ontL) and correct elemental analysis.
IR-spectrum (KBr), cm""1: 3400, 3010, 2900, 2700-2400, 1670, 1600, 1480, 1430, 1350, 1255, 1025, 950, 35 92Q, 880.IR spectrum (KBr), cm -1, 3400, 3010, 2900, 2700-2400, 1670, 1600, 1480, 1430, 1350, 1255, 1025, 950, 35 92Q, 880.
VOORBEELD XIVEXAMPLE XIV
Uitgaande van 2-broom-2-fenyl-3',4 *-methyleen- 8201970 - 18 - dioxyacetofenon en de betrokken benzylpiperazinen werden de volgende derivaten bereid volgens de werkwijze beschreven iiï vo.orbeeld III: a) 2-Fenyl-2-(4-benzyl-l-piperazinyl)-3' ,4'-5 methyleendioxyacetofenon, opbrengst 99 % (formule 3, R1 =Starting from 2-bromo-2-phenyl-3 ', 4 * -methylene-8201970-18-dioxyacetophenone and the appropriate benzylpiperazines, the following derivatives were prepared according to the procedure described in Example III: a) 2-Phenyl-2- (4-benzyl-1-piperazinyl) -3 ', 4'-5-methylenedioxyacetophenone, yield 99% (formula 3, R1 =
CgHg, = 4-benzyl-l-piperazinyl).CgHg = 4-benzyl-1-piperazinyl).
IR-spectrum (KBr), cm *: 3030, 3010, 2900, 2800, 2760, 1670, 1600, 1490, 1430.IR spectrum (KBr), cm *: 3030, 3010, 2900, 2800, 2760, 1670, 1600, 1490, 1430.
NMR-spectrum (CDCl^), ppm: 2,63 (is, 8H; 10 piperazine), 3,62 (s, 2H;>N-CH2-Ar), 4,93 (s, 1H;^CH-), 6,08 (s, 2H; -O-CHj-O), 6,89 (d, 1H; JQ = 8 Hz; H-Ar), 7,3- 7,6 (m, 10H; Ar-), 7,66 (d, 1H; Jm = 2 Hz; H-Ar), 7,94 en 7,81 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).NMR Spectrum (CDCl2), ppm: 2.63 (is, 8H; piperazine), 3.62 (s, 2H;> N-CH2-Ar), 4.93 (s, 1H; ^ CH-) 6.08 (s, 2H; -O-CHl-O), 6.89 (d, 1H; JQ = 8Hz; H-Ar), 7.3-7.6 (m, 10H; Ar-) , 7.66 (d, 1H; Jm = 2 Hz; H-Ar), 7.94 and 7.81 (dd, 1H; JQ = 8 Hz, Jm = 2 Hz; H-Ar).
b) Dihydrochloride: smp. 233,5-234°C (op- 15 brengst 95 %).b) Dihydrochloride: m.p. 233.5-234 ° C (yield 95%).
IR-spectrum (KBr), cm 3400, 3020, 2980, 2920, 2700-2200, 1660, 1500, 1495, 1455, 1290, 1260, 1030, 920, 750.IR spectrum (KBr), cm 3400, 3020, 2980, 2920, 2700-2200, 1660, 1500, 1495, 1455, 1290, 1260, 1030, 920, 750.
c) 2-Eenyl-2-i/4- (p-chloorbenzyl) -l-pipera- 20 zinyl7_3',4'-methyleendioxyacetofenon, opbrengst 99 % (formule 3, R1 - CgH^, R2 * 4-(p-chloorbenzyl)-1-piperazinyl) .c) 2-Enyl-2-1 / 4- (p-chlorobenzyl) -1-pipera-20-ylyl_3 ', 4'-methylenedioxyacetophenone, yield 99% (formula 3, R1 - C8H2, R2 * 4- (p- chlorobenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm 1: 3025, 3010, 2900- 2800, 1680, 1600, 1485, 1435, 1235, 1100, 1030, 930, 790.IR spectrum (KBr), cm 1: 3025, 3010, 2900-2800, 1680, 1600, 1485, 1435, 1235, 1100, 1030, 930, 790.
