FI64351C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV N-CYCLOHEXYL-N-METHYL-N- (2-AMINO-3,5-DIBROMO-BENZYL) -AMINE - Google Patents
NYTT FOERFARANDE FOER FRAMSTAELLNING AV N-CYCLOHEXYL-N-METHYL-N- (2-AMINO-3,5-DIBROMO-BENZYL) -AMINE Download PDFInfo
- Publication number
- FI64351C FI64351C FI762141A FI762141A FI64351C FI 64351 C FI64351 C FI 64351C FI 762141 A FI762141 A FI 762141A FI 762141 A FI762141 A FI 762141A FI 64351 C FI64351 C FI 64351C
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- Finland
- Prior art keywords
- methyl
- cyclohexyl
- formula
- amino
- acid
- Prior art date
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- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 title claims 3
- 239000002253 acid Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 11
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 11
- WMJWASKQHNPDBY-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(Br)C=CC=C1CBr WMJWASKQHNPDBY-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000002516 radical scavenger Substances 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 239000011135 tin Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 238000007883 cyanide addition reaction Methods 0.000 claims 1
- 235000020357 syrup Nutrition 0.000 claims 1
- 239000006188 syrup Substances 0.000 claims 1
- -1 2-amino-3,5-dibromobenzyl Chemical group 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005893 bromination reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000031709 bromination Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 2
- XDKMDDOCVPNVMB-UHFFFAOYSA-N 1-bromo-3-methyl-2-nitrobenzene Chemical compound CC1=CC=CC(Br)=C1[N+]([O-])=O XDKMDDOCVPNVMB-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- DGDAVTPQCQXLGU-UHFFFAOYSA-N 5437-38-7 Chemical compound CC1=CC=CC(C(O)=O)=C1[N+]([O-])=O DGDAVTPQCQXLGU-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- LRVPHKNSGVHIMB-UHFFFAOYSA-N n-methylcyclohexanamine;hydrobromide Chemical compound Br.CNC1CCCCC1 LRVPHKNSGVHIMB-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- LOOOTYOQFFOBCI-UHFFFAOYSA-N 2,4-dibromo-6-methylaniline Chemical compound CC1=CC(Br)=CC(Br)=C1N LOOOTYOQFFOBCI-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- ZTLCGLNRDJJEFV-UHFFFAOYSA-N CN(C(C1=C(C(=CC=C1)CC)[N+](=O)[O-])=O)C1CCCCC1 Chemical compound CN(C(C1=C(C(=CC=C1)CC)[N+](=O)[O-])=O)C1CCCCC1 ZTLCGLNRDJJEFV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- ZCBDEPONEUTHFL-UHFFFAOYSA-M [N+](=O)([O-])C1=C(C(=O)[O-])C=CC=C1C.[Ag+] Chemical compound [N+](=O)([O-])C1=C(C(=O)[O-])C=CC=C1C.[Ag+] ZCBDEPONEUTHFL-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229910052614 beryl Inorganic materials 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 108010072897 transcription factor Brn-2 Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
ra^l ΓβΙ m)^^ULUTUSJULKAISUra ^ l ΓβΙ m) ^^ RELEASE PUBLICATION
' UTLÄGGNJNGSSKRIFT OHOO I'UTLÄGGNJNGSSKRIFT OHOO I
C (45) Patentti oyännc-tty 10 11 1933 1ÄjjÖ? j Patent neddelat ^ ' / (51) Kr.lk.^nt.a." C 07 C 87/60 SUOMI —FINLAND (21) P*tenttlhakemu» — Patent»ns6knlng /621^1 (22) HikemhpSIvS — Ansökningjdag 27.0:. ;0 ^ (23) Alkupilvi — Glltlghetsdag 27-07-76 (41) Tullut Julkiseksi — BMvit offentllg 29-0-7.77C (45) Patent oyännc-tty 10 11 1933 1ÄjjÖ? j Patent patentdd / '(51) Kr.lk. ^ nt.a. "C 07 C 87/60 FINLAND —FINLAND (21) P * tenttlhakemu» - Patent »ns6knlng / 621 ^ 1 (22) HikemhpSIvS - Ansökningjdag 27.0 :.; 0 ^ (23) Primary Cloud - Glltlghetsdag 27-07-76 (41) Become Public - BMvit offentllg 29-0-7.77
Patentti- ja rekisterihallitus (44) Nihtivikslparwn ja kuul.Julkiisun pvm. —National Board of Patents and Registration (44) Nihtivikslparwn and heard. -
Patent- och reyssterstyreisen AnsdJkan utlagd och uti.skrift*.n pubPcerad 29-0 ' - -> (32)(33)(31) Pyydetty etuoikeus—Begird prlorltet 28.2 0.7?Patent- och reyssterstyreisen AnsdJkan utlagd och uti.skrift * .n pubPcerad 29-0 '- -> (32) (33) (31) Requested Privilege — Begird prlorltet 28.2 0.7?