NMR-spectrum (CDCl^), ppm: 2,51 (s, (H; 25 piperazine), 3,46 (s, 2H; ^N-CH2-Ar) , 4,82 (£3, 1H; -CH^) t 5,97 (S, 2H; -0-CH2”0-), 6,78 (s, 1H; JQ - 8 Hz; H-Ar), 7,2- 7,5 (4H; -Ar), 7,58 (d, 1H; Jm = 2 Hz; H-Ar), 7,69-7,82 (dd, J = 8 Hz, J = 2 Hz; H-Ar). o m _ d) Dihydrochloride: smp. 2l5-2l8°C (94 %).NMR Spectrum (CDCl 3), ppm: 2.51 (s, (H; 25 piperazine), 3.46 (s, 2H; ^ N-CH 2 -Ar), 4.82 (£ 3.1H; -CH ^) 5.97 (S, 2H; -O-CH 2 ”0-), 6.78 (s, 1H; JQ - 8 Hz; H-Ar), 7.2-7.5 (4H; -Ar ), 7.58 (d, 1H; Jm = 2 Hz; H-Ar), 7.69-7.82 (dd, J = 8 Hz, J = 2 Hz; H-Ar). Om _ d) Dihydrochloride : smp. 2l5-218 ° C (94%).
30 IR-spectrum (KBr), cm 3400, 3015, 2980, 2900, 2700-2200, 1660, 1590, 1490, 1440, 1250, 1100, 1025, 920, 800.IR spectrum (KBr), cm 3400, 3015, 2980, 2900, 2700-2200, 1660, 1590, 1490, 1440, 1250, 1100, 1025, 920, 800.
VOORBEELD KVEXAMPLE KV
Uitgaande van de in de voorbeelden XIII en 35 XIV beschreven α-ketoaminen en door reductie met natriumboor-hydride in licht alkalisch medium werden de volgende a,$-aminoalcoholen bereid onder de omstandigheden beschreven in de voorbeelden VIII en XII: 8201970 - 19 - a) d,1-erythro-1-(3', 4' -Methyleendioxyfeny1)- 2-fenyl-2-morfolino-ethanol, smp. 91-92°C (hexaan), opbrengst 65 % (formule 1, = CgHg, R2 = morfolinyl).Starting from the α-ketoamines described in Examples XIII and 35 XIV and by reduction with sodium borohydride in slightly alkaline medium, the following α-amino-alcohols were prepared under the conditions described in Examples VIII and XII: 8201970-19 - a ) d, 1-erythro-1- (3 ', 4'-methylenedioxyphenyl) -2-phenyl-2-morpholinoethanol, m.p. 91-92 ° C (hexane), yield 65% (formula 1, = C 8 Hg, R 2 = morpholinyl).
IR-spectrum (KBr), cm : 3480, 3030, 3010, 5 2970, 2890-2700, 1500, 1485, 1435, 1300, 1240, 1110, 1040, 875, 700.IR spectrum (KBr), cm: 3480, 3030, 3010, 5 2970, 2890-2700, 1500, 1485, 1435, 1300, 1240, 1110, 1040, 875, 700.
NMR-spectrum (CDCl^), ppm: 2,3-2,5 (4H; /CH 2~ 'S'Ar n:\ -), 3,1-3,5 (1H? -OH), 3,25 (d, 1H; J = 4 Hz; -CH ), xch9- N^ /OH - 3,67 (t, 4H; J = 4,6 Hz; 0 ), 5,20, (d, 1H; J = 4 Hz; ν0Η2- 10 ^CHOH) , 5,80 (s, 2H; 0-CH2-0), 6,3-6,6 (m, 3H; Ar-) , 7,12 (m, 5H; Ar-).NMR spectrum (CDCl 3), ppm: 2.3-2.5 (4H; / CH 2 'S'Ar n: \ -), 3.1-3.5 (1H? -OH), 3, 25 (d, 1H; J = 4Hz; -CH), xch9-N2 / OH - 3.67 (t, 4H; J = 4.6Hz; 0), 5.20, (d, 1H; J = 4 Hz; ΗOΗ2-10 ^ CHOH), 5.80 (s, 2H; O-CH2-0), 6.3-6.6 (m, 3H; Ar-), 7.12 (m, 5H; Ar-).
b) Hydrochloride: smp. 22l-224°C (99 %). IR-spectrum (KBr), cm"1: 3300, 3010, 2910, 2800-2400, 1490, 1480, 1230, 1125, 1030, 915, 880, 700.b) Hydrochloride: mp. 22l-224 ° C (99%). IR spectrum (KBr), cm -1: 3300, 3010, 2910, 2800-2400, 1490, 1480, 1230, 1125, 1030, 915, 880, 700.