Unkari-Ungern(HU) EE-2387 (7i) p GY T Gyogy szervegy es zet.i Gyär, 30 Kereszturi ut, Budapest- X,Hungary-Hungary (HU) EE-2387 (7i) p GY T Gyogy orgegy es zet.i Gyär, 30 Kereszturi ut, Budapest- X,
Urvkari-Ungnrn (lUOUrvkari-Ungnrn (lUO
(72' .’-l··,·:·. !'l>rr . ! m ι d a.prt, Tamar. Fodor, Budapest, Jesse*1 Räkoev-i , Budapest , .' Λ. ·,': - !'iniapes l , Fill Vfigo, Budapest, Unkari -Ungevn (HU )(72 '.'- l · ·, ·: ·.!' L> rr.! M ι d a.prt, Tamar. Fodor, Budapest, Jesse * 1 Räkoev-i, Budapest,. 'Λ. ·,' : -! 'iniapes l, Fill Vfigo, Budapest, Hungary -Ungevn (HU)
7,0-0 i' v Soi ntnr AU7.0-0 i 'v Soi ntnr AU
(0+) - :’,ykloheksyyli-N-metyyli-N-(2-ainino-3,B-dibromi-ber.tsyyli '--amiinin uusi valmistusmenetelmä - Nytt förfarande för framställninp av N-eyk-iohexyl-N-metyl-N-(2-amino-3,5-dibrom-bensyl)-aminNew process for the preparation of (0+) -: ', cyclohexyl-N-methyl-N- (2-amino-3, B-dibromo-beryl'-amine - Nyt förfarande för framställninp av N-eyk-iohexyl-N- methyl-N- (2-amino-3,5-dibromo-benzyl) -amin
Keksintö käsittelee uutta menetelmää kaavan I mukaisen N-sykloheksyyli-N-metyyli-N-(2-amino-3,5-dibromibentsyy1i)amiinin ja sen epäorgaanisten ja orgaanisten happojen kanssa muodostettujen happoadditiosuolojen valmistamiseksi:The invention relates to a new process for the preparation of N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of the formula I and its acid addition salts with inorganic and organic acids:
CHCH
^0--·“.-1 ~o 7Γ NH_ I 2^ 0-- · “.- 1 ~ o 7Γ NH_ I 2
Brbr
Kaavan I mukaisella yhdisteellä on erinomainen hengitysteiden limaa irrottava vaikutus ja se on hyödyllinen käsiteltäessä kroonisia hengityselinsairauksia.The compound of formula I has an excellent airway mucolytic effect and is useful in the treatment of chronic respiratory diseases.
6435164351
Kaavan I mukaisen N-sykloheksyyli-N-metyyli-N-(2-amino-3,5-dibromibentsyyli)amiinin valmistusmenetelmässä on lähtöaineena teollisessa valmistuksessa käytetty o-nitrobentsyylibromidia, joka saatetaan reagoimaan N-rnetyylisykloheksyyliamiinin kanssa. Saatu välituote pelkistetään, ja aromaattinen rengas dibromataan. Bromauksen saanto on vain 38,5 % ja synteesin kokonaissaanto on vain 32 %, ts. menetelmä ei ole taloudellinen (DE-patenttijulkaisu 1 169 939). Tämän menetelmän haittana on myös o-nitrobentsyylibromidin epätervel-lisyys ja silmiä ärsyttävä vaikutus.The process for the preparation of N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of the formula I uses as starting material o-nitrobenzyl bromide which is reacted with N-methylcyclohexylamine in industrial production. The resulting intermediate is reduced and the aromatic ring is dibromatated. The yield of bromination is only 38.5% and the total yield of the synthesis is only 32%, i.e. the method is not economical (DE patent 1,169,939). Another disadvantage of this method is the unhealthiness and eye irritation of o-nitrobenzyl bromide.
Toisen tunnetun menetelmän mukaan 3,5-dibromi-2-amino-tolu-eeni diasetyloidaan ja saatetaan reagoimaan N-bromimeripihkahappo-imidin kanssa, jolloin saadaan 3,5-dibromi-2-diasetaminobentsyyli-bromidi, joka sitten saatetaan reagoimaan N-metyyli-sykloheksyyli-amiinin kanssa, jota seuraa hydrolyysi kloorivetyhapon kanssa (DE-patentti julkaisu 1 169 939). N-bromimeripihkahapon kanssa suoritetun bromauksen saanto on 16 %, ja synteesin kokonaissaanto on hyvin alhainen, so. 7 %. 3,5-dibromi-2-diasetaminobentsyylibromidi on myös silmiä ärsyttävä, ja se on kiteytettävä uudelleen vähintään 4-6 kertaa ennenkuin saadaan riittävän puhdas lopputuote.According to another known method, 3,5-dibromo-2-amino-toluene is diacetylated and reacted with N-bromosuccinimide to give 3,5-dibromo-2-diacetaminobenzyl bromide, which is then reacted with N-methyl with cyclohexylamine followed by hydrolysis with hydrochloric acid (DE Patent Publication 1,169,939). The yield of bromination with N-bromosuccinic acid is 16%, and the overall yield of the synthesis is very low, i. 7%. 3,5-Dibromo-2-diacetaminobenzyl bromide is also irritating to the eyes and must be recrystallized at least 4-6 times before a sufficiently pure final product is obtained.