15 c) d, 1-erythro-1- (3', 4' -Methyleendioxyfenyl) - 2-£enyl-2-^4-benzyl-l-piperazinyl7ethanol, smp. 101-103°C (hexaan), opbrengst 80 % (formule 1, R^ = C6H5' R2 = 4-benzyl- 1- piperazinyl).C) d, 1-erythro-1- (3 ', 4'-methylenedioxyphenyl) -2-enyl-2- 4-benzyl-1-piperazinyl-ethanol, m.p. 101-103 ° C (hexane), yield 80% (formula 1, R 1 = C 6 H 5 R 2 = 4-benzyl-1-piperazinyl).
IR-spectrum (KBr), cm 1: 3300, 3010, 2960, 20 2940-2700, 1490, 1480, 1230, 1125, 1030, 700.IR spectrum (KBr), cm 1: 3300, 3010, 2960, 20 2940-2700, 1490, 1480, 1230, 1125, 1030, 700.
NMR-spectrum (CDCl.,), ppm: 2,55 (s, 8H; J at piperazine), 3,33 (d, 1H; J = 4,5 Hz; _CH/ j 3 51 (s 2H* N< -CH2-), 5,24 (d, 1H; J = 4,5 Hz; -CHOH), 5,86 (s, 2H; 0-CH2-0), 6,4-6,7 (3H; Ar-) en 7,00-7,4 (10H; Ar-).NMR spectrum (CDCl.,), Ppm: 2.55 (s, 8H; J at piperazine), 3.33 (d, 1H; J = 4.5 Hz; _CH / j 3 51 (s 2H * N < -CH2-), 5.24 (d, 1H; J = 4.5 Hz; -CHOH), 5.86 (s, 2H; 0-CH2-0), 6.4-6.7 (3H; Ar -) and 7.00-7.4 (10H; Ar-).
25 d) Dihydrochloride: smp. 228°C (ontl.), 98 %.D) Dihydrochloride: mp. 228 ° C (dec.), 98%.
IR-spectrum (KBr), cm 1: 3400, 3200, 3000-2900, 2700-2400, 1500, 1440, 1230, 1030, 930, 705.IR spectrum (KBr), cm 1: 3400, 3200, 3000-2900, 2700-2400, 1500, 1440, 1230, 1030, 930, 705.
e) d,1-erythro-1-(3',4'-methyleendioxyfeny1)- 2- feny1-2-^4-(p-chloorbenzyl)-1-piperazinyl7ethanol, smp.e) d, 1-erythro-1- (3 ', 4'-methylenedioxyphenyl) -2-phenyl-2- (4- (p-chlorobenzyl) -1-piperazinyl] ethanol, m.p.
30 133-136°C (acetonitril), opbrengst 72 % (formule 1, R^ =133-136 ° C (acetonitrile), 72% yield (formula 1, R4 =
CgHg, R2 = 4-(p-chloorbenzyl)-1-piperazinyl).CgHg, R 2 = 4- (p-chlorobenzyl) -1-piperazinyl).
IR-spectrum (KBr), cm ^ 3370, 3010, 2960- 2700, 1490, 1480, 1440, 1240, 1135, 1040, 995, 800, 700.IR spectrum (KBr), cm ^ 3370, 3010, 2960-2700, 1490, 1480, 1440, 1240, 1135, 1040, 995, 800, 700.