Lisäksi tunnetaan menetelmä, jossa o-nitrobentscehappoa käytetään lähtöaineena, ja N-raetyyli-N-sykloheksyyli-o-nitrobentsami-dia valmistetaan vastaavan happokloridin kautta saattamalla mainittu kloridi reagoimaan N-metyyli-sykloheksyvliamiinin kanssa. Sitten tämän jälkimmäisen yhdisteen nitroryhmä muutetaan aminoryhmäk-si Bechamp-pelkistyksellä, aromaattinen rengas dibromataan 3,5-ase-missa, ja lopulta oksoryhmä pelkistetään litiumaluminiumhydridillä (NL-hakemusiulkaisu 6 403 356) . Synteesin kokonaissaanto on vain 24 %, ja viimeisessä vaiheessa käytetty litiumaluminiumhydridi voi aiheuttaa tulipalon tai räjähdyksen.In addition, a process is known in which o-nitrobenzic acid is used as a starting material, and N-methylethyl-N-cyclohexyl-o-nitrobenzamide is prepared via the corresponding acid chloride by reacting said chloride with N-methylcyclohexylamine. The nitro group of the latter compound is then converted to an amino group by Bechamp reduction, the aromatic ring is dibromatized at the 3,5-positions, and finally the oxo group is reduced with lithium aluminum hydride (NL Application 6,403,356). The total yield of the synthesis is only 24%, and the lithium aluminum hydride used in the last step can cause a fire or explosion.
Mikään tähän asti tunnetuista menetelmistä ei ole sopiva kaavan I mukaisen yhdisteen taloudelliseen teolliseen valmistukseen.None of the methods known so far is suitable for the economical industrial production of a compound of formula I.
Keksinnön mukaiselle menetelmälle on tunnusomaista, että kaavan II mukainen 3-bromi-2-nitro-bentsyylibromidi J (II) S^no2The process according to the invention is characterized in that the 3-bromo-2-nitrobenzyl bromide of formula II, J (II)
Br 64351 saatetaan reagoimaan N-metyylisykloheksyyliamiinin kanssa, happoa sitovan aineen läsnäollessa edullisesti käyttäen ylimäärin N-metyy-lisykloheksyyliamiinia, saatu kaavan III mukainen N-sykloheksyyli-N-metyyli-2-nitro-3-bromibentsamiini f J \—/ (III) N02Br 64351 is reacted with N-methylcyclohexylamine, in the presence of an acid scavenger, preferably using an excess of N-methylcyclohexylamine, to give N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine of formula III f J 1 - / (III) NO 2
Br pelkistetään pelkistimellä, edullisesti Raney-nikkelillä ja hyd-ratsiinihydraatilla tai tinalla ja kloorivetyhapolla, ja saatu kaavan IV mukainen N-sykloheksyyli N-metyyli-2-amino-3-bromibentsamiini ch_ ' (iv) ^γΝ^Η2Br is reduced with a reducing agent, preferably Raney nickel and hydrazine hydrate or tin and hydrochloric acid, and the resulting N-cyclohexyl N-methyl-2-amino-3-bromobenzamine of formula IV ch_ '(iv) ^ γΝ ^ Η2
Br muutetaan, edullisesti eristämättä, ja haluttaessa happoadditiosuo-lan muodossa kaavan I mukaiseksi yhdisteeksi saattamalla se reagoimaan alkuainebromin kanssa, ja kaavan I mukainen yhdiste haluttaessa eristetään orgaanisen tai epäorgaanisen hapon kanssa muodostetun happoadditiosuolan muodossa.Br is converted, preferably without isolation, and if desired in the form of an acid addition salt to a compound of formula I by reaction with elemental bromine, and the compound of formula I is optionally isolated in the form of an acid addition salt with an organic or inorganic acid.
Kaavan II mukaisen 3-bromi-2-nitrobentsyylibromidin reaktio N-metyylisykloheksyyliamiinin kanssa suoritetaan happoa sitovan aineen läsnäollessa lämpötilassa välillä 60 - 110°C, edullisesti välillä 70 - 80°C. Väliaineena tai liuottimena käytetään varsinkin alifaattisia tai aromaatisia hiilivetyjä, kloorattuja hiilivetyjä tai alifaattisia alkoholeja. Happoa sitovana aineena voidaan kä yt-tää jokaista emästä, joka ei reagoi lähtöaineiden kanssa. Edullisesti käytetään N-metyyli-sykloheksyyliamiininylimäärää happoa sitovana aineena. Amiini voidaan ottaa talteen reaktion kuluessa muodostuneesta N-metyy1i-syk1oheksyy1iamiinihydrobromidistu ja voidaan käyttää uudelleen prosessLssa, no. sitä voidaan kierrättää.The reaction of the 3-bromo-2-nitrobenzyl bromide of formula II with N-methylcyclohexylamine is carried out in the presence of an acid scavenger at a temperature between 60 and 110 ° C, preferably between 70 and 80 ° C. Aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons or aliphatic alcohols are used in particular as media or solvents. Any base which does not react with the starting materials can be used as the acid-binding agent. Preferably, an excess of N-methyl-cyclohexylamine is used as the acid scavenger. The amine can be recovered from the N-methyl-cyclohexylamine hydrobromide formed during the reaction and can be reused in the process, no. it can be recycled.
Kaavan IV mukainen aminoyhd j ste voidaan valmistaa pel k i st. äimällä kaavan III mukainen N-sykloheksyyli-N-metyyli-2-nitro-2-bro-mibentsamiini sinänsä tunnetuilla pelkistämällä. Pelkistysaineena 4 64351 käytetään edullisesti hydratsiinihydraattia ja Raney nikkeliä _^alkoholiuoksessa tai vaihtoehtoisesti tina- tai tina(II)kloridia happamessa ympäristössä. Pelkistys suoritetaan lämpötilassa välillä 15 - 25°C haluttaessa reaktioseosta jäähdyttäen, jota seuraa lyhyt jälkireaktio. Kuitenkin tietyissä tapauksissa voidaan reaktioajan lyhentämiseksi käyttää korotettua lämpötilaa, edullisesti lämpötilaa välillä 60 - 100°C.The amino compound of formula IV can be prepared alone. by N-cyclohexyl-N-methyl-2-nitro-2-bromobenzamine of formula III by reduction known per se. As the reducing agent 4 64351, hydrazine hydrate and Raney nickel in alcoholic solution or alternatively stannous or stannous chloride in an acidic environment are preferably used. The reduction is carried out at a temperature between 15 and 25 ° C, if desired, with cooling of the reaction mixture, followed by a short post-reaction. However, in certain cases, an elevated temperature, preferably between 60 and 100 ° C, may be used to shorten the reaction time.
Kaavan IV mukainen N-sykloheksyyli-N-metyyli-2-amino-3-bro-mibentsamiini muutetaan lopputuotteeksi alkuainebromin avulla. Reaktion väliaineena tai liuottimena voidaan käyttää kloorattuja alifaat-tisia hiilivetyjä, alkoholin ja eetterin seosta tai jääetikkaa. Happoa sitovana aineena voidaan käyttää edullisesti natriumasetaattia tai epäorgaanisia emäksiä, kuten natriumkarbonaattia tai kaliumkarbonaattia. Bromaus suoritetaan edullisesti lämpötilassa välillä 10 - 25°C haluttaessa jäähdyttäen; jälkireaktio voidaan suorittaa korotetussa lämpötilassa, edullisesti 60°C:ssa.The N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of formula IV is converted to the final product by means of elemental bromine. Chlorinated aliphatic hydrocarbons, a mixture of alcohol and ether or glacial acetic acid can be used as the reaction medium or solvent. Sodium acetate or inorganic bases such as sodium carbonate or potassium carbonate can be preferably used as the acid scavenger. The bromination is preferably carried out at a temperature between 10 and 25 ° C, if desired with cooling; the post-reaction can be carried out at an elevated temperature, preferably 60 ° C.
Kaavan I mukainen N-sykloheksyyli-N-metyyli-N-(2-amino-3,5-dibromibentsyyli)-amiini voidaan eristää bromauksen aikana muodostuneen hydrobromidisuolan muodossa. Kaavan I mukainen emäs voidaan myös eristää emäksenä bromausreaktioseoksesta ja muuttaa haluttaessa happoadditiosuolaksi reaktiossa orgaanisen tai epäorgaanisen hapon kanssa. Edelleen kaavan I mukainen vapaa emäs voidaan vapauttaa happoadditiosuolastaan ja muuttaa muuksi happoadditiosuolaksi.The N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine of formula I can be isolated in the form of the hydrobromide salt formed during bromination. The base of formula I can also be isolated as a base from the bromination reaction mixture and, if desired, converted into an acid addition salt by reaction with an organic or inorganic acid. Furthermore, the free base of formula I can be liberated from its acid addition salt and converted into another acid addition salt.
Keksinnön edullisen sovellutuksen mukaan kaavan IV mukainen N-sykloheksyyli-N-metyyli-2-amino~3-bromibentsamiini bromataan pelkistyksen jälkeen eristämättä.According to a preferred embodiment of the invention, the N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of the formula IV is brominated after reduction without isolation.
Edelleen keksinnön edullisen sovellutuksen mukaan kaavan IV mukainen N-sykloheksyyli-N-metyyli-2-amino-3-bromibentSamiini saatetaan reagoimaan alkuainebromin kanssa sen jälkeen, kun se on muutettu happoadditiosuolakseen. Kaavan II mukainen lähtöaine 3-bromi-2-nitrobentsyylibromidi (uusi yhdiste, samoin kuin muut oheisen keksinnön mukaiset välituotteet) valmistetaan 3-bromi-2-nitrotolueenis-ta broomalla N-bromiperipihkahappoimidin kanssa.According to a further preferred embodiment of the invention, the N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine of the formula IV is reacted with the elemental bromine after being converted into its acid addition salt. The starting material of formula II, 3-bromo-2-nitrobenzyl bromide (a novel compound, as well as other intermediates of the present invention) is prepared from 3-bromo-2-nitrotoluene with bromine with N-bromosuccinimide.
Keksinnön mukaisen menetelmän reaktiovaiheet voidaan helposti suorittaa käytännössä ja ovat hyvin taloudellisia. Reaktiotuote voidaan valmistaa noin 80 % saannolla kaavan II mukaisesta 3-bromi-2-nitrobentsyylibromidista.The reaction steps of the process according to the invention can be easily carried out in practice and are very economical. The reaction product can be prepared in about 80% yield from 3-bromo-2-nitrobenzyl bromide of formula II.