NMR-spectrum (CDC1-), ppm: 2,47 (s, breed, J “ Ar 35 9H; piperazine en -OH), 3,24 (d, 1H; J = 4,5 Hz; _CH^ j 8201970 - 20 - 3,37 (s, 2H; -CH2-), 5,09 (d, 1H; J = 4,5 Hz; -CHOH_), 5,67 (s, 2H; 0-CH2“0), 6,3-6,5 (m, 3H; Ar-) en 6,9-7,2 (m, 9H; Ar-).NMR spectrum (CDCl-), ppm: 2.47 (s, broad, J 5 Ar 9H; piperazine and -OH), 3.24 (d, 1H; J = 4.5 Hz; CH 8 j 8201 970 - 20 - 3.37 (s, 2H; -CH2 -), 5.09 (d, 1H; J = 4.5 Hz; -CHOH_), 5.67 (s, 2H; 0-CH2 “0), 6 .3-6.5 (m, 3H; Ar-) and 6.9-7.2 (m, 9H; Ar-).
f) Dihydrochloride: smp. 250-256°C (ontl.), 95 %.f) Dihydrochloride: m.p. 250-256 ° C (dec.), 95%.
5 IR-spectrum (KBr), cm 3400, 3010, 2980, 2900, 2700-2300, 1495, 1485, 1430, 1240, 1030, 930, 810, 700.IR spectrum (KBr), cm 3400, 3010, 2980, 2900, 2700-2300, 1495, 1485, 1430, 1240, 1030, 930, 810, 700.
VOORBEELD XVIEXAMPLE XVI
d,1-erythro-l-(3',4'-Methyleendioxyfenyl)-2-/4-(p-methylbenzyl)-l-piperazinyl7propan-10 l-ol (formule 1, erythro, R^^ = CH3, R2 s 4-(p-methylbenzyl)-1-piperazinyl) a) De herkristallisatie-oplossing van d,l-threo-1-(3',4'-methyleendioxyfenyl)-2-/4-(p-methylbenzyl)-1-piperazinyl7propan-l-ol (voorbeeld XIIc) werd drooggedampt en 15 het residu werd opgelost in chloroform aan chromatografie onderworpen (silicagelkolom) door te elueren met chloroform en chloroform-methanolmengsels met toenemende polariteit. De threo-diastereoisomeer wordt eerst geëlueerd en vervolgens wordt de erythro-diastereoisomeer opgevangen. De erythro-dia-20 stereoisomeer heeft een smeltpunt van 136-138°C (methanol : water 3 : 1). Opbrengst: 8 %.d, 1-erythro-1- (3 ', 4'-Methylenedioxyphenyl) -2- / 4- (p-methylbenzyl) -1-piperazinyl-7-propan-10-ol (formula 1, erythro, R ^^ = CH3, R2 s 4- (p-methylbenzyl) -1-piperazinyl) a) The recrystallization solution of d, 1-threo-1- (3 ', 4'-methylenedioxyphenyl) -2- / 4- (p-methylbenzyl) -1 piperazinyl-7-propan-1-ol (example XIIc) was evaporated to dryness and the residue was dissolved in chloroform chromatographed (silica gel column) by eluting with chloroform and chloroform-methanol mixtures of increasing polarity. The threo diastereoisomer is first eluted and then the erythro diastereoisomer is collected. The erythro-dia-20 stereoisomer has a melting point of 136-138 ° C (methanol: water 3: 1). Yield: 8%.
IR-spectrum (KBr), cm 3140, 3020, 2990-2780, 1500, 1480, 1430, 1335, 1235, 1145, 1035, 1005, 930, 850, 820.IR spectrum (KBr), cm 3140, 3020, 2990-2780, 1500, 1480, 1430, 1335, 1235, 1145, 1035, 1005, 930, 850, 820.
25 NMR-spectrum (CDC13), ppm: 0,84 (d, 4H; J = 7,3 Hz; CH3-), 2,39 (s, 3H; CH3-Ar), 2,46-2,87 (m, 9H; .CH9-CH9\ CH-Nf Δ Δ N-), 3,54 (s, 2H; ^N-CH.-Ar), 4,90 (d, 1H; ch2-ch2^ J = 4,2 Hz,OCH0H), 6,04 (s, 2H; 0-CH2-0) , 6,90 en 6,99 (s, 3H; Ar-) en 7,32 (s, 4H; Ar-).NMR Spectrum (CDCl3), ppm: 0.84 (d, 4H; J = 7.3 Hz; CH3-), 2.39 (s, 3H; CH3-Ar), 2.46-2.87 ( m, 9H; CH9-CH9 \ CH-Nf Δ Δ N-), 3.54 (s, 2H; ^ N-CH.-Ar), 4.90 (d, 1H; ch2-ch2 ^ J = 4 , 2 Hz, OCHOH), 6.04 (s, 2H; 0-CH 2 -O), 6.90 and 6.99 (s, 3H; Ar-) and 7.32 (s, 4H; Ar-).