5 643515 64351
Kaavan II mukainen lähtöaine ei ole haitallinen ihmisen terveydelle, kuten tunnetuissa menetelmissä käytetyt bentsyvlibromi-johdannaiset ja niiden analogit.The starting material of formula II is not harmful to human health, such as the benzyl bromine derivatives and their analogues used in known methods.
Keksinnön yksityiskohtia kuvataan seuraavissa esimerkeissä.The details of the invention are illustrated in the following examples.
Esimerkki 1 a) 14,5 g (0,049 moolia) 2-nitro-3-bromibentsyylibromidia liuotetaan 100 ml:aan vedetöntä bentseeniä ja 11,2 g (0,098 moolia) N-metyyli-sykloheksyyliamiinia 50 ml:ssa vedetöntä bentseeniä lisätään sekoittaen. Reaktioseosta keitetään pystyjäähdyttimen alla 5 tuntia, seos jäähdytetään ja saostunut suola suodatetaan. N-metyyli-sykloheksyyliamiini voidaan ottaa talteen saostuneesta N-metyyli-sykloheksyvliamiinihydrobromidista 85 %:n saannolla. Suodos uutetaan 100 ml :11a vettä ja kuivataan vedettömällä magnesiumsulfaatilla. Bentseeni tislataan pois ja saatu 16 g raakatuotetta kiteytetään uudelleen 50 ml:sta etanolia. Saadaan 14,7 g (92 %) keltaista kiteistä K-sykloheksyyli-N-metyyli-2-nitro-3-bromibentsamiinia; sp. 59-61°C. Hydrokioridisuolan sulamispiste on 223-226°C.Example 1 a) 14.5 g (0.049 mol) of 2-nitro-3-bromobenzyl bromide are dissolved in 100 ml of anhydrous benzene and 11.2 g (0.098 mol) of N-methyl-cyclohexylamine in 50 ml of anhydrous benzene are added with stirring. The reaction mixture is refluxed for 5 hours, the mixture is cooled and the precipitated salt is filtered off. N-methyl-cyclohexylamine can be recovered from the precipitated N-methyl-cyclohexylamine hydrobromide in 85% yield. The filtrate is extracted with 100 ml of water and dried over anhydrous magnesium sulfate. The benzene is distilled off and the 16 g of crude product obtained are recrystallized from 50 ml of ethanol. 14.7 g (92%) of yellow crystalline β-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine are obtained; mp. 59-61 ° C. The melting point of the hydrochloride salt is 223-226 ° C.
Analyysi: laskettu kaavalle C..H _BrN_0_(molekyylipaino: 14 I y / I.Analysis: calculated for the formula C..H _BrN_0_ (molecular weight: 14 I y / I.
327,21) C 51,39 % H 5,85 % Br 24,42 % N 8,56 % saatu: C 51,62 % H 6,08 % Br 24,75 % N 8,64 %.327.21) C 51.39% H 5.85% Br 24.42% N 8.56% found: C 51.62% H 6.08% Br 24.75% N 8.64%.
b) 3,27 g (0,01 moolia) N-sykloheksyyli-N-metyyli-2-nitro- 3-bromibentsamiinia liuotetaan 20 ml:aan metanolia ja 0,3 g Ranev-nikkelikatalysaattoria 10 mlrssa metanolia sisältävä suspensio lisätään siihen. Sitten lisätään sekoittaen ja jäähdyttäen 1,25 g (0,025 moolia) hydratsiinihydraattia 10 ml:ssa metanolia. Reaktio-seosta kuumennetaan 1 tunnin ajan, katalysaattori poistetaan suodattamalla jäähdyttämisen jälkeen ja liuotin poistetaan haihduttamalla. Jäännöksenä saadaan 2,9 g (97 - 99 %) N-sykloheksyyli-N-me-tyyli-2-amino-3-bromibentsamiinia vihreän öljyn muodossa; p-tolu-eenisulfonihapposuolan sulamispiste oli 187-189°C.b) 3.27 g (0.01 mol) of N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine are dissolved in 20 ml of methanol and a suspension of 0.3 g of Ranev nickel catalyst in 10 ml of methanol is added. 1.25 g (0.025 mol) of hydrazine hydrate in 10 ml of methanol are then added with stirring and cooling. The reaction mixture is heated for 1 hour, the catalyst is removed by filtration after cooling and the solvent is removed by evaporation. 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine are obtained in the form of a green oil; The melting point of the p-toluenesulfonic acid salt was 187-189 ° C.
Analyysi: laskettu kaavalle C2iH29BrN2°3S (molekyylipaino: 469,43) C 53,73 % H 6,22 % N 5,97 S 6,83 % saatu: C 54,45% H 6,72% N 5,54 S 7,13% c) 5,9 g (19,9 mmoolia) N-sykloheksyyli-N-metyyli-2-amino- 3-bromibentsamiinia ja 1,63 g (19,9 mmoolia) vedetöntä natriumase-taattia liuotetaan 90 ml:aan jääetikkaa, ja jäillä jäähdytettyyn 64351 liuokseen lisätään 3,18 g (19,9 mmoolia) bromia tipoittain 30 ml:ssa jääetikkaa. Keltainen aine saostuu. Reaktioseosta kuumennetaan 2 tunnin ajan vesihauteella 60°C:ssa, jonka jälkeen reaktioseos kaadetaan 150 ml:aan vettä ja tehdään jäähdyttäen emäksiseksi 840 ml :11a 10-%:is-ta natriumhvdroksidiliuosta. Reaktioseos uutetaan kahdesti 250 ml:11a kloroformia, yhdistetyt orgaaniset kerrokset kuivataan, suodatetaan hiilellä ja haihdutetaan. Jäljelle jäänyt öljy, 6,9 g (91,5 %), liuotetaan 39 niiaan etanolia ja N-sykloheksyyli-N-metyyli-N-(2-amino-3,5-dibromibentsyyli)-amiinihydrokloridi erotetaan kloorivetyhapon ja eetterin seoksen avulla.Analysis: Calculated for C 21 H 29 BrN 2 O 3 S (MW: 469.43) C 53.73% H 6.22% N 5.97 S 6.83% Found: C 54.45% H 6.72% N 5.54 S 7.13% c) 5.9 g (19.9 mmol) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine and 1.63 g (19.9 mmol) of anhydrous sodium acetate are dissolved in 90 ml of: To an ice-cooled solution of 64351 is added 3.18 g (19.9 mmol) of bromine dropwise in 30 ml of glacial acetic acid. A yellow substance precipitates. The reaction mixture is heated for 2 hours in a water bath at 60 [deg.] C., after which the reaction mixture is poured into 150 ml of water and basified with cooling to 840 ml of 10% sodium hydroxide solution. The reaction mixture is extracted twice with 250 ml of chloroform, the combined organic layers are dried, filtered on charcoal and evaporated. The residual oil, 6.9 g (91.5%), is dissolved in 39 g of ethanol and the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride is separated off with a mixture of hydrochloric acid and ether.
Saanto: 7,2 g (87,7 %), sp. 242-245°C.Yield: 7.2 g (87.7%), m.p. 242-245 ° C.
Analyysi: laskettu kaavalle: C..H„.Br„N_C1 (molekvylipaino: 412,69) C 40,75 % H 5,13 % Br 38,73 % Cl 8,59 % N 6,79 % saatu: C 40,39 % H 5,27 % Br 38,34 % C1 8,63 % N 6,71 %.Analysis: Calculated for the formula: C..H „.Br„ N_Cl (molecular weight: 412.69) C 40.75% H 5.13% Br 38.73% Cl 8.59% N 6.79% Found: C 40 .39% H 5.27% Br 38.34% Cl 8.63% N 6.71%.
Muut suolat, jotka valmistettiin vapaasta emäksestä sopivalla hapolla alkoholissa ovat seuraavat:Other salts prepared from the free base with the appropriate acid in alcohol are as follows:
perkloraatti: sp. 132-134°Cperchlorate: m.p. 132-134 ° C
oksalaatti: sp. 181-183°C.oxalate: m.p. 181-183 ° C.
Vastaavan hydrobromidin sulamispiste on 227-228°C.The corresponding hydrobromide has a melting point of 227-228 ° C.
Lähtöaine, 3-bromi-2-nitrobentsyylibromidi valmistetaan seuraavasti : 15,9 g (0,088 mol) 2-nitro-3-metyylibentsoehappoa liuotetaan NaOH:n (3,52 g, 0,088 mol) liuokseen 350 ml:ssa tislattua vettä. Liuokseen lisätään tipoittain hopeanitraatin (14,96 g, 0,088 mol) liuos 150 ml:ssa tislattua vettä. Muodostunut sakka suodatetaan, pestään vedellä ja kuivataan.The starting material, 3-bromo-2-nitrobenzyl bromide, is prepared as follows: 15.9 g (0.088 mol) of 2-nitro-3-methylbenzoic acid are dissolved in a solution of NaOH (3.52 g, 0.088 mol) in 350 ml of distilled water. A solution of silver nitrate (14.96 g, 0.088 mol) in 150 ml of distilled water is added dropwise to the solution. The precipitate formed is filtered off, washed with water and dried.
24 g (0,0833 mol) näin saatua hopea-2-nitro-3-metyylibentsoaat-tia suspendoidaan 300 ml:aan absoluuttista hiilitetrakloridia, ja suspensioon lisätään tipoittain ja sekoittaen 14,4 g (0,09 mol) bromia. Muodostunut hopeabromidi suodatetaan pois kuumasta reaktioseoksesta, ja suodokseen lisätään 15 g (0,084 mol) N-bromisukkinimidiä ja 0,2 g dibentsoyyliperoksidia. Saatua reaktioseosta kuumennetaan palautus-jäähdyttäen UV-valossa 20 tuntia. Kiinteä aine suodatetaan, ja suodos haihdutetaan. Jäännös kiteytetään hiilitetrakloridi/petrolieetteriseok-sesta 1:1. Saadaan 8,6 g 3-bromi-2-nitrobentsyylibromidia, sp. 90-91 C.24 g (0.0833 mol) of the silver 2-nitro-3-methylbenzoate thus obtained are suspended in 300 ml of absolute carbon tetrachloride, and 14.4 g (0.09 mol) of bromine are added dropwise to the suspension with stirring. The silver bromide formed is filtered off from the hot reaction mixture, and 15 g (0.084 mol) of N-bromosuccinimide and 0.2 g of dibenzoyl peroxide are added to the filtrate. The resulting reaction mixture is heated to reflux under UV light for 20 hours. The solid is filtered off and the filtrate is evaporated. The residue is crystallized from a 1: 1 mixture of carbon tetrachloride / petroleum ether. 8.6 g of 3-bromo-2-nitrobenzyl bromide are obtained, m.p. 90-91 C.