30 b) Dihydrochloride: smp. 225-230°C (ontl.), opbrengst 95 %.B) Dihydrochloride: m.p. 225-230 ° C (dec.), Yield 95%.
IR-spectrum (KBr), cm 3400, 3030, 2980-2900, 2700-2400, 1500, 1490, 1435, 1235, 1035, 925, 800, 785 35 8201970IR spectrum (KBr), cm 3400, 3030, 2980-2900, 2700-2400, 1500, 1490, 1435, 1235, 1035, 925, 800, 785 35 8201970
Bte·· ' —~Bte ·· '- ~
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES502469A ES8203876A1 (en) | 1981-05-13 | 1981-05-13 | Novel cyclic alpha-amino derivative of 1-(3',4'-methylenedioxyphenyl)ethanol, manufacture and hypotensive and analgesic medicinal composition containing same |
| ES502469 | 1981-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8201970A true NL8201970A (en) | 1982-12-01 |
Family
ID=8482434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8201970A NL8201970A (en) | 1981-05-13 | 1982-05-13 | Process for the preparation of cyclic alpha-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol, as well as alpha-amino derivatives of 2-substituted 1- (3, 4'-methylenedioxyphenyl). |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5815970A (en) |
| BE (1) | BE893173A (en) |
| DE (1) | DE3218048A1 (en) |
| ES (1) | ES8203876A1 (en) |
| FR (1) | FR2511246B1 (en) |
| IT (1) | IT1190818B (en) |
| NL (1) | NL8201970A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02124884A (en) * | 1988-07-08 | 1990-05-14 | Zhongguo Yixuekexueyuan Yaowo Yanjiusuo | N-substituted amide derivative |
| US5710288A (en) * | 1993-04-21 | 1998-01-20 | Allergan | 1,3-benzodioxole and 1,2-dialkoxybenzene derivatives as ocular hypotensive agents |
| US5369127A (en) * | 1993-04-21 | 1994-11-29 | Allergan, Inc. | 1,3-benzodioxole and 1,2-dialkoxybenzene derivatives as ocular hypotensive agents |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2143073A1 (en) * | 1971-06-24 | 1973-02-02 | Kyowa Hakko Kogyo Kk | 1-(3,4-methylenedioxyphenyl)-2-alkylamino-ethanols - - with beta-blocking activity |
| DE2325633A1 (en) * | 1973-05-21 | 1974-12-12 | Boehringer Sohn Ingelheim | PIPERAZINE DERIVATIVES |
| JPS6032637B2 (en) * | 1976-06-22 | 1985-07-29 | ウェルファイド株式会社 | Amino alcohol derivative |
| DE2735589A1 (en) * | 1977-08-06 | 1979-02-15 | Beiersdorf Ag | 1-PHENYL-1-METHOXY-2-AMINO-AETHANE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
| ES497763A0 (en) * | 1980-11-24 | 1981-12-16 | Ferrer Int | PROCEDURE FOR OBTAINING NEW 2-AMINOETHANOLS |
| JPS57154183A (en) * | 1981-03-17 | 1982-09-22 | Mitsubishi Chem Ind Ltd | Omega-piperazinylalkanoylalkylene dioxybenzenes and their acid addition salts |
-
1981
- 1981-05-13 ES ES502469A patent/ES8203876A1/en not_active Expired
-
1982
- 1982-05-12 IT IT21219/82A patent/IT1190818B/en active
- 1982-05-13 BE BE0/208085A patent/BE893173A/en unknown
- 1982-05-13 NL NL8201970A patent/NL8201970A/en not_active Application Discontinuation
- 1982-05-13 JP JP57079279A patent/JPS5815970A/en active Pending
- 1982-05-13 DE DE3218048A patent/DE3218048A1/en not_active Ceased
- 1982-05-13 FR FR8208362A patent/FR2511246B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5815970A (en) | 1983-01-29 |
| IT1190818B (en) | 1988-02-24 |
| ES502469A0 (en) | 1982-04-01 |
| BE893173A (en) | 1982-08-30 |
| IT8221219A0 (en) | 1982-05-12 |
| FR2511246B1 (en) | 1986-08-14 |
| FR2511246A1 (en) | 1983-02-18 |
| DE3218048A1 (en) | 1983-01-05 |