Alkuperäinen emäliuos ja uudelleenkiteytyksessä saatu emäliuos yhdistetään ja haihdutetaan. Jäännöksenä saatu öljy vakuumitislataan, 7 64351 jolloin 60-66°C:ssa/Ό,08 mmHg kiehuva fraktio sisältää 2-nitro-3-bromitolueenia, joka voidaan panna kiertoon seuraavaan N-bromisuk-kinimidilla suoritettuun bromausvaiheeseen. Kun otetaan huomioon uudelieenkierrätetty materiaali, saadaan menetelmän saannoksi 55 %. Lähtöaineena käytetty 2-nitro-3-metyylibentsoehappo on kaupallises-ti helposti saatavissa olevan reagenssi.The original mother liquor and the mother liquor obtained in the recrystallization are combined and evaporated. The residual oil is vacuum distilled, 7 64351 whereby the fraction boiling at 60-66 ° C / .08 mmHg contains 2-nitro-3-bromotoluene, which can be recycled to the next bromination step with N-bromosuccinimide. Taking into account the recycled material, the yield of the method is 55%. The starting 2-nitro-3-methylbenzoic acid is a commercially available reagent.
Analyysi: laskettu kaavalle C^H^-B^NC^ (molekyylipaino: 294,95) C 28,50 % H 1,66 % Br 54,20 % N 4,74 % saatu: C 28,91 % H 1,90 1 Br 54,91 % N 4,70 %.Analysis: Calculated for C 28 H 18 N 2 O 2 NC 2 (molecular weight: 294.95) C 28.50% H 1.66% Br 54.20% N 4.74% Found: C 28.91% H 1, 90 1 Br 54.91% N 4.70%.
Esimerkki 2 3,27 g:aan (0,01 moolia) esimerkin la) mukaan valmistettua N-sykloheksyyli-N-metyyli-2-nitro-3-bromibentsamiinia lisätään 6 g (0,05 moolia) jauhemaista tinaa ja 16 ml vettä ja sitten lisätään tipoittain sekoittaen 16 ml väkevää kloorivetyhapon vesiliuosta. Reaktioseosta kuumennetaan 2 tunnin ajan vesihauteella, jonka jälkeen seos jäähdytetään huoneen lämpötilaan ja dekantoidaan, jonka jälkeen se tehdään emäksiseksi 20-%:isella natriumhydroksidin vesiliuoksella. Emäksinen liuos uutetaan 2 x 50 ml:11a kloroformia, yhdistetyt orgaaniset kerrokset kuivataan vedettömällä magnesiumsulfaatilla ja liuotin tislataan pois. Saadaan 2,9 g (97-99 %) N-syk-loheksyyli-N-metyyli-2-amino-3-bromibentsamiinia, josta N-sykloheksyyl i-N-metyyli-N-(2-amino-3,5-dibromibentsyyli)-ami inihydrokloridi valmistetaan esimerkissä 1c) kuvatun menetelmän mukai-sesti.Example 2 To 3.27 g (0.01 mol) of N-cyclohexyl-N-methyl-2-nitro-3-bromobenzamine prepared according to Example 1a) are added 6 g (0.05 mol) of powdered tin and 16 ml of water, and then 16 ml of concentrated aqueous hydrochloric acid are added dropwise with stirring. The reaction mixture is heated for 2 hours in a water bath, then cooled to room temperature and decanted, then basified with 20% aqueous sodium hydroxide solution. The basic solution is extracted with 2 x 50 ml of chloroform, the combined organic layers are dried over anhydrous magnesium sulfate and the solvent is distilled off. 2.9 g (97-99%) of N-cyclohexyl-N-methyl-2-amino-3-bromobenzamine are obtained, of which N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) Amine hydrochloride is prepared according to the method described in Example 1c).
Esimerkki 3Example 3
Esimerkissä 1b) kuvatun menetelmän mukaisesti valmistetusta N-sykloheksyyli-N-metyyli-3-bromi-2-aminobentsamiinista vaimistetaan vastaava hydrokloridisuola kuivan kloorivetyhappokaasun avulla eta-noliväliaineessa. Sulamispiste ei ole terävä aineen hygroskooppisen luonteen vuoksi ja se on luokkaa 100-120°C (haj.).From the N-cyclohexyl-N-methyl-3-bromo-2-aminobenzamine prepared according to the procedure described in Example 1b), the corresponding hydrochloride salt is quenched with dry hydrochloric acid gas in ethanol medium. The melting point is not sharp due to the hygroscopic nature of the substance and is of the order of 100-120 ° C (dec.).