| ES8203876A1 (en) | 1982-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2130393A1 (en) | Tetrahydronaphthyloxyaminopropanols, processes for their production and pharmaceutical preparations which contain these compounds as active ingredients | |
| DK157545B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 4-PHENYL-1-HYDROXYALKYLIMIDAZOLD DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. | |
| DK142989B (en) | PROCEDURE FOR MANUFACTURING FUROKUMARINS | |
| SU533336A3 (en) | The method of obtaining aminopropanol, their salts or optically active antipodes | |
| EP0496238A1 (en) | Substituted benzoxazepines and benzothiazepines, process for their preparation and their use as medicaments | |
| DE2333847A1 (en) | TETRAHYDRONAPHTHOLS, THEIR SALTS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| EP0429370B1 (en) | Thiophene derivatives, process for their preparation and pharmaceutical compositions containing them | |
| NL8201970A (en) | Process for the preparation of cyclic alpha-amino derivatives of 1- (3 ', 4'-methylenedioxyphenyl) ethanol, as well as alpha-amino derivatives of 2-substituted 1- (3, 4'-methylenedioxyphenyl). | |
| FR2522000A1 (en) | NOVEL THIOPYRANNOPYRIMIDINES, PARTICULARLY USEFUL AS HYPOGLYCEMIC AGENTS, AND THEIR MANUFACTURE | |
| Marxer | The Acylation and Alkylation of Imidazolines and Some New Types of Imidazolines1 | |
| DE2616484C3 (en) | Basic benzoyl ethers, their salts and quaternary ammonium compounds as well as processes for their preparation and pharmaceuticals containing them | |
| IL103229A (en) | Imidazolylmethyl-pyridine derivatives their preparation and pharmaceutical compositions containing them | |
| JPH02115166A (en) | Pyridylketoxime ether derivative and medicine composition containing the same | |
| DE3042844A1 (en) | 2- (1H-IMIDAZOL-1-YL) -ETHOXY DERIVATIVES OF CHINOLIN-2- AND 4-METHANOLS, METHOD FOR THEIR PRODUCTION, MEDICINAL PRODUCTS AND THE USE THEREOF | |
| CA2022812A1 (en) | Chalcone derivatives | |
| US3764609A (en) | 1 (dibenzo {8 4,d{9 {0 cyclohepten-5-yl), 1-(dibenzo {8 a,d{9 {0 cycloheptan-5-yl) and 1-(dibenzo {8 a,d{9 {0 cyclooctanyl)imidazoles | |
| US2810719A (en) | Morpholino alkyl ethers of hydroxybenzoic acid esters | |
| US2892847A (en) | Benzofuran-derivatives | |
| FR2505655A1 (en) | MEDICAMENTS CONSISTING OF NOVEL AMINODERIVES IN POSITION 1 OF 1- (3 ', 4'-METHYLENEDIOXYPHENYL) PROPAN-2-OL AND PROCESS FOR THE PRODUCTION THEREOF | |
| US3322778A (en) | Novel ether derivatives of benzmorphans | |
| Buzas et al. | Synthesis and psychoanaleptic properties of new compounds structurally related to diphenhydramine | |
| US3637853A (en) | O o'-bis(gamma-dimethylamino-propyl)-diisoeugenol and salts thereof | |
| Bruson et al. | Trinitro-phenylethyl Amines from TNT1 | |
| DE2755045A1 (en) | DICARBOXIMIDAMIDE AND THEIR SALTS, PROCESS FOR THEIR MANUFACTURING AND THEIR USE IN THE CONTROL OF INFLAMMATION | |
| RU2005717C1 (en) | Process for preparing aralkylamine derivatives or their acid addition salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| BT | A notification was added to the application dossier and made available to the public | ||
| A85 | Still pending on 85-01-01 | ||
| BA | A request for search or an international-type search has been filed | ||
| BB | A search report has been drawn up | ||
| BV | The patent application has lapsed |