1 g (3 mmoolia) N-sykloheksyyli-N-metyyli-3-bromi-2-aminobent-samiinihydrokloria ja 0,5 g (6 mmoolia) vedetöntä natriumasetaattia liuotetaan 20 ml:aan jääetikkaa ja 0,25 ml (4 mmcolia) bromia lisätään tipoittain huoneen lämpötilassa 5 ml:ssa jääetikkaa. Reaktio-seosta kuumennetaan 2 tunnin ajan vesihauteella 60°C:ssa sekoittaen. Kun seos on jäähtynyt, lisätään 50 ml vettä, jonka jälkeen seos tehdään emäksiseksi väkevällä ammoniumhydroksidiliuoksella ja uutetaan kahdesti 70 ml :11a eetteriä. Yhdistetyt uutteet: kuivataan knliumhyd-doksidilla ja haihdutetaan. Jäännöksenä saadaan 1,1 g 55jyä, joka 8 64351 liuotetaan 20 ml:aan etanolia ja N-sykloheksyyli-N-metyyli-N-(2-amino-3,5-dibromibentsyyli)amiinihydrokloridi erotetaan kloorivety-happoa sisältävällä eetterillä. Saadaan 1 g tuotetta, joka etanolista (70 %) uudelleenkiteytettynä painaa 0,95 g; sp, 242-244°C·1 g (3 mmol) of N-cyclohexyl-N-methyl-3-bromo-2-aminobenzamine hydrochloride and 0.5 g (6 mmol) of anhydrous sodium acetate are dissolved in 20 ml of glacial acetic acid and 0.25 ml (4 mmol) of bromine. is added dropwise at room temperature in 5 ml of glacial acetic acid. The reaction mixture is heated for 2 hours in a water bath at 60 ° C with stirring. After cooling, 50 ml of water are added, the mixture is basified with concentrated ammonium hydroxide solution and extracted twice with 70 ml of ether. Combined extracts: dried over potassium hydroxide and evaporated. 1.1 g of 55 are obtained as a residue, which is dissolved in 20 ml of ethanol and the N-cyclohexyl-N-methyl-N- (2-amino-3,5-dibromobenzyl) amine hydrochloride is separated off with ether containing hydrochloric acid. 1 g of product is obtained, which, recrystallized from ethanol (70%), weighs 0.95 g; mp 242-244 ° C ·
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUEE002384 | 1975-10-28 | ||
| HUEE002384 | 1975-10-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI762141A FI762141A (en) | 1977-04-29 |
| FI64351B FI64351B (en) | 1983-07-29 |
| FI64351C true FI64351C (en) | 1983-11-10 |
Family
ID=10995655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI762141A FI64351C (en) | 1975-10-28 | 1976-07-27 | NYTT FOERFARANDE FOER FRAMSTAELLNING AV N-CYCLOHEXYL-N-METHYL-N- (2-AMINO-3,5-DIBROMO-BENZYL) -AMINE |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5253836A (en) |
| AT (1) | AT351504B (en) |
| CH (1) | CH622488A5 (en) |
| CS (1) | CS199633B2 (en) |
| DE (1) | DE2633518A1 (en) |
| DK (1) | DK145293C (en) |
| ES (1) | ES450304A1 (en) |
| FI (1) | FI64351C (en) |
| PL (1) | PL103750B1 (en) |
| SE (1) | SE415654B (en) |
| SU (1) | SU580829A3 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5848872U (en) * | 1981-09-30 | 1983-04-02 | 松下電工株式会社 | Folding door hinge structure |
| JPS61139688U (en) * | 1985-02-18 | 1986-08-29 | ||
| JPS61206065U (en) * | 1985-06-15 | 1986-12-26 | ||
| DE19529432C1 (en) * | 1995-08-10 | 1997-05-15 | Boehringer Ingelheim Kg | Process for the preparation of benzylamine derivatives |
-
1976
- 1976-07-19 CH CH935976A patent/CH622488A5/en not_active IP Right Cessation
- 1976-07-20 SE SE7608246A patent/SE415654B/en unknown
- 1976-07-23 AT AT544276A patent/AT351504B/en not_active IP Right Cessation
- 1976-07-26 DE DE19762633518 patent/DE2633518A1/en not_active Withdrawn
- 1976-07-27 FI FI762141A patent/FI64351C/en not_active IP Right Cessation
- 1976-07-28 CS CS764956A patent/CS199633B2/en unknown
- 1976-07-30 SU SU7602386749A patent/SU580829A3/en active
- 1976-07-30 ES ES450304A patent/ES450304A1/en not_active Expired
- 1976-07-30 JP JP51091253A patent/JPS5253836A/en active Granted
- 1976-07-30 PL PL1976191536A patent/PL103750B1/en unknown
- 1976-07-30 DK DK346376A patent/DK145293C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FI762141A (en) | 1977-04-29 |
| AT351504B (en) | 1979-07-25 |
| ATA544276A (en) | 1978-01-15 |
| SE7608246L (en) | 1977-04-29 |
| JPS5616786B2 (en) | 1981-04-18 |
| CH622488A5 (en) | 1981-04-15 |
| DE2633518A1 (en) | 1977-05-12 |
| DK145293B (en) | 1982-10-25 |
| PL103750B1 (en) | 1979-07-31 |
| JPS5253836A (en) | 1977-04-30 |
| SU580829A3 (en) | 1977-11-15 |
| DK145293C (en) | 1983-03-14 |
| FI64351B (en) | 1983-07-29 |
| CS199633B2 (en) | 1980-07-31 |
| SE415654B (en) | 1980-10-20 |
| ES450304A1 (en) | 1977-10-01 |
| DK346376A (en) | 1977-04-29 |
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Owner name: E GY T GYOGYSZERVEGYESZETI GYAR |